Scientific American, October, 1988

Home , Max Essex, Robert Gallo, Scientific American, Stump the Schwab

OCTOBER 1988 SCIENTIFIC $2.95 ERICAN

A SINGLE -TOPIC ISSUE

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40 AIDS in 1988 Robert C.Gallo and Lue Montagnier

Where do we stand? What are the key areas of current research? The prospects for therapy or a vaccine? In their first collaborative article the two investigators who established the cause of AIDSanswer these questions and tell how HN was isolated and linked to AIDS.

52 The Molecular Biology of the AIDS Virus William A. Haseltine and Flossie Wong-Staal

Just three viral genes can direct the machinery of an infected cell to make a new HIV particle-provided that at least three other viral genes give the go-ahead. These regulatory genes give the virus its protean behavioral repertoire: they spur viral replication, hold it in check or bring it to a halt.

64 The Origins of the AIDS Virus Max Essex and Phyllis]. Kanki

The AIDSvirus has a past and it has relatives. Aninquiry into its family history can reveal how the related viruses interact with human beings and monkeys. The inquiry may also uncover vulnerabilities: some forms of the virus have evolved toward disease-free coexistence with their hosts.

72 The Epidemiology of AIDS in the U.S. William L. Heyward and james W. Curran

Since 1981 more than 66,000 people in the U.S. have contracted AIDS;by 1992 there may be 300,000 more cases-even if the incidence of infection begins to decline. By identifying risk groups and risky behaviors, epidemiology can suggest nonmedical strategies for controlling AIDS.

82 The International Epidemiology of AIDS jonathan M. Mann, james Chin, Peter Piot and Thomas Quinn

The pandemic is still in its early stages. Although no one is certain how many AIDScases have already developed, the World Health Organization estimates the number at 250,000. Furthermore, at least five million people worldwide are probably infected with the AIDSvirus.

90 HIVInfection: The Clinical Picture Robert R. Redfield and Donald S. Burke

To focus only on treating AIDSis to lose the battle against HN, the virus that causes it. AIDSis actually the final manifestation of a progressive immune disorder that may be silent for years. Early diagnosis and accurate staging of HN infection help physicians to optimize therapy.

The AIDSvirus can do no damage until it enters a target cell. The first step in invasion is the binding of a molecule on the viral membrane to a molecule on the membrane of the target. The receptor molecule, known as the CD4 antigen, exists primarily on certain immune-system cells.

AIDS Therapies Robert Yarchoan, Hiroaki Mitsuya and Samuel Broder

The prognosis for treatment was once grim, but now understanding of HIV's life cycle makes it possible to design drugs that take aim at specific targets. The authors describe an all-out effort to develop a number of drugs that can be administered in a concerted attack.

120 AIDS Vaccines Thomas]. Matthews and Dani P. Bolognesi

A vaccine against HN would be the most effective means of stemming the AIDScrisis. Several candidate vaccines are being tested in people, but HN is a devious enemy and there is no evidence that any of them will work. What kinds of obstacles are investigators up against?

128 The Social Dimensions of AIDS Harvey V. Fineberg

To cope with an ever increasing number of cases, pUblic-health officials must focus not only on medical and hospital concerns but also on prevention, largely through education. AIDSpatients require compassionate and effective care; there should be broad prohibition of discrimination.

DEPARTMENTS

8 Letters 140 The Amateur Scientist

12 50 and 100 144 Computer

Years Ago o Recreations

1888: A 335-foot chimney, Is it true that one machine u tallest in the U.S., has been can decode what another built near Newark, N.J. machine can encode?

14 Science and the Citizen 148 Books: William A. Blattner

136 Science and Business 152 Essay: Lewis Thomas

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© 1988 SCIENTIFIC AMERICAN, INC SCIENTIFIC TIlE COVER of this single-topic issue of SCIENTIFIC AMERJCAN shows a particle AMERICAN of the human immunodeficiency virus Established 1845 (HIV) forming at the outer membrane of an infected cell. (The new particle is the circular form at the upper right.) HIV, the AIDS virus, can enter a cell and EDITOR: Jonathan Piel remain latent until it is activated to BOARD OF EDITORS: Armand Schwab, Jr., Man make new viral components. The par aging Editor; Timothy Appenzeller, Associate ticles then self-assemble in the process Editor; Timothy M. Beardsley; John M. Ben· depicted on the cover. HIVcauses a ditt, Issue Editor; Laurie Burnham; Elizabeth Corcoran; Ari W. Epstein; Gregory R. Green· broad spectrum of diseases, of which well; John Horgan; June Kinoshita; Philip Mor· AIDSis only the culmination. rison, Book Editor; Tony Rothman; Ricki L Rusting; Russell Ruthen; Karen Wright

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6 SCIENTIFIC AMERICAN October 1988

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© 1988 SCIENTIFIC AMERICAN, INC characteristics should, however, be at Hyde suggests that Trembley might LETTERS tributed to Antony van Leeuwenhoek, have learned of Leeuwenhoek's obser· the draper of Delft,who described it in vations through Christiaan Huygens. a letter to the Royal Society of London But Huygens died in 1695, seven years To the Editors: on December 26, 1702, some eight before Leeuwenhoek's report and 15 In "The Neurobiology of Feeding in years before Trembley's birth. Unfor years before Trembley was born. Leeches," by Charles M. Lent and Mi tunately, the description was forgot Without meaning to detract in any chael H. Dickinson [SCIENTIFIC AMERI ten, partly because of Leeuwenhoek's sense from Leeuwenhoek's important CAN, June) there is a minor inaccuracy self-effacing nature and because he observation, we would like to empha in a statement of comparative glut lacked the tenacity or the time and size that although he described the tony. Lent and Dickinson say: "Massive energy to follow up on his bewildering budding of hydras and characterized amounts of blood are ingested-from range of microscopic discoveries. It is them as animals, Leeuwenhoek did seven to nine times the weight of the very probable that Trembley learned not realize that he had witnessed ani leech itself, among the largest meals of hydras when he moved to Holland mal reproduction that was asexual. of any animal." A ratio of fed-to-unfed (possibly from Christiaan Huygens), Trembley's contribution was to prove weight of nine to one will impress since Leeuwenhoek was always happy through numerous experiments that many readers, but that figurepales to share his discoveries. the polyps are,in his words,"an excep when compared to the performance of tion to an allegedly universal rule,that some blood-sucking arthropods. TREVOR HYDE there is no reproduction without copu The world record probably goes to lation," a finding that flew in the face female ticks of the family Ixodidae. Tecumseh, Ontario of the centuries-old so-called "general These arachnids commonly attain a rules " on animal generation. fed-to-unfed ratio of between 75 and Leeuwenhoek is fully recognized to 125 to one following a sojourn of To the Editors: day as the great microscopist and ob seven to 14 days on the host. (Some Dr. Hyde certainly has a point; we server of his time. Our premise is that authors have suggested that the upper probably should not have deleted Abraham Trembley should also be limit may approach 200 to one.) Im mention of Leeuwenhoek during the seen as a major figure, whose elegant pressive as the latter figures may editing of our article. To quote from experiments on hydras marked the seem, even they account for only a page 4 of our translation into English dawn of experimental zoology. fraction of the total blood imbibed by of Trembley's Mlzmoires, Trembley the tick. During the feeding period points out that hydras were first re HOWARD M. LENHOFF itself, excess fluid in the blood meal ported in 1703 by both Leeuwenhoek is constantly excreted, together with and an "anonymous Englishm an ": SYLVIAG. LENHOFF undigested hemoglobin in some spe "These animals were not hitherto cies. It turns out that the gorged entirely unknown.They are mentioned weight of the tick may represent as in the Philosophical Transactions of To the Editors: little as 20 percent of the weight of 1703 .... The observations on these It is fascinating to note that the blood actually removed from the host. little creatures made by Leeuwenhoek biological link Rose E. Frisch discuss Thus the unfed female of the infa and by an anonymous Englishman are es in "Fatness and Fertility " [SCIENTIF mous Dermacentor andersoni (the recorded there. There is much consis IC AMERICAN, March) was recognized vector of Rocky Mountain spotted fe tency between the observations of long ago by the peoples of the south ver and tick paralysis in North Ameri these two gentlemen. Both noticed western Sahara and is currently ap ca), weighing in at only seven to 10 one of the most remarkable character plied in their premarital behaviors. milligrams, imbibes approximately istics of the polyps, that is, their natu Among the Moors, including such 4,000 milligrams of host blood! Inci ral mode of multiplying. They were groups as the Trarza, Tagant and Hod, dentally, the ticks do not excrete this struck by it and certainly would not brides-to-be are forced to drink huge excess fluid by way of the Malpighian have failed to study it further had they quantities of camel's milk until they tubules (the analogue of the kidney in possessed a substantial number of become obese, a condition that is con insects and ticks). Instead the salivary polyps." (Leeuwenhoek had only a few sidered to be both sexually appealing glands secrete this fluid back into the polyps and the Englishman just one.) and an indication of wealth, since this host's circulation, and most of the We have to take Trembley at his special treatment demands up to 10 tick-borne pathogens transmitted to word when he says (page 94), "I was liters of milk per day. Logically, a fe the host go along for the ride. unaware of the discoveries made by male thus endowed WOUld, in time of the two naturalists when chance intro famine (an ever-present threat in the W. REUBEN KAUFMAN duced me to the polyps." For one, Sahara), be able not only to give birth Trembley's formal education had been to a normal child but also to breast Department of Zoology not in the natural sciences but in feed it for one or even two years, as is University of Alberta mathematics. Furthermore, his books prescribed by the Koran. This process and correspondence show him to be of natural lipidic investment may well highly deferential in giving credit to be pre-Islamic, since similar practices To the Editors: other observers. And like the great still exist among Jews in Tunisia. They The recent article on the historical Leeuwenhoek he was extremely gen represent a living example of an evolu aspects of Trembley and his work on erous in sharing his discoveries. As tionary strategy against famine and hydras ["Trembley's Polyps,"by How Count William Bentinck wrote in 1744, the resulting threat to human fertility. ard M. Lenhoff and Sylvia G. Lenhoff; Trembley "makes himself a Point SCIENTIFIC AMERICAN, April) was very d'honneur of being communicative, CLAUDE PAQUE interesting. The discovery of this or and concealing nothing of what he ganism and some of its remarkable knows [about the polyps)." Rabat, Morocco

8 SCIENTIFIC AMERICAN October 1988

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© 1988 SCIENTIFIC AMERICAN, INC yards long, and are essentially light in "The way in which railroad officials AND every particular except that they are keep track of their freight cars, which 50 100 unable to affect the retina." are run thousands of miles over oth er railroad lines, has no doubt excit YEARS AGO "The only place in which amber has ed the wonder of many. Nearly all the been found in paying quantities is in great roads employ a corps of what are the Baltic Sea. In former years the known as 'lost car searchers' or 'trac production of amber depended prinCi ers.' Every freight car is numbered and SCIENTIFIC pally on the storms occurring in the used for a certain purpose, and wheth winter time, for when the sea was er it be a 'gondola,' or flat open car, or AMERICAN convulsed the amber lying on the bot a box car, it can be traced from one tom was thrown up on the shore; but end of the country to the other. At last OCTOBER. 1938: "In 1928, Dr. Hans human enterprise stimulated by the one great trunk-line road has dis Berger of Jena reported that it is possi demand for amber has changed all pensed with the searcher in favor of a ble to show and record a quite strange thiS, and for the last twenty-five years large force of clerks, with the tele electrical rhythm of the human brain. various engineering appliances have graph and telephone as auxiliaries." Borrowing a vacuum tube, Berger built been used for getting out the amber in an amplifier powerful enough to mag the quickest and cheapest way." "We illustrate in this issue the great nify weak electric impulses a million chimney recently erected at Kearney, fold. This powerful amplifier, in the "The buffalo has now become so near Newark, N.j., by the Clark Thread hands of Berger and later of many scarce that the death of one is record Co. It possesses the distinction of be others, has disposed of the old, static ed as a matter of news in the daily ing the tallest chimney in America, and picture of the brain. Today, a motion papers. A Laurel, Montana, correspon the fourth tallest in the world. It is the picture of the true, the dynamic brain dent of the Forest and Stream writes highest one ever built for boiler fur can be exhibited. And already features that, on July 30, a buffalo bull came naces; twenty-one boilers of 200 h.p. of this cinema are being practically within 200 yards of a round-up camp each will depend upon the great chim applied to common but heretofore at Rock Creek, about thirty miles ney, whose total height is 335 feet. It is completely baffling medical problems, south of the Yellowstone. Two cow believed that much more of the waste such as epilepsy, man's fitfulmalady." boys at once started in pursuit, armed heat can be economized than is usual, with revolvers, and after a chase of as, owing to the great height of the "Two hundred and four miles an ten miles brought him down. He was chimney, a comparatively slight heat hour is the speed at which a stretched so old and thin that even the hide was in the products of combustion will rubber band snaps, as measured by not worth saving." generate ample draught." ultra-high-speed motion pictures re cently taken in the laboratory of Gus tavus j. Esselen, Inc., consultants."

"It is interesting to consider what transatlantic flying boats may be like in a very few years. According to a paper by I. M. Laddon and T. P. Faulk ner in the Consolidator, even the latest Boeing Clipper is but a forerunner of greater things to come. These authors predict: (1) an increase in size to a gross weight of 400,000 pounds and more; (2) 300 passengers, with bag gage, mail, and express, and a range sufficient to cross any ocean non-stop; (3) speeds of over 300 miles an hour in the stratosphere."

OCTOBER. 1888: "Professor Oliver j. Lodge has been endeavoring to man ufacture light by direct electric ac tion without the intervention of heat, utilizing for the purpose Maxwell's theory that light is really an electric disturbance or vibration. The means adopted is the oscillatory discharge of a Leyden jar, whose rate of vibration has been made as high as 1,000 mil lion complete vibrations per second. The waves so obtained are about three The highest chimney in the U.S., recently erected at the Clark Thread Works

12 SCIENTIFIC AMERICAN October 1988

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AYlaY The right choice.

al was rejected, however. As adopt AIDS and the Election ed, the Republican platform does not Currently neglected, it mention discrimination or advocate could be a sleeper issue special measures to protect the civil rights of infected people, although it uring the next president's term does support expedited review of AIDS of office the number of Ameri drugs. It also states that educational cans dead or dying from AIDS materials should emphasize avoiding D 16 PHYSICAL SCIENCES will probably exceed 250,000. The Na sex outside marriage and drug abuse tional Academy of Sciences and the 27 BIOLOGICAL SCIENCES as the best ways to avoid infection. Institute of Medicine earlier this year The AIDSAction Council and other estimated that the direct annual cost 32 MEDICINE advocacy groups scorn the document of caring for AIDSpatients will rise to and denounce its moralizing. more than $10 billion by 1991. Such a 37 OVERVIEW The Democratic Party's response to toll would seem to merit high-level the epidemic is distinctly more ag concern. Yet neither presidential can his selection of Senator Dan Quayle of gressive. The Democratic platform ad didate has given much attention to the Indiana as running mate. Since Octo vocates comprehensive pUblic-health subject. One reason may be that politi ber, 1987, Quayle has voted five times education, the adoption of the public cal strategists regard AIDSas a no-win to restrict the content of educational health-community consensus on test topic that evokes fear and deep-seat materials on AIDS,and he opposed a ing and counseling (which is general ed biases. plan that set aside $30 million to sup ly understood to call for universally Both Governor Michael Dukakis and ply the drug zidovudine (also called available, anonymous testing together Vice-President George Bush have en AZT) to indigent patients. with counseling and education), civil dorsed the report of the President's Bush himself, however, has shown rights protection for infected people Commission on AIDS,which calls for interest in the epidemic. During the and an expedited review of drugs. Federal legislation to protect the civil past year he has had briefings from Dukakis himself mentioned AIDSin rights of people infected with HlV . officials of the National Institutes of his acceptance speech, and he recent Most pUblic-health figuresthink that, Health and from Senator Lowell P. ly played to the cameras by visiting without such measures, fear of dis Weicker, Jr., of Connecticut, who has an AIDSho spice. Like Bush, however, crimination will keep potential carri introduced legislation that would pro he supports mandatory testing of cer ers from seeking tests, making them tect the civilrights of infected people. tain groups, including members of the more likely to spread the disease. Ex Bush has also met with AIDSpatients. armed forces and donors to blood, perience seems to justify the concern. According to Anthony S. Fauci, a prom organ and sperm banks. He also favors Workers at the University of South inent AIDS researcher and the director testing of immigrants-but only those Carolina School of Public Health re of the National Institute of Allergy and from countries with a high incidence ported that the number of homosexu Infectious Diseases, Bush has called of HlV infection. al men coming forward to be tested him several times for information on AIDSactivi sts generally give Dukakis fell by 51 percent at one voluntary scientific points and "asked all the high marks for his record in Massa testing site in South Carolina after the right questions." Bush cheered the chusetts. That state currently spends state enacted a law requiring that the AIDSlobby recently by urging the Food more per capita on AIDSthan any oth names and addresses of infected indi and Drug Administration to expedite er, and it was the first to conduct a viduals be recorded. the approval of drugs that have shown statewide mailing of AIDSinformation. Yet people who are politically active potential against AIDS. Dukakis has supported state legisla on behalf of AIDSvictims do make Unlike Dukakis, Bush supports "rou tion prohibiting discrimination, and distinctions between Bush and Duka tine" testing of people seeking mar the drug-addiction treatment program kis. For one thing, Bush is often seen riage licenses, of patients in clinics in Massachusetts has been signifi as being compromised by his associa treating drug abuse or sexually trans cantly expanded. He did, however, op tion with the current administration, mitted diseases and of all would-be pose proposals to initiate a needle-ex which has approached the AIDSis sue immigrants. He thinks, however, that change program for drug addicts. Du gingerly. For instance, a Federal mass testing should be mandated by the kakis' running mate, .Senator lloyd mailing providing information about states rather than by the Federal Gov Bentsen of Texas, has been briefed on the disease was not sent out until May ernment. He recognizes that confiden AIDSby publi�:-health experts such as of this year, some seven years after tiality is "imperative" and believes ed Mervyn Silverman, president of the the epidemic was first recognized. The ucational materials on AIDSshould be American Foundation for AIDSRe Administration has also consistently tailored to address the concerns of search and the former director of asked for less money for fighting the groups vulnerable to infection. public health in San Francisco, and epidemic than Congress wanted. Presi During the drafting of the Republi June E. Osborn, dean of the School dent Reagan has not even implement can platform Weicker offered amend of Public Health at the University of ed the principal recommendations of ments that would have put the party Michigan. his own commission's report. on record as supporting the report of How will these contrasting records In addition to being unhappy with the President's Commission on AIDS. weigh in the electoral scales? The dis the administration Bush represents, In deference to the wishes of the par ease could meld those it threatens AIDSadvocates were disappointed by ty's powerful right wing the propos- into a strong single-issue constituen-

14 SCIENTIFIC AMERICAN October 1988

A new computer system provides accurate, timely reports at an annual cost savings of $152,000. Designed and built by Hughes Aircraft Company, the Parts Logistics Analysis Network (PLAN) is used to track data on electronic components from their inception as engineering requirements through procurement, receiving, inventory, and the work cycle of Hughes satellite programs. PLAN" digests" requests for specific data banks, and promotes user control through"friendly" connections. PLAN also enables those who are most familiar with the data to manage the information, and requires minimal programmer intervention of system control languages.

Hughes has earned the 1987 Herschel Award for improving the sensitivity and producibility of infrared detector arrays. The technological breakthrough was achieved by using and adapting a process of liquid phase epitaxy developed by Hughes. Detector arrays make infrared imaging possible for applications such as satellite-generated weather and remote Earth sensing information, and night vision systems for military vehicles. The award is the highest yearly accolade given to an organization by the Infrared Information Symposia Specialty Group on Infrared Detectors.

Heat pipe technology will be used to cool future nuclear-powered space systems for the first time. Heat pipes are passive thermal control devices that are used to cool computers, signal processors, communications devices, and various other equipment in military and commercial applications. Under development by Hughes for NASA's SP-I00 Advanced Radiator Program, the heat pipe's radiators will be as large as 8,881 square feet and will take on exotic shapes. Because they must be able to unfold after deployment from the Space Shuttle, the radiators will require the first-time use of heat pipes with rotating or flexible joints. The heat pipes' projected cooling medium will be a liquid metal, such as cesium, mercury, or potassium, and will operate at either 600 or 950 degrees Kelvin.

A new Space Based Radar Program will involve the placement of a constellation of sensor platforms in the Earth's orbit between 600 and 6,000 nautical miles in altitude for wide area surveillance of ships, aircraft, and cruise missiles. Hughes, as a member of the Grumman-led team, will define technology requirements and an implementation plan for the radar RF and processing sections, which will interface with Grumman's SBR system. An operational demonstration-validation phase will lead to a first launch in the mid-1990's. The Space Based Radar Program is ajoint U.S. Air Force and Navy program.

Support Systems in Southern California designs, develops, and manufactures some of the most sophisticated training simulators and a wide array of automatic and manual test systems. In addition, field engineering and technical support of a wide range of electronic systems keep Hughes' systems operating at top efficiency worldwide. Opportunities are available for a variety of engineers qualified by degree or work experience. They include systems, radar, MATE control and support software engineers, logic designers and image processors. Please send your resume to Lowell Anderson, Professional Employment, Dept. S2, Hughes Aircraft Company, P. 0. Box 9399, Long Beach, CA 90801-0463. Equal opportunity employer. U.S. citizenship required.

For more information write to: P. O. Box 45068, Los Angeles, CA 90045-0068

HUGHES © 1988 Hughes Aircraft Company Subsidiary of GM Hughes Electronics © 1988 SCIENTIFIC AMERICAN, INC cy; a close election could turn on such revelations a joint conference of the Indeed, as the OTA report points out, a block vote. Whatever the outcome of Senate and House of Representatives Corrtex itself would be useless for the election, the AIDS epidemic and its ordered the department to institute monitoring either a low-threshold lim retinue of volatile political, social and the readiness program recommended it or a ban on tests; its accuracy is poor policy issues will be waiting-bigger by Kidder. at low yields and it cannot detect se than ever-for the next president and At about the same time the Office of cret tests. But irOnically the joint ex his administration. -Tim Beardsley Technology Assessment, which advis periment may promote seismic verifi es Congress on technical matters, is cation more than it promotes Corrtex. sued a report on seismic verification As part of the experiment, the U.S. and that had been delayed by Energy De the U.S.S.R have exchanged informa Test-Ban Countdown partment censors for several months. tion about the geology of their respec As START stalls, arms controllers The report disputed the Administra tive test sites and about the yield of fo cus again on nuclear testing tion's contention that the Soviets have past tests. These data, as well as those violated the 1974 Threshold Test Ban generated by the blasts in August and he perennial debate over nucle Treaty, which limits yields to 150 kilo this fall, should help to calibrate seis ar-weapon tests has been over tons. (The bomb that destroyed Hiro mic sensors. Tshadowed during the past year shima had a 13-kiloton yield.) The re The prospects for a treaty limiting or two as the superpowers tried to port also concluded, contraryto the or banning tests depend to a large negotiate missile reductions. Now that Administration's assertions, that seis extent on the outcome of the pres the intermediate-range nuclear forces mology is equal to the task of remote idential election. Governor Michael (INF) treaty has been ratified and the ly monitoring underground blasts. Dukakis has favored a test ban; Vice strategic arms reduction talks (START) The OTA found that with an array of President George Bush has pledged have bogged down, however, testing seismographs in the Soviet Union the to uphold his predecessor's policy. has once again taken center stage. U.S. could monitor "with high confi By overriding any presidential veto, a Arms-control advocates still contend dence" a treaty prohibiting tests that two-thirds majority of Congress could that banning nuclear explosions or have yields above 10 kilotons. An ex unilaterally legislate limits on testing. greatly limiting yields would promote perimental seismic array is already Congressional insiders say such a ma stability by preventing the develop being installed in the Soviet Union by jority may vote for the "phased ap ment of increasingly lethal nuclear the Natural Resources Defense Coun proach" toward a nuclear ban out explosives. The Reagan Administra cil, a private group that favors a test lined in the OTA report. The plan calls tion still responds that testing is cru ban, in collaboration with the Soviet for an initial threshold of 10 kilo cial to deterrence and should cease Academy of Sciences. tons, which "would then be lowered only in that millennial age when nucle Meanwhile the Administration has as information, experience and c on ar arms are banished from the earth. begun to pursue aggressively its own fidence increase." A lO-kiloton lim But events of the past year have testing-related agenda. Insisting that it, most arms specialists agree, would weakened several of the Administra seismic sensing cannot verify Soviet greatly constrain the development tion's key positions on testing. Admin compliance with the Threshold Test of directed-energy nuclear warheads istration officials have maintained, for Ban Treaty, Administration officials and other potentially destabilizing example, that tests are needed to en have championed a highly intrusive weapons. -John Horgan sure that weapons in the stockpile are yield-measurement technique. Called "reliable." Late last year Ray E. Kidder, Corrtex, it requires running an instru a weapons designer at the Lawrence mented cable down to the buried nu PHYSICAL SCIENCES Livermore National Laboratory, did a clear device and then measuring how study that concluded otherwise. The rapidly the cable is crushed by the Department of Energy can maintain explosion. To establish the efficacy of a viable arsenal without testing "for Corrtex, the Administration has con Starshower the foreseeable future," Kidder said, vinced the Soviets (who favor a total Galactic arms trigger by making exact duplicates of aging ban, verified by seismic monitoring) to the birth of hosts of stars warheads whose reliability has been take part in the so-called joint verifica proved. Kidder urged the Energy De tion experiment. In August, Soviet offi he majestic, sweeping arms of partment, which oversees the produc cials monitored an underground nu classic spiral galaxies have long tion of nuclear weapons, to institute clear blast at the Nevada Test Site with Tpuzzled astronomers. For one a "readiness program" so that the a Corrtex device. This fall a U.S. team thing, they are littered with newly materials and expertise needed for will monitor an explosion at Semipala formed stars. Do the stars take shape remanufacturing weapons are avail tinsk, the Soviet test site. simply because the arms are rich in able in the event of a test ban. Administration officials have gone the gas clouds that are the raw ma The Administration's position on re to unusual lengths to publicize the terial of star formation? Or do the liability was further undermined in joint experiment, hailing it as a major arms play some active role in star June when Representative Edward j. step toward the "ultimate goal" of a birth? Recent high-resolution milli Markey of Massachusetts released a ban on testing. Privately officials in the meter-wave radio observations of the confidential memorandum written in White House have acknowledged to Whirlpool Galaxy, the prototypical spi 1986 by a physicist at the Los Alamos SCIENTIFIC AMERICANthat they have ral, have painted a picture that strong National Laboratory. In the memoran another aim. By creating the appear ly supports the latter view. It appears dum the physicist warned his superi ance of progress toward a test ban, the that the gravitational field of galactic ors that some of the Energy Depart officials said, they hope to divert at arms can trigger the birth of stars. ment's statements about the need to tention from the achievements of gen The observations, reported in Na ensure reliability through testing were uine test-ban proponents and so re ture, were made at the Owens Valley "on thin ground." Soon after these duce their momentum. Radio Observatory in California by

16 SCIENTIFIC AMERICAN October 1988

Biogen Vision

Applying Rational Drug Design To AIDS

n September 11th, 1987, an and shields healthy cells from mals, and no untoward effects important advance in AIDS potential infection. of CD4 in heal thy control Oresearch was announced to animals. the scientific community. Dr. Based on these positive test Richard Fisher, Biogen's Director results, Biogen is now prepar of Molecular Biology, reported on ing to commence human clini the biological activity of a recombi cal studies with CD4 later in nant, soluble form of the human 1988. Tr ials will be conducted cell surface protein called CD4. at UCLA Medical Center and at Massachusetts General Hos The Discovery pital, in Boston. These tests will determine the safety of Te st results showed that this CD4 in AIDS patients. molecule could inhibit the infec tivity ofHIV (Human Immunodefi In cancer research, Biogen was ciency Virus) in vitro. Thus a novel first to develop alpha inter scientific path was opened into the feron, an important anti discovery of potentially active cancer and anti-viral drug. agents against the AIDS virus. Licensed to Schering Corpora tion, alpha interferon is being used in the treatment of leuke The First Soluble Receptor The CD4 receptor protein is anchored mia, cancers, and viral infec tions. Biogen's expression of CD4 to the surface of white blood cells (shown above) by a transmembrane marked the first time that this sol HIV CD4 Biogen is also a leader in the uble receptor had been developed connection. binds to the application of recombinant as a potential therapeutic for receptor, then invades the cell. DNA approaches for the diag human disease. Biogen combined nosis and prevention of hepati an understanding of the AIDS virus Biogen Leadership tis B. Over 200 million people and the application of the most worldwide suffer from this The scientific advances Biogen advanced genetic engineering tech chronic viral infection. has achieved in recombinant pro niques to create this breakthrough teins are an outgrowth of our Our scientists are at work on development. rational approach to drug design. numerous other products that The infectious process begins We have been a leader in pharma ar� currently in clinical trials when HIV binds to certain white ceutical development for more or in various stages of research blood cells via a protein receptor, than 10 years. and development. called CD4, located on the surface of the cell. The virus infects the -With CD4, Biogen scientists As this revolutionary research in body by first attaching to the CD4 reported results of in vitro test rational drug design continues, sci protein to gain entry into the cell, ing in 1987, and in 1988 we entific advancements are �ure to where it multiplies and eventually commenced testing of CD4 in follow. And one name will often be kills the cell. When studied in rhesus monkeys. Results to linked to these novel achieve vitro, Biogen's soluble CD4 binds date show signs of positive bio ments: Biogen, a company with a directly to HIV or infected cells, logical activity in infected ani- vision. BCBEN Fourteen Cambridge Center Cambridge, MA 02142

© 1988 SCIENTIFIC AMERICAN, INC Stuart N. Vogel of the Rensselaer Poly regions of greater density: the spiral the clouds, cause some to collapse technic Institute and his co-workers, "density waves" that theories of galaxy into stars. Vogel points out, however, using the technique of radio interfer formation predict. that arms cannot be the only trigger of ometry. The Whirlpool Galaxy is more The most significantobservation, star formation, since some galaxies do than 30 million light-years away, but however, was that newly formed mas not have arms. -T.MB. by recording the distinctive emissions sive stars, detected by their envelopes from chemical elements and com of ionized hydrogen, were not concen pounds in the galactic arms the in trated exactly in the arms but were Weighty Matters vestigators were able to produce a localized somewhat "downwind" of detailed map of position and velocity. them. The superabundance of young A test of gravity in Greenland These are the most detailed observa stars just past each arm was great casts doubt on Newton's law tions of another galaxy to date. er than the arm's high concentration The workers found, as they expect of star-forming molecular gas clouds ould Newton's 300-year-old law ed, that the clouds of molecular gas alone could explain. The likeliest ex of gravity finally be succumbing (mainly hydrogen) from which stars planation is that the gravitational Cto age? Several recent findings coalesce are concentrated in the spiral shock the molecular gas clouds under seem to deviate from the theory, and arms, which also contain the highest go as they enter an arm somehow now the most meticulous test yet-a densities of dust and stars. More sig triggers the formation of stars, which measurement of the gravitational field nificant, they also found that the gas appear downwind perhaps 30 million in a mile-deep borehole in the Green appears to be rotating about the ga years after the encounter between the land ice sheet-has turned up further lactic nucleus faster than the arms gas and the spiral arm. evidence of a discrepancy. themselves do, which is a prediction Vogel says his team is not ready The implications could be profound. of some theoretical models. As the to say exactly why entering an arm Such small adjustments to gravity are clouds catch up with an arm and enter touches off star formation in clouds in fact predicted by all the most prom it they undergo a violent change in of gas, but one possibility is that by ising attempts to forge a unified the velocity and are redirected inward drawing gas clouds together the gravi ory of the fundamental forces-the along the arm by its strong gravita tational fieldof the arm causes them ultimate goal of physics. These new tional field. This gravitational effect to collide more frequently. The colli effects, which some people call a confirms that the arms of a galaxy are sions might, by increasing the mass of fifth force and even a sixth force, are expected to compare to gravity in strength, but they act over perhaps a few hundreds or thousands of meters, As the density wave of a galactic arm compresses whereas gravity has an infinite range. One possible consequence of such gas clouds, the resulting shock triggers starbirth new effects is that within the range of the new forces, Newton's inverse square law (the strength of gravity falls as the square of the distance between two masses) may not be true. Another is that unlike standard gravi ty, which acts only on mass, the new effects may depend on some aspect of an object's composition, such as the total number of baryons (protons and neutrons). Nearly a dozen experi ments have sought-inconclusively to detect one of the effects (see "Force of a Different Color" in "Science and the Citizen," December, 1987). The Greenland project is the latest in a series of attempts to detect a violation of the inverse-square law by measur ing local gravitational fields and com paring them to calculations based on the density of the surrounding terrain. An earlier experiment done inside an Australian mine found a repulsive effect of roughly 1 percent of the strength of ordinary gravity, acting over a range of a few hundred meters. A second experiment, carried out on a 600-meter television tower in North Carolina, found an attractive effect of about 2 percent of the strength of TWO ARMS of the WhirlpoolGalaxy are shown in ,a composite image. The galaxy gravity acting over a distance of 300 rotates counterclockwise; colors indicate relative velocities of molecular clouds. meters. The calculations worked out The velocities change near a density wave. Contours show emissions (rom ionized even better when both an attractive hydrogen, which marks the fo rmation of stars downstream (rom the density wave. and a repulsive effect were presumed.

18 SCIENTIFIC AMERICAN October 1988

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© 1988 SCIENTIFIC AMERICAN, INC Skeptics argue that these apparent raculous that, after proposing his the the behavior of the entire solar system effects could result from anomalies ory of gravitation, Newton himself chaotic. Unless, of course, God decides in local mass density, such as a hid declared that periodic divine interven to intervene. -Tony Rothman den lode of metal ore. The Greenland tion was necessary to ensure it. Pierre group, led by Mark E. Ander of the Los Simon de Laplace was not satisfied Alamos National Laboratory and Mark with that explanation. In the 18th cen Pacific Sea-saw A Zumberge of the University of Cali tury he proved to the satisfaction of fornia at San Diego, therefore chose a his peers that the solar system should A natural fe edback loop may highly homogeneous site: a borehole in fact be stable. The feat earned la explain El Nino's recurrences surrounded by a two-kilometer-thick place the title of the French Newton, expanse of ice. The team took elab and his work is considered the corner very three to five years the sur orate precautions: the bedrock was stone of celestial mechanics. face waters of the central and mapped by 42,000 high-frequency ra Yet Laplace's proof WllS not rigor Eeastern Pacific Ocean become dar scans, and careful surveys deter ous, and all attempts to make it so unusually warm at the Equator. These mined the height of the ice surface to have failed. Now, in fact, two investiga heating episodes, called El Ninos, can within a centimeter. A gravimeter took tors assert that such a proof may not disturb a wide range of marine life in more than 100 readings at half a doz exist, because the solar system is, the region and are also thought to en locations, at depths of between 200 strictly speaking, unstable. The claim cause unusual flooding or drought in and 1,600 meters. is made by Gerald Jay Sussman and other parts of the globe. Expanding The researchers assumed the densi Jack Wisdom of the Massachusetts In knowledge of the mechanism driving ty of the bedrock might range between stitute of Technology, who report in the warming recently enabled meteo 2.7 and three grams per cubic centi Science that the orbit of Pluto is chaot rologists to predict the latest El Nino meter; densities outside this range are ic. With the help of the Digital Orrery, successfully. Yet a fundamental fea geologically improbable. Finally, dif a one-cubic-foot computer built by ture has remained a mystery: what ac ferent members analyzed the data at Sussman and friends in 1984 to study counts for the reversal of El Nino a least three times. Their preliminary planetary motions, they have evolved year or two after it begins-and then conclusion: there appears to be a sin the motion of the five outermost plan for its return sometime later? gle, attractive effect whose strength ets through the next 845 million years. Nicholas E. Graham and Warren B. is between 1.7 and 3.9 percent that They find that the orbit of Pluto be White of the Scripps Institution of of gravity. It is thought to act over comes unpredictable on a time scale Oceanography report in Science that a distance of somewhere between 10 of about 20 million years. they have found support for one ex meters and slightly more than one Such unpredictability is the hall planation. El Nino, they and other kilometer. mark of a chaotic system. Until recent workers say, is part of a natural, self The new findings agree with the re ly it had been thought that if two sustaining cycle of warming and cool sults from North Carolina but seem to identical particles-or planets-were ing that is controlled by interacting contradict those from Australia. It may started off at nearly the same position oceanic and atmospheric factors. be possible to reconcile all three re with nearly identical velocities, they The warming cycle can be said to sults by including both an attractive would follow nearly identical trajec begin when the sea-surface tempera and a repulsive effect, but then the tories.In the past decade that view has ture at the Equator in the eastern Pa theoretical model "gets rather con changed. Now it is known that even cific rises significantly. As a conse trived," according to Ander's colleague relatively simple systems manifest so quence the atmospheric-pressure dis Richard Hughes. To help determine called chaotic behavior. For instance, tribution over the equatorial Pacific whether these effects are real or are the orbit of an asteroid in a model changes, dramatically weakening the instead caused by hidden anomalies solar system conSisting of only the easterly trade winds that flow west in the environment, the group is al sun and Jupiter may become chaot ward along the Equator. The altered ready planning future experiments in ic. That is, two asteroids starting off winds generate disturbances in the the Pacific Ocean and in Antarctica, at infinitesimally differing positions upper layer of the ocean known as where the ice is twice as thick as the and velocities will follow wildly dif Kelvin waves; these travel eastward ice in Greenland. -June Kinoshita fering orbits. For them to follow iden along the Equator, reaching the east tical orbits they must be started off ern boundary of the Pacific within two with absolutely identical initial condi or three months. God Takes a Nap tions-something that is impossible. The Kelvin waves-which in this Sussman and Wisdom have uncov part of the cycle are essentially propa A computer findsthat ered a similar phenomenon involving gating regions of deep, warm water Pluto's orbit is chaotic Pluto. In their numerical simulations reinforce the heating of the eastern they follow pairs of Plutos whose or Pacific, primarily by depressing the hat the earth has circled the sun bits are initially almost identicaL The thermocline: the boundary between for five billion years and the sun orbits, however, diverge exponentially the warmer upper layer and the cooler Trises between the monoliths at with time-a sure sign of chaotic be deeper waters. The eastern thermo Stonehenge like clockwork every June havior-until after several hundred cline is normally shallow, so that the 21 are things taken for granted. Yet million years one Pluto may be on the sea surface is cooled by cold water the gravitational interaction of the opposite side of the solar system from upwelling from below; when the ther sun, the nine known planets and the the other. Like all models, Sussman mocline is deep, water continues to asteroids is so complicated that one and Wisdom's model makes simplifi flow upward, but the water brought to might more reasonably expect planets cations. But if it represents the real the surface is relatively warm. to spiral into one another or wander solar system, Pluto's chaotic motion The role of Kelvin waves in causing off into deep space. Indeed, the solar must eventually be transferred to that an El Nino has long been recognized. system's long-term stability is so mi- of the other planets, thereby making The processes that lead to cooling and

20 SCIENTIFIC AMERICANOctober 1988

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© 1988 SCIENTIFIC AMERICAN, INC Take a laakat the caryour kid It is the product of five years Just look at it. The sleek lines. CutlassS upreme of engineering and design, the The smooth shape. Styling des- Ordinarily, we wouldn't make result of over a million miles of tined to become the standard of such a bold prediction. But then, testing.In the purest sense of a new generation. the 1989 Cutlass Supreme is any the word, theCutlass Supreme But advanced styling isn't the thing but ordinary: is a totally new Oldsmobile� only reason the Cutlass Supreme

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© 1988 SCIENTIFIC AMERICAN, INC to a restoration of pre-El Nino condi particle accelerator, known as the July heat wave some aging microelec tions have been more elusive. Graham, Stanford Linear Collider (SLC), was tronic parts overheated and failed in White and others propose that the ready to roll. After months of delay alarming numbers inside the unrefrig cooling is the result of events that and a slew of unforeseen technical era ted shed housing the linac. occur outside the equatorial wave problems, they had succeeded in Longer-term obstacles arise from guide: the region bounded by about bringing two tightly focused particle the untried design of the machine. The three degrees north and south lati beams, one of electrons and one of "kicker magnets," which extract parti tude. In the off-equatorial regions the positrons, into head-on collision-the cles from "damping rings" where they warming of the eastern sea disturbs most precise beam collision ever at are squeezed down to the required wind patterns over the central Pacif tempted. "That was the good news," densities, proved unequal to the task. ic, leading to an oceanic upwelling in said Kaye D. Lathrop, an associate di Unexpectedly large effects induced by that region, which in turn gives rise rector of SlAe."A lot of people had the electrical current of the beams to westward-moving Rossby waves. said we wouldn't be able to make such prevented the damping rings from At this point in the cycle the Rossby small beams collide." making adequately short bunches of waves are essentially regions in which The bad news was that there were the particles. The positron source, the warm upper layer is thinner than not enough collisions. The collisions a metal target that emits positrons usual (in other words, where the ther are supposed to churn out Zo's ("Z when it is bombarded by electrons, mocline is elevated). naughts"), heavy particles whose prop must be made more durable. There The Rossby waves travel more slow erties elucidate certain fundamental also are not enough instruments yet ly than the Kelvin waves, but within a aspects of matter. But by the end of to adjust errors in the position and year or two they are thought to reach July no Zo's had been seen. Indeed, quality of the beams accurately. the western border of the Pacific, trav the machine achieved useful colli Lathrop was philosophical about el along the border back into the equa sions only 3 percent of the time that the setbacks: "To put the best face on torial region and become shallow, it was running. Alarmed by this set it, we've learned what we have to do." fast-moving Kelvin waves. The arrival back, SlACdirector Burton Richter as For the next few months, weekdays of these waves in the eastern Pacific sumed direct control of the project will be spent studying and fine-tuning raises the thermocline there, allows on August 1 and assigned teams to the SLC and weekends will be devot cold water to surface and enables the tackle the multitude of problems be ed to producing collisions. The plan easterly winds to gain strength. setting the machine. is now to get the SLC up and running At first, surface cooling is further re The SLC is trying to achieve colli stably in February. -JK inforced by the easterlies, which gen sions by an untried method: boosting erate shallow, eastward-moving Kel electrons and positrons to high ener vin waves in the central equatorial Pa gies in a linear accelerator, or linac, Planetary Consomme cific. Yet the cooling in the equatori and then aiming the beams at each al waveguide helps to trigger the next other. Unlike conventional machines, Terrestrial experiments heating phase. It leads to wind pat in which beams collide repeatedly as mimic alien atmospheres terns in the off-equatorial areas that they whirl in opposite directions along produce downwelling and deep (rath the same circular track, the SLC has rom the makers of synthetic pri er than shallow) Rossby waves. These only one shot at a time. To compen mordial soup come two new fla westward-moving Rossby waves even sate, the beams have to be squeezed to Fvors: Titan and Uranus. Back in tually turn into deep Kelvin waves, unprecedented densities. 195 3 investigators first simulated the which, when they reach the east, de When Richter first proposed the earth's primordial atmosphere. They press the thermocline, thus raising the idea in 1980, he decided to piggyback zapped a gas mixture with electricity, sea-surface temperature once again. the new design onto the existing two which yielded a soup of organic mole By examining various indicators of mile-long Stanford Linear Accelerator, cules. Now this technique has been the movement of Rossby waves-such which was built in the early 1960's. modified by astronomers trying to as wind patterns and changes in sea The linac would accelerate both elec simulate chemical processes in the level and water temperature-in the tron and positron beams and inject present-day atmospheres of the plan off-equatorial regions, Graham and them into an oval track; they would go ets and moons of the outer solar sys White have determined that the Ross around the track in opposite direc tem. The simulations may help to ex by waves appear to have been in the tions and slam into each other on the plain the planets' color and atmos expected places when El Ninos have other side. This decision, calculated to pheric chemistry, and they may even occurred in the past. They also note catapult the SLC ahead of a rival Euro provide insight into the origin of life that models including calculations of pean machine of conventional design in this solar system and others. Rossby-wave activity predicted the costing 10 times as much, has created Whereas the primordial-soup exper 1986-87 El Nino a year in advance of problems of its own. iment was based on conjecture about its onset. -Ricki Rusting The old linac was designed to pro the earth's ancient atmosphere, the duce beams with energies of about 25 new simulations rely on information billion electron volts (GeV) and diame collected by the Voyager 2 spacecraft ters of a few millimeters, but the SLC during its flybys of Saturn and Uranus. More Setbacks at SlAC must produce two 50-GeV beams fo Carl Sagan, W. Reid Thompson and Aging technology adds cused down to less than 10 microns Bishun N. Khare of Cornell Universi to a linear collider's woes and aim them at each other. Among ty duplicated in their laboratory the other things, it turned out that some conditions found in the upper at his past spring physicists at the of the older power supplies are too mospheres of Titan (Saturn's largest Stanford Linear Accelerator Cen jittery to achieve such precision; it moon) and Uranus. Hydrogen, helium, Tter (SlAc)jubilantly announced could take six months to replace them. nitrogen and methane were mixed at that the center's unconventional new To add to these troubles, during the pressures and concentrations typical

SCIENTIFIC AMERICAN October 1988 25

© 1988 SCIENTIFIC AMERICAN, INC of those atmospheres. The gases were QUESTAR' pumped continuously through glass tubing, and a coil of wire was wrapped ... the priceless telescope around a section of the tubing. A high voltage current flowing through the wire created an intense magnetic field in the gas, The field energized the gas molecules and stripped electrons from them, forming a state of matter known as a plasma. The laboratory plasma mimics the aurora, in which atmospheric gases are bombarded by charged particles accelerated by a planet's magnetic field. Chemical reac tions are known to abound in plane tary auroras. The laboratory plasma was Similarly fecund, creating many different organ ic molecules, including hydrocarbon chains up to seven carbon atoms long. As these chemicals and others flowed farther through the glass tubing, they were separated for analysis. Some gas es condensed at room temperature. Others solidified in places where the tubing was cooled in baths of dry ice and liquid nitrogen. After the simula tion had run for a few days, enough material was produced to be detected and analyzed. The astronomers were thereby able to study the chemistry of Titan and Uranus at a level of detail not possi ble for the Voyager spacecraft or tel escopes. The Titan experiments pro duced a brownish organic solid whose optical properties agreed well with Voyager and ground-based measure ments of the omnipresent Titan haze. Over the lifetime of Titan this material may have accumulated on the moon's surface in a layer hundreds of me ters thick. The investigators also report that the nitrogen-rich atmosphere of Titan produced a great variety of prebiotic chemicals called nitriles. Nitriles are precursors of amino acids, the basic building blocks of proteins. "Some thing similar may have happened on the early earth, but on Titan the pre biological chemistry is probably still born: the temperatures are far be low the freezing point of water," Sa gan observes. The Uranus experiment, reported in Journal of Geophysical Research, sim ulated a hydrocarbon smog that is created by the aurora in the planet's hydrogen-and-methane atmosphere. In the reaction chamber of the simu lation, the astronomers collected sol id hydrocarbons on glass slides. They

QUt��TAR. THt WORI O'S tlNF.�T. MOST H.RSATIU measured optical properties of the hy TU.ES( OPt. IS OES( RIBU) IN OUR BOOKl.ET. SF NO drocarbons and found they account S3 TO (OVt.R MAil ('OSTS ON THIS (ONTINtNT. B\ QUE S TA R AIR TO S. AMERI( A. $4; HIROPt.& N. AtRI( A. S5.00; for the subtle hues of yellow, red, INQlJlRt OlIR txn .... �;:tH�:!;'1 �:. AROler mJ) no, 59. Dept. 21'). 'l'" 1I0pe.I'A 1119311 brown and black that tinge the blue I'hone (215) 1162-5277 green globe of Uranus. The Cornell

26 SCIENTIFIC AMERICAN October 19 88

BIOLOGICAL SCIENCES gre�t River Ganga ... Postprandial Warmth Certain fish rise to the surface in order to digest better High up in an ice cave, fromthe waters of the melting Gangotri oes a warm bath make you Glacier, the Ganga River begins. hungry? For certain fish the The view is breattitaking,as mag Danswer apparently is yes. Ac "-�"'1711'."''' to meet peaks rise 20,000fee t cording to a report in Nature, these sJ<.r- fish, juvenile Bear Lake sculpins, feed NQithern India is a land brilliant on the chilly bottom of Bear Lake (in of COfltniSts . Valleys yielding st.Mlc:lenly to Utah and Idaho) during the day and rise to the warmer surface waters peaks. Deep silences giv at night to digest. The warm water thunderous rush of speeds their metabolism, accelerating the rate at which they absorb their trf'!kklnO enthusiast, food and making it possible for them ".",aTa.."which to eat a larger meal the next day. all of Daily vertical migrations are not un :ItoI' them lnelta, common among fish species, but they offer some of usually occur for other reasons. For thewor ld's example, a fish might come up to the �trugged surface to feed on plankton during the rewarding night and then return to the depths and during the day in order to hide from predators or to conserve energy by slowing its metabolism in cold wa ter. Indeed, the authors of the re port, WayneA Wurtsbaugh and Darcy Neverman of Utah State University, thought they were dealing with one of these migration patterns, until they discovered that the sculpins' stom achs were fullest at dusk, just before the fish rose to the surface. Inside the stomachs were the remains of organ isms that live only on or near the bottom. The fish could not have been rising to the surface to eat; perhaps they were rising to digest. To test their hypothesis that warm surface water acts as an aid to diges tion, the investigators fed a collection of sculpins a full meal and kept them in separate tanks, some at five degrees o Ye s! I'd like to plan an exciting visit to India. Celsius (the temperature of the bot Please send me information. tom waters) and some at 15 degrees (the temperature of water near the Name surface at night). The fish kept at 15 degrees digested their stomach con Address tents at a rate of 23 percent per hour and had evacuated 80 percent of their City State Zip meal within 7.5 hours. The fish kept at five degrees, on the other hand, digest Mail to: Government of India To urist Office Dept. MH, 30 Rockefeller Plaza ed only 3.2 percent of their stomach North Mezzanine, New Yo rk, NY 1011 2 contents per hour; at that rate it would have taken them 50 hours to evacuate New York 212-586-4901 Chicago 312-236-6899 80 percent of the meal. Los Angeles 213-380-8855 SA10S How much real good does such an

SCIENTIFIC AMERICAN October 1988 27

© 1988 SCIENTIFIC AMERICAN, INC increased rate of digestion do for the fish? After all, in warmer water the fish must expend more energy simply to maintain their metabolism. To answer 1989 GERARD PIEL AWA RD this question, Wurtsbaugh and Never man raised separate groups of fish in FOR SERVICE TO SCIENCE the laboratory. Some were grown in water held at a constant temperature IN THE CAUSE OF HUMANKIND of five degrees and others were grown in water whose temperature fluctuat ed daily between five and 15 degrees, mimicking the temperature range that would be encountered by a migrat Nominations are requested ing fish. The fish were fed only during the day. The results were dramatic: for the first Gerard Piel Award to be presented by AAAS sculpins raised in water whose tem at the 1989 Annual Meeting in San Francisco. The Award, perature fluctuated grew three times established by the Board of Directors of SCIENTIFIC as fast as fish reared at a constant low temperature. -Ari W. Epstein AMERICAN, recognizes contribution to the formation of public policy and opinion respecting the wise use of science in the cause of human well-being and fulfillment. Yeast Meets Est(rogen) It may recognize life work or episodic cont ributions to A microorganism responds such issues as population inc rease, economic develop to a vertebrate hormone

ment, poverty and environmental conservation. The hat distinguishes man from honor and will receive a medal and a $10,000 prize. Both yeast? At the macroscopic lev· Wel the differencesbetween the individuals and organizations are eligible. two species are obvious and substan· tial, but at the level of individual cells distinctions begin to blur. When the No nomination form is re focus narrows to the molecules that constitute genes, similarities rather quired, but all nominations should be typed and should than differences prevail, not only in include the following information: nominee's name, the structures of the molecules but address, institutional affiliation and title; a brief bio also in the processes by which they are regulated. At least, that seems to graphical resume; and a statement of justification for the be the gist of a growing number of nomination. Organizational nominations should include studies in which gene regulators are swapped between human cells and information about the nature, form and work of the or yeast cells. ganization. All nominations must include the name, The most recent piece of evidence comes from Pierre Chambon and his address and telephone number of the individual making colleagues at the National Institute the nomination. of Health and Medical Research and the National Center for Scientific Re· search in France. In Nature, Chambon, Daniel Metzger and John H. White Nominations, as well as ques describe how they grafted the genes tions about the award, should be addressed to: for a human gene regulator and the strip of DNA to which it binds into Dr. Albert H. Teich, Head, the genome of common baker's yeast. In human cells the regulator, a pro Office of Public Sector Programs, tein called an estrogen receptor, is AAAS,13 33 H Street, N.W., responsible for Switching on certain Washington, D.C. genes when it is signaled by the fe 20005. male developmental hormone estro (Telephone 202/326-6600) gen. The receptor binds estrogen, at taches to its target site in the DNA and somehow-no one knows just how Deadline for receipt of nominations is November 15, 1988. triggers gene expression. Yeast cells do not ordinarily re spond to estrogen, but when cells were equipped with a receptor and a binding target, their genes were also activated by doses of the hormone. That means the molecular events that

28 SCIENTIFIC AMERICAN October 1988

© 1988 SCIENTIFIC AMERICAN, INC That's a fairly odd phrase - I "when you realize the fu ture's behind you." But a for ward thinkingcompany knows exactly what it means. Quite simply, the kind of company you are tomorrow depends a great deal on the moves you made yesterday, the decisions you make today. In recent years the moves we've made , the decisions we've reached have renewed our spirit. It took introspec tion, belt-tightening, and some tough calls. No w we're smarter, more flexible, and more responsive to change. It all strengthened our belief that the way to step toward to morrow is not to fo llow, but to lead. With fresh thinking that allows us to do business as we've never done it before. Tod ay we're involved in em erging technologies that can lead to new business opportu nities tomorrow . Projects like the development of synthetic metals for increased safety in commercial aviation. A new venture with the Baylor Col lege of Medicine to produce an early cancer detection kit. And a proprietary synthesis technology for the fo rmulation of non-toxic pest control . When you look back at where we've been, then for ward to where we're going, you'll find we're a company recharged and marching on. For more information write to Greg Derrick, Phillips Petroleum, 16 D-4 Phillips Bldg., Bartlesville, OK 74004.

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PHilLIPS W WHEN YOU REALIZE THE FUTURE'S BEHIND YOU, YOU DON'T TAKE YOUR STEPS LIGHTLY.

© 1988 SCIENTIFIC AMERICAN, INC For the first time,computers users in the of world using familiar commands. Announcing ETA System V. ETA System V meets all the requirements of AT&T's Until today, if you used a system based on the real AT&T System V Interface Definition (SVID) Release 3.0. It has UNIX System V operating system, your lips were sealed passed all 5,500 tests in the System V Verification Suite. It is when it came to working with a supercomputer. Making the also the only supercomputer operating system to support move to true supercomputing meant having to learn a features like ipc, semaphores and shared memory. Unlike complicated proprietary operating system. non-standard operating systems, ETA System V has the Those days are over. Because the first native operating advantages of byte addressability, virtual memory support, system for a supercomputer based on AT&T's UNIX System V BSD sockets and r-commands. has arrived -ETA System V ETA System V makes it possible to develop applications For the first time, users can work with the most powerful on industry-standard workstations compatible with AT&T's

II:; Copyrii!ht./988. Control Data Corporation. • UNIX is a registered trademark of AT&T. ETA and ETAJO are trademarks of ETA Sys tems, Inc.

© 1988 SCIENTIFIC AMERICAN, INC can a mUNIX SystemV V and then compiletalk and run them to on any truements. These applicationssupercomputer. include SPSS, IMSL and DI3000. ETAlO Supercomputer-from the affordable ETA10-P, the If you know AT&T's UNIX System V,you now have a ETAlO-Q and ETAlO-E to the world's most powerful voice in supercomputing. Beginning today. supercomputer, the ETA10-G. Talk to your Control Data representative, or: ETA Now, all your present applications based on AT&T's Systems, Inc., 1450 Energy Park Drive, St. Paul, MN 55108. UNIX System V can be ported easily to ETAlO Super Phone: (612) 642-3460. computers. Programs that once took months to port now take hours. Because programs based on AT&T's UNIX System V don't have to be rewritten. ETA is also developing a library of applications specifically ETA 10 SUPERCOMPUTERS. for AT&T's UNIX System V users in higher education environ-

© 1988 SCIENTIFIC AMERICAN, INC tum on human genes in response to binding of the receptor to its target SCIENCE'S LATEST BREAKTHROIlGH must take place in yeast cells as well. The findingis far from heret ical, since yeast and human beings are as sumed to have evolved from the same ancestral organism. Studies published in the past few years had foreshad owed the French workers' conclusions by demonstrating the converse: that some yeast gene activators function perfectly well in human cells. The au thors note, however, that it is more surprising to find that the estrogen The new Seventh Edition of Va n Nostrand's SCIENT/FIC ENC YCLOPEDIA is packed with information covering nearly receptor system works in yeast, be every aspect of today's science, engineering, and technological disciplines. It now contains over 3,200 pages cause even in vertebrates the hor replete with 6,773 entries (805 of which are new and revised), over 3,000 photographs, diagrams, drawings, and mone affects only cells following a charts, 446 tables, plus a 152-page quick-reference index. specialized developmental pathway. The discovery may have practical Alphabetically arranged by topic, the latest edition of the SCIENTIFIC ENCYCLOPEDIA is written in non-technical ramifications. Unlike many other mi language and illustrated with a wealth of photos, drawings, diagrams, and charts. It covers animal life, bioscience, croscopic organisms, yeast is eukary chemistry, earth and atmospheric sciences, energy sources and power technology, mathematics and information sciences, materials and engineering sciences, medicine, anatomy, and physiology, physics, plant sciences, space, otic: yeast cells have nuclei and a host of cellular processes in common with and planetary sciences-all in two 8%" x 1P/S" volumes. human cells. The genetics of yeast is SAVE $25. 00 BY ORDERING SOON! simpler than that of any other eukary Order before December 31, 1988 and you can save $25.00 off the regular price of $175.00. Think about it. The world ote, and so the organism has become a of scientific information at a very logical price of $150.00. favorite tool among genetic engineers. For fa stest service, 1 (606) 525-6600 or 1 (606) 525-7778. Biotechnology companies already em CAU FAX ploy yeast to make recombinant pro Scientific Encyclopedia � teins because yeast cells tend to pack � VAN NOSTRAND REINHOW age proteins in much the same way Mail Order Service as human cells do. Chambon thinks P.O. Box 668, Florence, Kentucky 41022-0668 S 8723 the estrogen-receptor system could act as a switch for turning on pro tein production in such yeast cells, since a gene linked to the system re mains unexpressed until estrogen is supplied. �Cambridge In basic research the biochemical � BioScience functions of yeast commonly serve as models for the functions of more complex organisms. Any complex sys tem that can be transferred into yeast Recombigen® HIV* is amenable to precise manipulation. Hence the French finding raises the possibility of probing in greater de tail the human es trogen receptor as Diagnostic Testing fo r well as vertebrate gene activation in AIDS Antibody Detection general. -Karen Wright

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For information on CBC infectious disease technology, to a mitochondrial gene or the Company's 1987 Annual Report, write: Corporate nvestigators believe they have dis Communications, Cambridge BioScience, 365 Plantation St., covered evidence of a new kind of Biotechnology Research Park, Worcester, MA 01605. Igenetic disease. Douglas C. Wallace Call (800) 637-8376 or (508) 797-5777. of the Emory University School of Med icine and his co-workers have found a *Availability pending U.S. FDA approval. probable disease-causing mutation af fecting a gene that is not in the nucle us of human cells but in the mitochon "Meeting the Challenge of Today's Health Care Problems" dria: the sausage-shaped organelles

32 SCIENTIFIC AMERICAN October 1988 © 1988 SCIENTIFIC AMERICAN, INC that are the power plants of the cell. Although most of the DNA in cells is STATE OF KUWAIT apportioned among the chromosomes in the nucleus, it has long been known KUWAIT UNIVERSITY, COLLEGE OF SCIENCE that mitochondria also incorporate The Kuwait University College of Science invites applications for posts of small amounts of the genetic material. Professor, AssOCiate Professor and Assistant Professor for the academic year Many investigators consider this fact, 1989/90 tenable September 1, 1989 in the following disciplines: together with certain peculiarities of the mitochondrial genetic code, as evi Dept. of Mathematics: Computer Science. Mathematical ModelIng dence that mitochondria evolved from (The department is interested in promising free-living bacteria that symbiotically holders of a Ph.D. in all speciallzations of Math and Computer Science colonized larger cells hundreds of mil lions of years ago. Dept. of Physics: (Asst. Prof.• Assoc. Prof.) Lasers and their ap Mitochondrial DNA encodes some plIcations (experimental). Modem Optics (ex of the proteins engaged. in oxidative perimental) Laser applIed atomic physics phosphorylation, the primary source spectroscopy (experimental) of cellular energy. Unlike chromoso Dept. of Chemistry: (Asst. Prof.• Assoc. Prof.) Organic mal DNA, mitochondrial DNA is inher chemistry (spectroscopy) ited excluSively from the individual's Dept. of Geology: Crystallography and Mineralogy. mother; fathers do not pass on their Marine Geology mitochondria to their offspring. This unique maternal inheritance pattern Dept. of Zoology: (Prof. or Assoc. Prof.) Biology of Chordates. prompted Wallace and his colleagues Molecular Biology. Marine Biology to speculate that mutations in mito chondrial DNA could be a hidden The language of instruction of the College of Science is English. The meth od cause of disease. T ey decided to of teaching is based on the credit hour system. All applicants must hold a h Ph .D. or its equivalent Monthly salaries are as search for diseases that exhibit mater at the time oj application. fo llows: Professor 1070 - 1230 nal inheritance-that occur in both KD KD Assoc. Prof. (Asst. Prof.) 875 -1035 males and females but are transmitted KD Asst. Prof. (Lecturer) 680 -840 only through females. KD The current exchange rate is 1 (Kuwaiti dinar) = $3 .50 approx. Several rare neuromuscular and KD Annual air passage for appOintee. spouse and up to three children below the neurodegenerative diseases seemed age of twenty. Tuition allowance for children through secondary levelin to fit the pattern. They are typically accordance with University regulations. rather variable and cause metabolic defects and mitochondrial abnormali One month basiC salary gratuity is provided at the end of the contract for ties that lead to the degeneration of each year served. Summer and mid-year paid leave are provided together with muscle or nerve fibers. Often symp fr ee furnishedaccomodation and utilities. There is no income taxin Kuwait. toms do not appear until adulthood. Application formsmay be obtained from: One such disease has now apparently Kuwait University Office been traced to a speCific mutation. It is 3500 International Dr. N.W. Leber's hereditary optic neuropathy, Washington, DC 20008 which among other things causes the All applications together with a non-returnable copy of academiC qualifica optic nerve to degenerate in young tions (including transcripts of graduate programs) . a copy oflast year's adults, leading to blindness. student teaching evaluation of performanceand representative publications In order to trace the illness to its should be sent by registered post directly to: genetic source, Wallace and his col Dean, College of Science laborators employed both genetic P. O. Box 5969 probes and enzymes that cut DNA at 13060 Safat. KUWAlT All applications must be received by November 30. 19 88. specific sites, so that comparisons could be made between individuals afflicted with the neuropathy and indi viduals who were free of the illness. Wallace told colleagues at a recent seminar held at the Jackson laborato ry that his team eventually found a mutation in mitochondrial DNA that was present in nine out of 11 people of various races who had the disease; none of 45 unaffected people showed WE'RE the abnormality. The mutation affects FIGHTING FOR one of the mitochondrial proteins en YOUR LIFE gaged in oxidativephosphorylation. The workers propose that it some how impairs mitochondrial function American t so that the optic nerve is speCifically Heart and progressively damaged. The finding could suggest new ther Association v apies. Wallace is already treating a

~~SCIENTIFIC AMERICAN October 1988 33~~

© 1988 SCIENTIFIC AMERICAN, INC Leber's patient who is not yet blind from a bone-lengthening technique nourishes the bone, suffers damage. with nutrients that bolster mitochon that, although developed in the U.S.S.R By adjusting the rods, the patient or drial function. -T.MB. 40 years ago, was not exported until the physician can in effect stretch the this decade. Named after Gavriel A bone between the rings. The bone may llizarov, the Soviet physician who pio grow in the region of the initial inci neered it, the procedure exploits the sion by as much as one centimeter Making Bones Better ability of bone and soft tissue to grow every 10 days; it takes about twice as A remarkable Soviet method fo r in response to tension. long for the new bone to harden. regenerating bones comes west The Ilizarov procedure begins with a The apparatus is also able to relatively simple operation, according straighten bones, Paley says, much as ntil recently most people suf to Dror Paley of the University of Mary orthodontic braces straighten teeth. fering from bones shortened land School of Medicine at Baltimore, a Of course, wearing the apparatus has Uby accident, genetic abnormal leading practitioner in the U.S. Typical its drawbacks. The wires piercing the ity or disease have had little recourse ly the surgeon first inserts flexible skin sometimes cause infection, and for treatment. The usual method of pins through opposite ends of a bone. the limb being stretched often aches. lengthening a bone, which involves The pins radiate outward through the Victor H. Frankel of the Hospital for cutting it and bolting bone from an flesh and are attached, spokelike, to Joint Diseases Orthopaedic Institute other part of the body or from a do two rings outside the skin. The two in New York maintains, nonetheless, nor into the gap, requires a traumatic rings are in turn connected by rods that the procedure has proved less operation and cannot help many pa whose length is adjustable. The sur traumatic and risky than bone graft tients. Sometimes the new bone fails geon then cuts around the perimeter ing and other forms of major ortho to meld with the old. Moreover, the of the bone at some point between pedic surgery. soft tissue surrounding the bone may the rings. The incision must be deep llizarov and other Soviet and Soviet not be able to accommodate signifi enough so that the bone parts slightly bloc surgeons trained in his technique cant lengthening. when pulled from opposite ends but have done more than 500,000 oper Now some patients may benefit . not so deep that the marrow, which ations over the past few decades and have published extenSively. Why has Western medicine been so slow to adopt the procedure? "The original llizarov's procedure ,requires an operation that is literature was in Russian, and the tech nique was developed in a small city in less traumatic than most major orthopedic surgery western Siberia," notes Frankel, who learned of the llizarov procedure in 1984 and first performed it-on a woman whose leg had been crushed in a car accident-less than two years ago. "Frankly, it seemed a little unbe lievable at first." -].H

~~Bypass Blues The benefits of surgery decrease with time~~

t has been accepted for some time that coronary-bypass surgery can Irelieve the pain of angina and im prove the lives of those who undergo the operation by increasing their toler ance for physical exercise. But does it also extend their lives? There the facts have been less clear. Recent results from a large European study of bypass recipients suggest that the procedure does extend life. The benefits in lon gevity, however, decrease with time, and they apply primarily to those with the severest heart disease. In bypass surgery a vessel (often a portion of the saphenous vein, which runs behind the knee) is joined to an occluded coronary artery, producing a shunt that supplies additional blood to the heart. Questions about this pro cedure are of concern to society as a BONE-LENGTIlENING BRACEdesigned by Gavriel A nizarov is fitted to a patient by whole as well as to individual physi surgeons at the University of Texas Southwestern Medical Center at Dallas. cians and patients. Last year in the U.S.

~~34 SCIENTIFIC AMERICAN October 19 88~~

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© 1988 SCIENTIFIC AMERICAN, INC more than 200,000 bypass procedures were carried out in non-Federal hospi OVERVIEW Use the coupon below tals alone. The recent results, published in the The Bionic Mind New England journal of Medicine, are the latest from the European Coronary Electrodes in the brain may To order Surgery Study, a multicenter trial that someday-aid paralysis victims has been under way since 1973. In the first three years of the study 767 y means of assorted ingenious patients were enrolled and random gadgets, some people paralyzed additional ly assigned to bypass surgery or to Bby disease or by a trauma to the treatment with medication alone. The nervous system can control a comput • patients were tracked continuously er-thereby actuating a wheelchair, a thereafter; some patients have now speech synthesizer or even their ener COpies been followed for 12 years. vated limbs-by swiveling an eye, flex After fiveyears there was a clear ing a tongue or blOwing through a difference between the two groups: 92 straw. Far more accommodating pros percent of the surgical patients were thetic systems may be in the works. If of this still alive, compared with 83 percent the efforts of several somewhat quix of those treated with drugs. The dif otic biomedical engineers bear fruit, ference was highly significant statisti victims of paralysis will someday ex cally. After 12 years, however, the dis ert control over their bodies-and en important parity had become less substantial: 71 vironments-by thinking. percent of surgery patients and 67 Any voluntary action-the closing of percent of those treated with drugs a fist, for example-begins with the remained alive, and the differencewas generation of minute electrical im issue of much less significant in a statisti pulses by neurons in the brain. Leap cal sense. ing from neuron to neuron, these im When the two groups were exam pulses pass through the spinal cord ined in more detail, it became clear and peripheral nerves and finally to SCIENTIFIC that patients with severe disease de the muscles that control the hand, rived the greatest benefits to longevi causing them to contract. If the neural ty. Two signs of severe coronary-artery pathway between the brain and the AMERICAN disease are the narrowing of several hand is severed, the brain's command coronary vessels and the involvement never reaches its destination. Please act promptly - of the left anterior descending coro Workers are now seeking to restore nary artery, one of the main branch the connection between thought and the supply is limited es of the coronary circulation. Those action by developing devices that can signs were found to be the "most pow detect neural commands, either in the SCIENTIFIC AMERICAN erful predictor of benefit from early brain or along the neural pathway, and p.o. Box 3187, Harlan, IA 51593 surgical treatment," according to the transform them into electronic ones. authors of the study. The electronic signals could control Send me __copie s of What accounts for this pattern? In external hardware, perhaps an artifi the October single-topic an editorial in the same issue of the cial gripper; they could also feed back issue devoted to AIDS. New England journal, Thomas Killip of to so-called stimulating electrodes the Beth Israel Medical Center (devel that can induce the paralyzed muscles ___ oper of a widely used scheme for clas to contract and thereby restore some My check for $ Sifying episodes of myocardial infarc function to the limb. is enclosed. tion) concludes that "the important The investigators stress that clinical new information is that surgical re trials of thought-sensing electrodes Prices per copy lief is not necessarily long lasting." are still far off and that their research The reason, Killip continues, is that may not result in practical prosthetic 1-24 ...... $2.95 after surgery the bypass grafts dete systems in this century. Indeed, David 25-49 ...... $2. 25 riorate and atherosclerosis continues J. Edell of the Massachusetts Insti 50-99 ...... $2 .00 to progress in the native arteries. tute of Technology says he tries, in 100 or more ..... $1 .75 When this happens, the answer is describing his work, not to raise the (Above prices U,S, only: Elsewhere, add generally a second bypass operation, a hopes of quadriplegics and other vic $1 ,00 per copy for postage and handling,) procedure that is distinctly riskier tims of neurological disorders. Even ______than the first. For the physiCian, the the most soberly worded reports on Name implication of the current work is that his research, he notes, leave him inun Address ______bypass surgery should be done quick dated by telephone calls and letters, ly on those with severe coronary many from people eager to be re disease but should be reserved un search subjects. "People don't appre til later in more moderate cases. ciate how much fundamental science City ______"The challenge to the clinician," Kil still has to be done," he says. lip concludes, "is to recommend the The biggest challenge consists in State/Zip ______optimal time for bypass surgery, if determining which signals to pick up N8KAOOO indicated." -john Benditt and how to detect them. For most of

~~SCIENTIFIC AMERICANOctober 1988 37~~

© 1988 SCIENTIFIC AMERICAN, INC the past eight years Edell has been bits can control the firing of neurons SCIENTIFIC doing what he calls "nuts and bolts" in their spinal cord. work: searching for nontoxic conduc The question of voluntary control AMERICAN tors that can survive in the warm, salty over neural activity, particularly in the In Other Languages environment of the body for extend brain, is a crucial one. Two related ed periods, establishing how large an questions investigators must face, ac electrode should be to pick up a clear cording to Kensall D. Wise of the Uni signal and determining how close one versity of Michigan, who has been' L.LE 3,50 SCIENZE0/copy L. 35, 000/year L. 45,000/(abroad) Editorial, subscription correspondence: electrode can be to another before working on neural sensors since 1966, Le Scienze S.p.A., Via G. De Alessandri, 11 they detect the same neural signals. are where the electrodes should be 20144 Milano, Italy Advertising correspondence: Recently he and his colleagues have placed and how many neurons they Publietas, S.p.A., Via Cino de Duca, 5, settled on a fork-shaped silicon device must monitor to generate usable com 20122 Milano, Italy whose tines are studded with as many mands. Wise says a single neuron may 'I.t�I�� as 130 electrodes spaced from 25 to not be able to initiate a unique com Y880/copy Y9600/year YI3,000/(abroad) 100 microns apart. Each electrode can mand, since it may take part in more Editorial, subscription, advertising correspondence: Nikkei Science, Inc. detect the firing of a separate neuron. than one mental activity. He points No. 9·5, I·Chome, Otemachi The tines are honed to be extraordi out, moreover, that although earlier Chiyoda·ku, To kyo, Japan narily sharp so that the device can be research has revealed connections be INVESTIGACION Y inserted into tissue without tearing it. tween some regions of the brain and CIENCIA 450 Ptas/copy 4950Ptas/year $35/(abroad) Edell says the device appears to be such functions as vision, hearing and Editorial, subscription, advertising correspondence: compatible with the nervous systems motor activities, investigators still Prensa Cientifica S.A., Calabria, 235·239 of rabbits; it has survived for up to have only a vague concept of how the 08029 Barcelona, Spain two years at a time without damag nervous system initiates and carries ing the surrounding tissue. In one set out actions. SCIENCE of experiments he severed the sciatic The part of the brain that can envi 27FF/copy 26SFF/year 315FF/year (abroad) Editorial, subscription, advertising correspondence: nerves-which control muscles in the sion throwing a ball, Wise adds, is to Pour la Science S.A.R.L., hind leg-of rabbits and attached elec tally separate from the part that initi 8, rue F�rou, 75006 Paris, France trode arrays to the brainward side of ates the muscle contractions needed the nerve. If a rabbit moved or tensed to carry out the act. Thus brain im S�JlYll its leg, the array recorded signals from plants may not allow quadriplegics to 9.80 OM/copy 99 OM/year 112.2 0DM/(abroad) Editorial, subscription correspondence: the severed nerve. These experiments, achieve a speCific feat-activating an Spektrum der Wissenschaft GmbH & Co. Edell says, suggest that an electrode artificial arm, for example-simply by Moenchhofstrasse, IS 0·6900 Heidelberg, array attached to nerves in an ampu envisioning the act. Patients may have Federal Republic of Germany tee's stump might provide signals that to undergo a monitoring period to de Advertising correspondence: Gesellschaft Fur Wirtschaftspublizistik would help him to control an artificial termine what mental activity triggers Kasernenstrasse 67 limb or other prosthetic device. a speCific pattern of pulses; they may 0·4000 Duesseldorf, Federal Republic of Germany Edell suspects it may be easier to then have to learn to control the activi exert mental control over the firingof ty in order to command a prosthetic �q individual neurons in the peripheral device. Wise notes, however, that neu 1.40RMB/copy 16RMB/year $24/(abroad) nerves and even in the spinal cord, ral electrodes should help workers to Editorial, subscription correspondence: ISTIC·Chongqing Branch, P.O. Box 2104, where much "information process map the nervous system and describe Chongqing, People 's Republic of China ing" takes place, than it is in the brain. it more accurately with neural net For people paralyzed from the neck works and other models. This infor B MIIPE HAl'K 1I 2R/copy 24R/year $70/(abroad) down, however, brain implants may be mation in turn should advance the Editorial correspondence: the only answer. work on neural prostheses. MIR Publishers 2, Pervy Rizhsky Pereulok Edell is now undertaking an experi William ]. Heetderks of the National 129820 Moscow U.S.S.R. ment to determine whether a rabbit Institute of Neurological and Commu Subscription correspondence: Victor Kamkio, Inc. can deliberately initiate the firing of nicative Disorders and Stroke neural 12224 Parklawn Drive, a neuron or group of neurons in its prosthesis program, which funds Edell Rockville, MD 20852, USA motor cortex, a region of the brain and Wise, among others, says he has a TUDOMANY that controls physical activity. He has rather simple initial goal in mind for 98 Ft/co\,y 1,176Ft/year 2,100Ft/(abroad) built a box that has an automatic food the research. He hopes that neural Editoria corlespondence: dispenser connected to a light. When sensors-implanted in the motor cor TUDOMANY H ·1536 Budapest, Pf 338 the light goes on, food enters the tex, perhaps, and linked to stimulat Hungary Subscription correspondence: box-but only if the rabbit does a ing electrodes attached to peripheral "KULTURA" certain physical task The trick, for the nerves-may enable a quadriplegic to H·3891 Budapest, PI. 149 Hungary rabbit, is to figure out what the task is. control a single hand. In the distant The rabbits have previously learned to future, he adds, brain implants may perform such tasks as blocking the even be able to restore memory or f�\ light with their nose (thereby blocking cognitive function lost as a result of Il

~~38 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC Repligen. scientists are working around the clock to transform our knowledge of the AIDS virus into a vaccine. And the scientists we're working with in the private, government, and academic sectors are among the best in the field. Its these partnerships that make us believe we'll be the company to develop the AIDS vaccine. And hopefully, we'll do it in time to save thousands of lives .

~~RepliGen Repligen Corp., Cambridge, MA~~

© 1988 SCIENTIFIC AMERICAN, INC NEW AIDS-VIRUS PARTICLES burst from a thin tube called a Karolinska Institute in Stockholm. (The colors are artificial.) microvillus extending from the surface of an infected cell in The virus, which is now called the human immunodeficiency culture. The micrograph, which has an enlargement of more virus (HIV), belongs to the category called retroviruses. It was than 500,000 diameters, was made by Lennart Nilsson of the discovered and linked to AIDSby the authors of this article.

~~40 SCIENTIFIC AMERICAN October 1988~~

~~AMERICAN October 1988 Volume 259 Number 4~~

~~• AIDS In 1988~~

In their first collaborative article the investigators who discovered HIV introduce a single-topic issue on AIDS. They recount the discovery and offer prospects for vaccine, for therapy and for the epidemic

~~by Robert C. Gallo and Luc Montagnier~~

recently as a decade ago it was sue of Scientific American have set out pothesis that the retroviral life cycle widely believed that infectious to answer. includes an intermediate DNA form, A disease was no longer much of Like other viruses,retroviruses can which Temin had called the provirus. a threat in the developed world. The not replicate-without taking over the The details of viral replication quickly remaining challenges to public health biosynthetic apparatus of a cell and fell into place. there, it was thought, stemmed from exploiting it for their ownends. What In spite of such discoveries, by the noninfectious conditions such as can is unique about retroviruses is their mid-1970's no infectious retroviruses cer, heart disease and degenerative capacity to reverse the ordinary flow had been found in human beings, and diseases. That confidence was shat of genetic information-from DNA to many investigators firmlybelieved tered in the early 1980's by the advent RNA to proteins (which are the cell's no human retrovirus would ever be of AIDS. Here was a devastating dis structural and functional molecules). found. Their skepticism had several ease caused by a class of infectious The genetic material of a retrovirus is grounds. Many excellent scientists agents-retroviruses-that had first RNA In addition, the retrovirus carries had tried and failed to find such a been found in human beings only a an enzyme called reverse transcript virus. Moreover, most animal retrovi few years before. In spite of the star ase, which can use the viral RNA as a ruses had been fairly easy to find, tling nature of the epidemic, science template for making DNA The viral because they replicated in large quan responded quickly. In the two years DNA can integrate itself into the ge tities, and the new virus particles were from mid-1982 to mid-1984 the out nome (the complement of genetic in readily observed in the electron mi lines of the epidemic were clarified, a formation) of the host. Having made croscope; no such phenomenon had new virus-the human immunodefi itself at home among the host's genes, been found in human beings. In spite ciency virus (HN)-was isolated and the viral DNA remains latent until it of this skepticism, by 1980 a pro shown to cause the disease, a blood is activated to make new virus par longed team effortled by one of us test was formulated and the virus's ticles. The latent DNA can also initi (Gallo) paid off in the isolation of the targets in the body were established. ate the process that leads to tumor first human retrovirus: human T-lym Following that initial burst, progress formation. photropic virus type I (HJLV-I). has been steady, albeit slower. Yet in HTLV-I infects Tlymphocytes, white some respects the virus has outpaced etroviruses and their cancer blood cells that have a central role in science. No cure or vaccine is yet avail causing potential are not new the immune response. The virus caus able, and the epidemic continues to Rto science. At the beginning of es a rare, highly malignant cancer spread; disease-causing retroviruses this century several investigators iden called adult T-cell leukemia (ATL) that will be among the human population tified transmissible agents in animals is endemic in parts of Japan, Africa for a long time. In view of that pros that were capable of causing leuke and the Caribbean but is spreading pect, it is essential to ask where mias (cancers of blood cells) as well to other regions as well. Two years af- we stand in relation to AIDS in 1988. as solid-tissue tumors. In the succeed How was HN discovered and linked ing decades retroviruses were identi ROBERT C. GAllO and LUC MONTA to AIDS?How does the virus cause fied in many animal species. Yet the GNIER are the investigators who estab its devastation? What are the chances life cycle of retroviruses remained ob lished the cause of AIDS.Gallo is chief that AIDS will spread rapidly outside scure until 1970, when Howard M. of the Laboratory of Tumor Cell Biology the known high-risk groups? What are Temin of the University of Wisconsin at the National Cancer Institute. Mon tagnier is professor of virology at the the prospects for a vaccine? For thera at Madison and (independently) David Pasteur Institute in Paris and director of py? How can the epidemic most effec Baltimore of the Massachusetts Insti research at the French National Center tively be fought? Those are some of tute of Technology discovered reverse for Scientific Research (CNRS). the questions this article and this is- transcriptase, confirming Temin's hy-

~~SCIENTIFIC AMERICANOctober 1988 41~~

© 1988 SCIENTIFIC AMERICAN, INC ter the discovery of HlLV-I the same sible. however. to explain a new syn France. The members of the French group isolated its close relative. HlLV drome by the appearance of a new group wanted to test that hypothesis. II. HlLV-II probably causes some cases infectious agent. and they had the biological materials of a disease called hairy-cell leukemia to do so. because the. group included as well as T-cell leukemias and lym o one of us (Gallo) the likeliest clinicians with patients afflicted by phomas of a more chronic type than agent was a retrovirus. It had AIDS or pre-AIDS. What they lacked. those linked to HlLV-I. The two virus Talready been shown that the however. was the collaboration of vi es. however. share some crucial fea AIDS pathogen. like HlLV-I. could be rologists experienced in work with tures. They are spread by blood. by transmitted by sexual intercourse and retroviruses. sexual intercourse and from mother by blood. Furthermore. Max Essex of The French author of this article and to child. Both cause disease after a the Harvard School of Public Health his colleagues Frant;oise Barre-Sinous long latency. and both infect T lym had shown that a retrovirus of cats si and Jean-Claude Chermann at the phocytes. When AIDS was firstrecog called feline leukemia virus (FeLV) Pasteur Institute fittedthat descrip nized. these properties took on great could cause either cancer or immune tion. They were engaged in several additional significance. suppression. Since in most species the lines of work on cancer and interferon. The first AIDS cases were diagnosed infectious retroviruses are closely re including attempts to find retrovirus in 1981 among young homosexual lated. it seemed plausible that the es in patients with cancer. particular men in the U.S. [see "The Epidemiology same was true in human beings. Hence ly in cultures of lymphocytes. A mem .. of AIDS in the U.S.. by William L. Hey the initial hypothesis was that the ber of the working group. Willy Ro ward and James W. Curran. page 72]. cause of AIDS was a close relative of zenbaum of the Salpetriere Hospital. Although the syndrome was puzzling. HlLV-I. That hypothesis. as it turned asked whether they were interested in it soon became clear that all its vic out. was wrong. Nonetheless. it was analyzing tissues from a patient with tims suffered from a depletion of a fruitful. because it stimulated the lymphadenopathy. or swollen glands. specific subset of T cells-T4 cells search that led to the correct solution. (Lymphadenopathy can be an early and that as a result they fell prey to The retrovirus hypothesis for the sign of the process that culminates in pathogens that would easily be con origin of AIDS reached the other one of AIDS. Such a patient was chosen be trolled by a healthy immune system us in France in the following way. cause finding a virus early in the dis [see "HIVlnfection: The Clinical Pic Almost as soon as AIDSwas first diag ease seemed more meaningful than ture." by Robert R Redfield and Don nosed. a working group on the syn finding one later. when AIDS patients ald S. Burke, page 90]. A variety of drome had been formed by a circle of were infected with many opportunis hypotheses were advanced to explain young clinicians and researchers in tic agents.) The answer was yes. and AIDS. including breakdown of the vic France. One member of the group. in January. 1983. a specimen from tims' immune systems following re Jacques Leibowitch of the Raymond the swollen lymph node of a young peated exposure to foreign proteins Poincare Hospital in Paris. had had homosexual arrived at Montagnier's or even to sperm-during homosex some contact with Gallo's team and laboratory. ual intercourse. It seemed more plau- carried the HlLV hypothesis back to The specimen was minced. put into tissue culture and analyzed for re verse transcriptase. After two weeks of culture. reverse-transcriptase ac tivity was detected in the culture me dium. A retrovirus was present. But which one? The first possibility that had to be tested was whether the virus was one of the known HlLV·s. or per haps a close relative of them. That possibility was tested using specific HlLV-I reagents supplied by Gallo. The virus did not react significantly with the HlLV-I reagents; a similar result was later obtained with HlLV-Il rea gents. A strenuous effort was begun to characterize the new agent. Among the first results of that effort was the finding that the new virus (which was named lymphadenopathy associated virus. or LAV) grew in T4 cells but not in related cells called T8; that finding was made by David Klatz mann and Jean-Claude Gluckman of the Salpetriere Hospital in collabora tion with the Pasteur group. It was shown that the virus could kill T4 cells or inhibit their growth. Electron micro HIV VIRION. or particle. is a sphere 1.000 angstrom units (one ten-thousandth of a millimeter) across. The sphere contains a core that holds the virus's genetic material: graphs of the new virus were different RNA The core is a truncated cone; from the end it appears as a disk. The virion is from those of HlLV-I and resembled wrapped in a membrane like that of a cell. from which protein "knobs" extend. The those of a retrovirus of horses. A viral knobs are faintly visible in the micrograph. which has an enlargement of 200.000 protein called P25 (or P24) that is not diameters and was made by Hans Gelderblom of the Robert Koch Institute in Berlin. present in HlLV-I was identified. In

~~42 SCIENTIFIC AMERICAN October 1988~~

~~LIPID BILAYER~~

VIRION STRUCTURE is shown in cross section. The knobs consist of a protein called gp 120, which is anchored to an· other protein called gp4 1. Each knob in cludes three sets of protein molecules (box at left). The virus's core includes a protein called p25 or p24. In the core, along with the RNA that carries the vi rus's genetic information, is an enzyme known as reverse transcriptase. Reverse transcriptase enables the virus to make DNA corresponding to the viral RNA. The DNA inserts itself into the host cell's chromosomes and remains latent until it is activated to make new virus particles.

~~SCIENTIFIC AMERICAN October 1988 43~~

© 1988 SCIENTIFIC AMERICAN, INC collaboration withvirologists from stemmed partly from the fact that it was shown that 48 isolates obtained the Claude Bernard Hospital a blood among people infected with HIV are beginning in early 1983 from AIDS pa test for lAY antibodies was formulat some who are also infected with the tients and people in risk groups were ed. Several examples of lAYor lAV HTIV's. Moreover, only a minority all the same type of virus, which was like viruses were isolated from homo albeit a substantial one-of AIDSpa called HTIV -III on the American side. A sexual men, hemophiliacs and central tients had shown serological evidence blood test was formulated and used to Africans. of lAY infection. In addition, when it show that HTIV-III was present in al Early results of applying the blood was first isolated, lAY could not be most all people with AIDS, in a variable test were suggestive but not fully con grown in large amounts in continuous proportion of people at risk of the clusive. lA V antibodies were found in cell lines. Without large quantities of disease (including people who had a large fraction of lymphadenopathy virus it was difficult to prepare specif received blood contaminated by the patients but in only a minority of AIDS ic lAY reagents that could be used to virus but had no other risk factors) patients. Yet the proportion increased show that all people with AIDS or pre and in no healthy heterosexuals. The as the sensitivity of the test improved. AIDS were infected by the same type cause of AIDS had been conclUSively By October, 1983, it had reached 40 of virus. established. percent. At that point one of us (Mon Therefore on the American side These results confirmed and ex tagnier) was convinced lA V was the much effort was concentrated on tended the ones from France. lA V and best candidate for the cause of AIDS. grOwing the pathogen from the blood HTIV-III were soon shown to be the of AIDS patients in mass, continuous same virus. Before long an interna o the other one of us the evi culture. By the end of 1983 that task tional commission had changed its dence did not seem so clear. For had been accomplished by the Gallo . name to HIV, to eliminate confusion Tone thing, results had been ob team: several cell lines had been iden caused by two names for the same tained (by Gallo and Essex) indicating tified that could support the growth of entity and to acknowledge that the that some AIDS patients are infected the new agent. The first reagents for virus does indeed cause AIDS. Thus with HTIV-I or a variant of that virus. speCifically typing this virus were rap contributions from our laboratories It is now known that those results idly made. Employing those reagents, in roughly equal proportions-had demonstrated that the cause of AIDS is a new human retrovirus. TYPE OF EVIDENCE DESCRIPTION That HIV is the cause of AIDS is by now firmly established. The evidence ANIMAL SYSTEMS Several types of retroviruses can cause severe for causation includes the fact that immune deficiencies in animals. For example, the feline leukemia virus (FeLV) can cause either HIV is a new pathogen, fulfilling the immune deficiency or cancer, depending on original postulate of "new disease, slight genetic variations in the virus. new agent." In addition, although the original tests found evidence of HIV A virus related to HIV, the simian immunodeficiency virus (SIV), can cause AIDS in macaque infection in only a fraction of people monkeys_ The second AIDS virus, HIV-2, may also with AIDS, newer and more sensitive cause AIDS in macaques. methods make it possible to find such evidence in almost every individu EPIDEMIOLOGY In every country studied so far, AIDS has ap- al with AIDS or pre-AIDS. Studies of peared only after the appearance of HIV. blood-transfusion recipients indicate Using the most recent technology, HIV can be that people exposed to HIV who have isolated from almost 100 percent of the people no other risk factors develop AIDS. The with AIDS_ I epidemiological evidence shows that in every country studied so far AIDS Earlier in the epidemic, the virus was present I in the groups at risk for the disease and in al- has appeared only after HIV. What is most no healthy heterosexuals_ more, HIVinfects and kills the very T4 cells that are depleted in AIDS. Al BLOOD-TRANSFUSION DATA A study of people who received blood transfu- though the causative role of HIV in sions in 1982-83 (when the fraction of blood AIDS has been questioned, to us it donors infected with HIV was about 1 in 2,000) seems clear that the cause of AIDS is as showed that of 28 people who got AIDS, the v-i- I well established as that of any other rus could be found in all 28. Furthermore, for I each recipient who got AIDS an infected donor human disease. could be found_ Today most of those infected Soon after the causation was estab donors have also developed AIDS. lished, a series of findingsbegan to Elimination of HIV in blood transfusions by an- fill in the scientific picture of HIV. In tibody screening has drastically reduced the a remarkably short time the genetic number of AIDS cases reSUlting from transfu- material of the virus was cloned and sions.

_._----- sequenced (in our laboratories and several others). The genetic complexi TEST-TUBE STUDIES In the laboratory the virus kills the very T4 cells whose depletion is the hallmark of AIDS. It ty of HIV began to emerge when a gene also infects and alters the function of cells of the I called TAT was discovered by William monocyte-macrophage lineage, which may serve A Haseltine of the Dana-Farber Cancer as a reservoir of infection in AIDS patients. Institute, Flossie Wong-Staal of the Na I tional Cancer Institute and their col EVIDENCE TIIAT HIVCAUSES AIDS is by now as firm as that for the causation of any laborators [see "The Molecular Biology other human disease. As the table shows, the supporting data come from a range of of the AIDS Virus," by William A Ha sources, including epidemiology, analysis of blood-serum samples and cell biology. seltine and Flossie Wong-Staal. page

~~44 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC MAIN TARGETSOF mv are two white blood cells: the lympho depletion of the T4 population. Unlike T4 cells, the macro cyte and the macrophage_ A lymphocyte is shown at the left phage is not killed by HIV. It may serve as a reservoir for tbe and a macrophage at the right_ In particular, a subset of lym virus. The macrophage may also carry mv to the brain, there phocytes called T4 cells are infected; the hallmark of AIDSis a by accounting for the nervous-system pathology seen in AIDS.

52]. Such complexity is significant be Several additional findings rounded of the original AIDS virus but a new cause it underlies the capacity of HIV out the early discoveries. The poten virus designated HN-2. Soon a second to remain latent for a long period, . tial of the epidemic to spread beyond example was isolated by workers at then undergo a burst of replication, a the original risk groups was shown the Claude Bernard Hospital; many pattern that may hold the key to the when Robert R. Redfield and one of us others followed. pathology of AIDS. (Gallo) demonstrated that HIV can be In evolutionary terms HIV-2 is clear There were other significant early transmitted during heterosexual in ly related to HIV-1, the virus responSi findings. One of us (Gallo), with his tercourse. Members of the Gallo team ble for the main AIDS epidemic. The colleagues MikulasPopovic and Su also showed that the genetic makeup two viruses are similar in their overall zanne Gartner, showed that HIV could of the virus is highly variable from structure and both can cause AIDS, infect not only the T4 cell but also strain to strain, a fact that may com although the pathogenic potential of another type of white blood cell, the plicate the attempt to formulate an HN-2 is not as well established as that macrophage. The same one of us, AIDS vaccine. of the first AIDS virus. HN-2 is found working with his colleagues Beatrice After the rapid initial advance the mainly in West Africa, whereas HN-1 is H. Hahn, George M. Shaw and Wong pace slowed somewhat and began to concentrated in central Africa and oth Staal, found HIV in brain tissues. It approximate that of a more mature er regions of the world. The finding of seems possible that the macrophage, area of research. Yet the continuing HIV-2 suggests that other undiscov which can cross the blood-brain bar work was not without surprises. In ered HIVs may exist, filling out a spec rier, may bring virus into the brain, October, 1985, one of us (Montagnier) trum of related pathogens. explaining the central-nervous-system was engaged in analyzing blood sam The isolation of HN-2 immediate pathology seen in many AIDS patients. ples brought to his laboratory by a ly raises the question of the evolution visiting investigator from Portugal. ary origins of these viruses[see "The ow the virus infects both T4 Many of the samples were from people Origins of the AIDS Virus," by Max cells and macro phages became who had lived in Guinea-Bissau, a for Essex and Phyllis]. Kanki, page 64]. Al Hclear when Robin A Weiss of mer Portuguese colony in West Africa. though the answer to that question the Chester Beatty Laboratories and, Among them were some people who has not been found, some hints have independently, Klatzmann and the had been diagnosed by Portuguese cli been providedby the discovery in oth Pasteur group showed that HN enters nicians and investigators as having er primate species of related virus its target cells by interacting with the AIDS in spite of the fact that their es called simian immunodeficiency molecule called CD4 [see "HIV Infec blood showed no sign of HN infection. viruses (SN's). The first such virus, tion: The Cellular Picture," by Jonathan One sample, in fact, was negative found in the macaque monkey, is des N. Weber and RobinA Weiss, page 100]. for HN using the most sophisticated ignated SN macaque. Isolated and CD4 has a significant role in the im techniques available at the time. Yet characterized by Ronald C. Desrosiers mune function of T4 lymphocytes and workers in the laboratory were able and his co-workers at the New England also serves as a marker for that group to isolate a virus from the patient's Regional Primate Research Center in of cells. The early work by the British blood. DNA "probes" (short pieces of collaboration with Essex and his col and French teams showed that HN DNA from the HIV genome) were then league PhylliS ]. Kanki, SN macaque infects cells by binding to CD4. Hence prepared. If the new virus were close has been shown to be closely related only cells bearing that marker can be ly related to the original AIDS agent, to HIV-2, raising the possibility that infected. (Although CD4 is the mark those probes would bind to its genetic HIV-2 may have come into human be er for the T4 cells, it is also found in material. As it turned out, there was ings relatively recently from another smaller numbers on some macrophag little binding, and it became clear that primate species. es, allowing them to be infected.) the new isolate was not simply a strain No such close simian relative has

~~SCIENTIFIC AMERICAN October 1988 45~~

© 1988 SCIENTIFIC AMERICAN, INC SURFACE·REPUCA PREPARATION reproduces an infected cell acid, washed and examined in the electron microscope. The and HIV particles. Such a preparation is made by dehydrating virus is distributed at the periphery of the cell and as free the cell, freeze·drying it and applying thin layers of platinum particles. The micrograph, which has a magnification of 40,000 and carbon to its surface. The resulting replica is cleaned with diameters, was made by Gelderblom's colleague Muhsin Ozel.

~~46 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC been found for HN-1 (although the sponses, in which the immune system panic? The answer is no, for several right group of primates may not yet attacks the body's own tissues, may reasons. The most obvious is that pan have been studied in sufficient detail). also be at work. What is more, HIV ic does no good. The second reason is Hence the origin of HN-1 remains infected cells may send out protein that it now seems unlikely HIV infec more mysterious than the origin of signals that weaken or destroy other tion will spread as rapidly outside the its relative HN-2. It is likely, however, cells of the immune system. In addi original high-risk groups in the indus that HN-1 has been in human be tion HN is fragile, and as the virus trial countries as it has within them. A ings for some time. One of us (Gallo), particle leaves its host cell, a molecule third reason is that this disease is not with Temin, has used the divergence called gp120 frequently falls off the beyond the curative power of science. among HN strains and the virus's virus's outer coat. As Dani P. Bolognesi Although current knowledge is imper probable rate of mutation to estimate of the Duke University Medical Center fect, it is sufficient to provide confi how long the virus has infected peo and his co-workers have shown, gp120 dence that effective therapies and a ple. It was tentatively concluded that can bind to the CD4 molecules of un vaccine will be developed. HN has infected human beings for infected cells. When that complex is The possibilities for therapy are par more than 20 years but less than 100, recognized by the immune system, ticularly impressive [see "AIDS Thera an estimate compatible with those by cells thus marked may be destroyed. pies," by Robert Yarchoan, Hiroaki Mit other workers and with our knowledge That list does not exhaust the pOSSi suya and Samuel Broder, page 110]. In of the epidemic. bilities. One of us (Montagnier) is ex the first phase of the search for AIDS ploring the possibility that the binding therapies it was necessary to exploit here was HN hiding all those of the virus to its target cells triggers any drug that seemed to provide even years, and why are we only the release of enzymes called proteas a remote chance of combating HIV Wnow experiencing an epidem es. Proteases digest proteins, and if infection. A variety of compounds for ic? Both of us think the answer is that they were released in abnormal quan mulated for other purposes were tak the virus has been present in small, tities, they might weaken white blood en off the shelf and tested. Most were isolated groups in central Africa or cells and shorten their lives. The vari of little value, but one (AZT), original elsewhere for many years. In such ous proposed mechanisms are not ex ly formulated as an anticancer drug, groups the spread of HN might have clusive, and several may operate at turned out to be the first effective been quite limited and the groups once. Yet one is probably central, and anti-AIDS agent. More recently, an ex themselves may have had little con some of the most significant work on perimental regimen in which AZT is tact with the outside world. As a result AIDS is that of distinguishing the cen alternated with the related compound the virus could have been contained tral mechanism from the peripheral known as dideoxycytidine offers even for decades. ones that accompany it. greater promise. That pattern may have been altered Although it is clear that a large when the way of life in central Afri enough dose of the right strain of ringing AZT into clinical use was ca began to change. People migrating HN can cause AIDS on its own, cofac a significant accomplishment, from remote areas to urban centers no tors can clearly influence the progres Bbecause it gave hope that AIDS doubt brought HN with them. Sexual sion of the disease. People whose im would not remain incurable forever. mores in the city were different from mune systems are weakened before As a form of therapy, however, AZT is what they had been in the village, and HN infection may progress toward not perfect and will probably be sup blood transfusions were commoner. AIDS more quickly than others; stimu planted by less toxic agents formulat Consequently HN may have spread lation of the immune system in re ed on the basis of what is known about freely. Once a pool of infected people sponse to later infections may also the HIV life cycle. One promising agent had been established, transport net hasten disease progression. is CD4, the molecule that serves as works and the generalized exchange Interaction with other pathogens the viral receptor. Early tests show of blood products would have carried may also increase the likelihood that that soluble CD4 can bind to the virus it to every corner of the world. What AIDS will develop. Specifically, a her and prevent it from infecting new had been remote and rare became pes virus called human B-cell lympho cells. Many other drugs are in trials; global and common [see 'The Interna tropic virus (HBL V) or human herpes one of them, perhaps combined with tional Epidemiology of AIDS,"by Jona virus 6 (HHV-6) that was discovered in compounds that bolster the immune than M. Mann, James Chin, Peter Piot the laboratory of one of us (Gallo) can system, may provide therapy for HIV and Thomas Quinn, page 82]. interact with HN in a way that may infection. What weapons are available against increase the severity of HN infection. In asseSSing the progress that has this scourge? Perhaps the best weap Ordinarily HHV-6 is easily controlled been made toward achieving fully ef on is knowledge. One key form of by the immune system. In a person fective AIDS therapy, it must be kept in knowledge is a deeper understanding whose immune system is impaired mind that this work has two facets. In of HN, its life cycle and the mecha by HN, however, HHV-6may repli addition to combating a complex and nisms by which it causes disease. Al cate more freely, becoming a threat evasive pathogen, it must pioneer though HN kills T4 cells directly, it has to health. In addition, although one of entirely new areas of medicine. The become clear that the direct killing of the main hosts of HHV-6 is a white reason is that there are few effective those cells is not sufficient to explain blood cell called the B cell, the virus treatments for viral diseases-and al the depletion seen in AIDS. Indirect , can also infect T41ymphocytes. If the T most none for retroviruses. There are mechanisms must also be at work. cell is simultaneously infected by HN, various reasons for this, among them What are they? HHV-6 can activate the latent AIDS the fact that viruses (unlike bacteria, Many possibilities have been sug virus, further impairing the immune for which effective therapies exist) al gested. Infection by HIV can cause in system and worsening the cycle. ways appropriate the biosynthetic ap fected and uninfected cells to fuse Clearly, in spite of rapid progress paratus of the host cell. As a result into giant cells called syncytia, which there are many gaps in our under drugs effectiveagainst viruses tend to are not functional. Autoimmune re- standing of HN and AIDS. Should we damage mammalian cells. Yet we are

~~SCIENTIFIC AMERICAN October 1988 47~~

© 1988 SCIENTIFIC AMERICAN, INC of transmission has been practically eliminated in the industrial countries. To help change this situation the World AIDS Foundation has made im proving the situation in central Afri ca its highest priority. The founda tion (along with its parent, the Fran co-American AIDS Foundation) was formed as part of the agreement that resolved a lawsuit between France and the U.S. over the AIDS blood test. The parent foundation receives 80 percent of the royalties from the French and American blood tests; the World AIDS Foundation in turn receives 25 per cent of that. Much thought has been given to how to allocate the funds, and the firstproject (carried out in con junction with the World Health Orga nization) will be realized in several Af rican countries. It will include train ing technicians to perform blood tests, establishing one HlV-free blood center mv PARTICLES COVER AN INFECTEDCELL in culture. A central problem in obtaining and increasing public education about specific reagents for establishing the cause of AIDSwas that of getting mv to grow HIV transmission. in continuous mass culture. The problem was first solved in Gallo's laboratory with Efforts such as this one, coupling a cell line designated H9. An H9 cell is shown, magnified about 10,000 diameters. public and private funds and energies, The small bumps at the center are mv particles. The micrograph was made by Ozel. will be essential to stopping AIDS. As we stated above, both of us are certain that science will ultimately find a cure confident that the dual goals of pio· the spread of HlV infection, as there and a vaccine for AIDS. But not tomor neering science and clinical effective· has been in some groups in the devel· row. The AIDSvirus (and other human ness will be met. oped world. The lesson here is that retroviruses) will be with us for a long What is true of therapy is also true there is a need for education about time. During that time no intelligent of vaccines: an AIDS vaccine will be a HIV infection-in clear, explicit Ian· person can expect the necessary solu pioneering scientific achievement [see guage and as early as possible. tions to come solely from authorities "AIDS Vaccines," by Thomas j. Mat· Yet there are parts of the epidemic such as scientists, governments or thews and Dani P. Bolognesi, page 120]. where education alone is not suffi corporations. All of us must accept Since the HIV genome has the capacity cient, and it is in those areas that responsibilities: to learn how HIV is to integrate into the chromosomes of humanity will be tested. Users of intra· spread, to reduce risky behavior, to the host cell, little serious considera· venous drugs, for example, are noto· raise our voices against acceptance tion has been given to using prepara· riously resistant to educational cam· of the drug culture and to avoid stig tions containing the whole virus as a paigns alone. It seems clear that the matizing victimsof the disease. If vaccine. AnAIDS vaccine must consist effort to control AIDS must be aimed we can accept such responsibilities, of subunits, or parts, of the virus in in part at eradicating the conditions the worst element of nightmare will the right combination. Yet experience that give rise to drug addiction. Those have been removed from the AIDS with subunit vaccines is slight. Indeed, conditions are in turn linked to so· epidemic. so far only a few subunit vaccines have cial and economic patterns. Eliminat· proved practical. Much work is under ing the disease may entail eliminating way to find the combination of HIV some of the social differentialsthat FURlHER READING ISOLATION OF A T-LYMPHOTROPIC RETRO subunits that will yield the greatest form the substratum of drug abuse VIRUS FROM A PATIENT AT RISK FOR protective response. As in the case of [see "The Social Dimensions of AIDS," ACQUIRED IMMUNE DEFICIENCY SYN therapy, we believe there will be a by Harvey V. Fineberg, page 128]. DROME (AIDS). F. Barre-Sinoussi et al. practical vaccine against HIV. in Science, Vol. 220, No. 4599, pages Perhaps an even more persuasive t is also the case that in some areas 868-871; May 20, 1983. reason for hope is that even without of the developing world education ISOLATION OF A NEW HUMAN RETROVI RUS FROM WEST PATIENTS WITH a vaccine or a cure, what is already Ialone will not stem the epidemic. AFRICAN AIDS. Fran�ois Clavel et al. in SCience, known could bring the epidemic un· Education is necessary, but it must be Vol.233, No.4761, pages 343-346; July der control. The blood supply has accompanied by other measures. In 18, 1986. already been largely secured by the central Africa-the part of the world THE FIRST HUMAN RETROVIRUS. Robert C. presence of a blood test. Moreover, the most beleaguered by AIDs-thereare Gallo in Scientific American, Vol. 255, modes of transmission of HIV-blood, few facilities for blood testing and few No.6, pages 88-98; December, 1986. sexual intercourse and from mother technicians trained to perform tests. THE AIDS VIRUS. Robert C.Gallo in Scien to child-are firmly established. Hence Furthermore, the blood tests used in tific American, Vol. 256, No. 1, pages any individual can drastically reduce the U.S. and Western Europe are too 46-56; January, 1987. COMMENTARY: THE CHRONOLOGY OF his or her risk of infection. If such expensive to be helpful. As a result the AIDS RESEARCH. In Nature, Vol.326, No. knowledge were applied everywhere, virus is still being spread by contam 6112, pages 435-436; April 2, 1987. there would be a sharp leveling off in inated blood, long after that form

~~48 SCIENTIFIC AMERICANOctober 1988~~

It started out as a trip across town. transfusion to our medical pro But perhaps the most important Suddenly, you're in an ambulance rac cedures. It's vital. weapon in fighting this disease is in ing to the hospital. It's an emergency. Which is why Du Pont worked to formation. To that end Du Pont has A matter of life and death. You've lost create a highly accurate method of created a booklet, Understanding AIDS. blood. The doctors tell you that testing to help protect the nation's It separates facts from myths and you're going to need a transfusion. b!ood supply from the deadly AIDS explains the real risks. Now, you're really scared. ViruS. At Du Pont, we make the things The AIDS virus has changed the Today, that testing system serves that make a difference. way we think about transfusions. It's over 1,200 hospitals in more than 20 To receive a complimentary copy made us cautious. What hasn't states , helping millions of people feel of Understanding AIDS, call toll-free: changed is the importance of the more secure that the blood they may 800-441-7515. one day need to live won't be haz ardous to their health.

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© 1988 SCIENTIFIC AMERICAN, INC The Molecular Biology of the AIDS Virus HIV is genetically complex. An array of regulatory genes enables it to remain latent or replicate at various rates. This intricate control may underlie key features of the disease

~~by William A Haseltine and Flossie Wong-Staal~~

nfection with the AIDSvirus takes Underlying this variable course are first transcribed into messenger RNA many guises. First the virus (the complex interactions between HIV and (mRNA), which then serves as the tem human immunodeficiency virus, or its host cells. The virus behaves differ plate for the production of proteins. HIV)I often replicates abundantly, and ently depending on the kind of host The genes of a retrovirus are encoded free virus appears in the fluid sur cell and the cell's own level of activity. in RNA; before they can be expressed rounding the brain and spinal cord In T cells it can lie dormant indefinite the RNA must be converted into DNA and in the bloodstream. Fevers, rash ly, inextricable from the cell but hid Only then are the viral genes tran es, flulike symptoms and sometimes den from the victim's immune system; scribed and translated intb proteins in neurological complaints can accompa when the same cells are stimulated, the usual sequence. ny this first wave of HIV replication. however, it can destroy them in a burst The cycle begins when an HIV parti Then, within a few weeks, the amount of replication. In other cells, such as cle binds to the outside of a cell and of virus in the circulation and the the immune-system cells called mac injects its core. The core includes two cerebrospinal fluid drops precipitous rophages and their precursors, called identical strands of RNA as well as ly and the initial symptoms disappear. monocytes, the virus grows continu structural proteins and enzymes that Yet the virus is still present; it can be ously but slowly, sparing the cell but carry out later steps in the life cycle. found not only in the T4 lymphocytes, probably altering its function. One enzyme is responsible for con the subset of immune-system cells What accounts for this diverse be verting the viral genetic information originally thought to be its only target, havior and its destructive conse into DNA This DNA polymerase first but also in other classes of immune quences? The answer is to be found in makes a single-strand DNA copy of the cells, in cells of the nervous system the life cycle of the virus, and in the viral RNA An associated enzyme, ribo and intestine and probably in some tiny package of genetic instructions nuclease, destroys the original RNA, bone-marrow cells. From two to 10 that controls it. The genetic blueprint and the polymerase makes a second years after the start of this asympto for the structure and life cycle of HIV DNA copy, using the first one as a matic period, replication of the virus is about 100,000 times smaller than template. (The polymerase and the ri flares again and the infection enters the genetic information of a human bonuclease together are often called its final stage. cell: a mere 9,749 nucleotides (the reverse transcriptase.) units that encode information along The viral genetic information, now the genetic material). Since 1984, in the form of double-strand DNA (the hoids appoint Wll11AM AHASELTINE when HIV became available in a work same form in which the cell carries its ments at the Dana-Farber Cancer Insti able form, the full power of contempo own genes), migrates to the cell nucle tute, the Harvard Medical School and rary molecular biology and genetic the Harvard School of Public Health. He us. A third viral enzyme, called an received his doctorate in biophysics analysis has been turned on this scrap integrase, may then splice the HIV ge from Harvard and became interested in of genetic information. The past four nome-its full complement of genetic retroviruses in 1972 as a postdoctoral years have been full of surprises. HIV information-into the host cell's DNA student at the Massachusetts Institute governs its life cycle in novel and un Once there the viral DNA (the "provi of Technology. Haseltine's current re foreseen ways, and their study may rus") will be duplicated together with search concerns retroviruses in leuke hold the key not only to the control of the cell's own genes every time the cell mia, disorders of the central nervous AIDSbut also to a clearer understand divides. Thus established, infection is system and AIDS.FLOSSIE WONG-STAAL is head of the section on the molecular ing of how cells regulate their own permanent. genetics of hematopoietic cells at the growth and activity. The second half of the viral life cy National Cancer Institute. She holds a cle-the production of new virus par Ph.D. in molecular biology from the Uni n broadest outline the life cycle of ticles-takes place only sporadically, versity of California at Los Angeles. Af HIV is that of a retrovirus. Retro and only in some infected cells. It NCI ter joining the in 1973, she became viruses were so named because begins when nucleotide sequences in interested in the role of retroviruses theyI reverse what seemed to be the the so-called long terminal repeats and oncogenes in disease-an interest (LTR'S), she pursued as the first human retrovi normal flow of genetic information. which are stretches of DNA ruses were discovered. In cells the genetic material is DNA; at the ends of the viral genome, di when genes are expressed, the DNA is rect enzymes belonging to the host

~~52 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC CULMINATION of HIV's life cycle is the production of new cell.) The viral genes that are responsible for the growth are virus. A cultured T cell is shedding newly formed virus parti emplaced in the nucleus of the infected cell. The electron mi cles, which are visible as small disks with a dark core. (Many crograph was made by Hans Gelderblom of the Robert Koch In particles have budded into vacuoles, enclosed sacs within the stitute in Berlin; the magnificationis about 25,000 diameters.

~~SCIENTIFIC AMERICAN October 1988 53~~

© 1988 SCIENTIFIC AMERICAN, INC cell to copy the DNA of the integrat of the cell as they are produced; a fatty what is left of the long ones into ed virus into RNA Some of the RNA acid at the end of each one attaches it four segments each. Three of the will provide the genetic material for to the inside of the cell membrane. As segments collapse to form a bullet a new generation of virus. Certain oth these precursors aggregate, they bind shaped core surrounding the RNA and er RNA strands serve as the mRNA's to one another and form a spherical enzymes, but the remaining segment that guide cellular machinery in pro structure that bulges outward under stays attached to the inside of the ducing the structural proteins and en the cell membrane. Two strands of cell membrane. zymes of the new virus. viral RNA are drawn into this nascent Hence the completed virion enclos The particles, or virions, are assem virion as it takes shape. es itself in a patch of host-cell mem bled from multiple copies of two dif One of the enzymes contained in the brane as it buds from the cell. This ferent protein molecules in a ratio of longer precursor protein carries out so-called envelope carries the final about 20 to one. The more abundant the final step in producing mature structural element of HIV: the enve molecule is the precursor of the pro virus. The enzyme, a protease (a pro lope protein. The protein, which juts tein shell that will enclose the RNA tein-cleaving enzyme), cuts itself free from the membrane like a set of mi and enzymes in the completed virions. of the protein chain and cleaves oth nute spikes, is made and transported The other molecule is larger; it con er enzymes (the DNA polymerase, ri to the cell surface independently of tains the same structural components bonuclease and integrase, as well the core proteins. Each spike is a com but includes additional segments that as additional molecules of protease) plex of two or three identical units will become the viral enzymes. The from long precursor molecules. It that in turn consist of two associated two proteins migrate to the periphery then divides the short precursors and components. One component, called

~~CELL~~

~~) NUCLEUS~~

LATENCY CONTROLLED GROWTH LYSIS mv INFECTION begins(top) when a virion, or virus particle, provirus can then remain latent, giving no sign of its presence binds to the outside of a susceptible cell and fuses with it, (a). Alternatively, it can commandeer cellular mechanisms to injecting the core proteins and two strands of viral RNA The copy its genes into RNA, some of which is translated into viral proteins remain associated with the RNA as it is copied into a proteins on structures called ribosomes. The proteins and single strand of DNA, which is duplicated as the original RNA additional RNA are then assembled into new virions that bud is degraded. The double-strand DNA (the "provirus") migrates from the cell. The process can take place slowly, sparing the to the nucleus and is integrated into the cell's own DNA The host cell (b), or so rapidly that the cell is lysed, or ruptured (c).

~~54 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC glycoprotein 120 (gp120) for its size by an encounter with an antigen (a intervening genetic material must be and the fact that it is heavily glycosyl foreign molecule that evokes an im spliced out before the transcript can ated-coated with sugars-rests out mune response). The tat gene is un be made into protein. The effect of the side the cell and the other, gp41, is usual in both its structure and its resulting small protein is dramatic: embedded stemlike in the membrane. effects. It is made up of two widely it can boost the expression of viral These glycoprotein complexes, swept separated sequences of nucleotides; genes to 1,000 times the level seen in up by the budding virus as it acquires after it is transcribed into mRNA the HIV mutants lacking the tat gene. The its envelope, are crucial to HIV's ability to infect new cells. ENVELOPE �,�"looI.U «);l'�/ PROTEIN elaborate set of genetic con �trols determines whether this cycle of replication will be played out and how fast it will pro ceed. In addition to three genes for the proteins of the core and envelope, the HIV genome includes at least six oth er genes. Some and perhaps all of these genes act to regulate the pro duction of viral proteins: one regu lator speeds up protein synthesis generally, another speeds the produc tion of only some kinds of proteins and a third gene represses protein CORE synthesis. Since the regulatory genes PRECURSOR themselves encode proteins, each one affects not only the structural genes but also the regulatory genes, includ ing itself. Their discovery, by our groups at 2 the Dana-Farber Cancer Institute and the National Cancer Institute and by other workers, came as a surprise. The animal retroviruses that had been studied earlier have no such regulato ry apparatus. In the early 1980's regu latory genes were found in the first two human retroviruses, the leukemia viruses HTIV-I and HTIV-ll. But those discoveries did not foreshadow the number and complexity of HIV's regu latory pathways. The pathways have been studied in part by observing the growth of virus in which one or another regulatory component has been inactivated by a DNA POLYM ERASE 3 PROTEASE ---r;.��-----J� AND RIBONUCLEASE mutation. Insight into the function of individual regulatory elements has also come from studying them in iso �---:---ftjr-- P 2 4 lation: transferring them individually from into the genetic material of P7, P9 HIV INTEGRASE experimental cell lines. Each regulato ry gene encodes a protein that inter acts specifically with a "responsive" element: a short sequence of nucleo tides elsewhere in the genome. The regulatory protein is said to act in trans, because it exerts its effects at a ASSEMBLY of a new virion takes place at the cell membrane. Three kinds of protein go distance; the responsive sequence af into making the particle: the envelope protein (actually a complex of two or three fects adjacent genes and is said to act units, each unit made up of an external molecule associated with a molecule em bedded in the membrane) and two precursor proteins of differinglength As in cis. Individually or through their (1). the proteins aggregate at the cell membrane, it starts to pinch off. One precursor interplay the pathways can specify ex molecule draws two strands of viral RNA into the nascent virion, and a protease, plosive viral replication, steady and or protein-cleaving enzyme, cuts itself free of a long precursor (2). The protease moderate growth or quiescence. completes the formation of the virion by cleaving other enzymes-an integrase, a A regulatory gene known as tat, for DNA polymerase and ribonuclease, and more protease-from the long precursors trans-activator, is responsible for the and then cutting each of the precursors into four pieces. One piece (p 17) remains burst of replication seen, for example, attached to the patch of cell membrane that surrounds the completed particle (3), in T4 cells that have been stimulated and the other three pieces (p24, p7 and p9) form a bullet-shaped inner core.

~~SCIENTIFIC AMERICAN October 1988 55~~

© 1988 SCIENTIFIC AMERICAN, INC stimulatory effect extends to all the at the start of the viral genome and is into proteins. The mechanism is not viral proteins, both the components of included in the mRNA transcript of likely to be unique to HIV , and it is the virus particles and the regulatory every HIV gene. Just how the protein expected to shed light on the means proteins-including the tat protein it and the TARsequence interact is not by which higher organisms regulate self. Because of this positive feedback, clear, nor is it known how the inter gene expression. an enormous amount of virus is made action boosts protein synthesis. It very quickly when tat is activated. has been proposed, variously, that tat hereas tat boosts the produc To exert its effects the tat protein and TARincrease the transcription of tion of viral proteins indis depends on a short sequence of nucle mRNA's from the viral DNA, the stabili criminately, a second regula otides known as TAR(for trans-acting ty of completed mRNA's and the effi Wtory gene, rev-the regulator of virion responsive sequence), which is found ciency with which they are translated protein expression-has differential effects. It enables the integrated virus to produce selectively either regulato ry proteins or virion components. In addition to a rev protein, which like the tat product is encoded by noncon tiguous nucleotide sequences that are spliced together in the mRNA, the rev pathway includes two other sequenc es. One of them prevents transcripts that include it from being turned into protein; the other sequence responds to the rev protein and overrides the first one's repressive effect. The repression sequence is called the cis-acting repression element, or CRS. CRS sequences are built into the mRNA's that specify virion proteins: the core proteins, replication enzymes and envelope protein. The spliced, short mRNA's for regulatory proteins such as the tat protein and the rev HIV BUDS from the surface of a cell. The particle is at the stage of assembly shown protein itself lack the CRS sequence. In CRS in 2 in the illustration on the preceding page; the envelope proteins studding the absence of rev, the sequence the patch of cell membrane that will cloak the mature particle are visiblein this elec keeps the long mRNAtemplates for tron micrograph, enlarged 120,000 diameters. The image was made by Gelderblom. virion proteins from accumulating. Instead the truncated mRNA's that specify regulatory proteins, and that CRS VPR REV REV have had spliced out, build up and DO D are translated into protein. The presence of the rev protein TAT VPU TAT resets this genetic switch. The pro GAG � []J 0 � tein acts by way of a sequence called CAR-the cis-acting rev-responsive se POL ENV [ill] quence, which like CRS is found in the VIRAL DNA long mRNA's-to counteract CRS. Full length mRNA's now accumulate, and the production of regulatory proteins GENE (FORMER NAMES) FUNCTION gives way to the production of pro teins that make up a new generation CAG CORE PROTEINS of virus. In this way the rev pathway ENZYMES POL may control the shift from silent in ENV ENVELOPE PROTEIN fection to active viral growth. TAT (TAT-3, TA) POSITIVE REGULATOR Once replication is under way, how REV (ART, TRS) DIFFERENTIAL REGULATOR ever, interaction between the rev and tat mechanisms may hold viral growth VIF (SOR, A, P' ,Q) INFECTIVITY FACTOR in check. The two pathways can coun VPR (R) NOT KNOWN teract each other: the tat product in NOT KNOWN VPU creases its own production and the NEF (3' ORF, B, E', F) NEGATIVE REGULATOR production of the rev protein, whereas the rev protein slows its own synthe GENETIC STRUCTUREof HIV includes the nine genes identified so far, which are sis and that of tat because it favors the arranged along the viral DNA (top) and flanked by the long terminal repeats (LTR'S). accumulation of full-length mRNA's The LTR'S, which do not code for any protein, serve to initiate the expression of other viral genes. Only three genes-gag, pol and env--encode components of virus par instead of the spliced mRNA's that ticles; other genes serve to regulate the expression of these virion genes. Several form regulatory proteins. The result regulatory genes are divided into noncontiguous pieces; the gene segments are is a kind of homeostasis, marked by spliced together in the RNA transcript from which protein is made. Because the DNA steady levels of both the tat and the can be read in three ways, as many as three genes can coexist on one DNA segment. rev proteins and modest production

~~56 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC of virus. Because controlled growth enables a virus to reproduce itself for years without killing off its host cells, such genetic regulation may be an adaptive feature for any retrovirus that infects a long-lived species such as human beings. Indeed, the other 1 human retroviruses, HlLV-I and -II, also have tat-and revlike controls. - How can a regulatory pathway alter nately favor the synthesis of proteins from two different sets of genes? Re sults from a series of experiments - suggest that the rev pathway does ® not directly affect the production of + � � VI�lGROmH mRNA or protein. Instead it may act by governing the transport of mRNA's. This hypothesis assumes the exis tence of several subcompartments within the infected cell's nucleus; mRNA's would meet differentfates depending on which subcompartment + @ NETWORK OF INTERACTIONS among HIV regulatory genes controls viral growth. they were shunted into. Each gene, through its protein product and the sequence in the viral genetic materi· CRS + Under this hypothesis the se al that responds to it, affects the expression not only of the genes� for virion- com quence ordinarily would interact with ponents but also of the other regulatory genes and (in a feedback effect) itself. cellular transport mechanisms to con The tat gene acts by positive feedback and activates (red arrows)all HIV genes; fine the mRNA's it marks (the mRNA's nef acts by negative feedback and represses (blue arrows)all the genes. The rev for virion proteins) in a nuclear sub gene represses regulatory genes but activates virion genes, favoring viral growth. compartment that contains splicing mechanisms and powerful degrada tive enzymes. There the transcripts infected cells, it directs a higher rate twined with the activities of the other would be either spliced to remove of transcription of cellular genes if it regulatory pathways. The countervail the eRS sequences or degraded. Any lacks the sequence. The nef product ing effects of the nefand tat pathways spliced transcripts, which would now amplifies NRE'S effect. could lead to prolonged steady-state encode regulatory proteins, could Just how the nefprotein does so is a production of both proteins and con then be exported from the nucleus to puzzle. In contrast to the tat and rev trolled viral growth-a consequence the protein factories in the cytoplasm proteins, which are concentrated in similar to that of the interplay be of the cell. the nucleus, close to the HIV genes tween rev and tat.The interaction of If the rev protein is present, on the they affect, the nef protein is found nef and rev, on the other hand, could other hand, the CARsequence would mainly outside the nucleus in the cy foster instability and underlie HIVs respond by overriding the CRS sig toplasm. Indeed, the molecule bears a characteristic extreme variations in nal. Then full-length mRNA's would be fatty acid that probably locks it onto growth rate. shunted to a nuclear subcompartment the inside of the cell membrane. How Both pathways are negative-feed in which they would escape splic can this distant factor interact with back loops. The nef protein slows its ing and degradation; from there they the NRE sequence in the viral genome? own production as well as the produc would be exported and made into viri It is likely that the nefprotein exerts tion of the rev product by suppress on proteins. In view of this hypothesis its effect through intermediary mole ing transcription of all viral genes, it is noteworthy that the rev protein cules made by the host cell. The pro whereas the rev protein achieves the is distributed unevenly in the nucleus tein displays several activities similar same effects by slowing the produc of HIV-infected cells, as one might ex to those of molecules that initiate or tion of regulatory proteins in favor of pect it to be if it exerts its effect in a take part in the cell's own Signaling structural ones. The interaction holds specific subcompartment. pathways, which relay chemical mes the potential of an all-or-nothing re sages received at the cell membrane sponse. A high initial concentration of n addition to an activator (tat) and to processes within the cell. For exam the nef protein would suppress all a selective regulator (rev), HIV is ple, the biochemistry of the nef pro further gene expression and the vi equipped with a negative regula tein resembles the biochemistry of rus would lie quiescent; a high initial tor,I which slows the transcription of cellular agents that can trigger the concentration of rev would suppress the viral genome. The gene is called activation of a protein kinase, a kind further production of regulatory pro nef(negative-regulatory factor), and it of enzyme that directly stimulates teins (including nef) in favor of struc may be responsible for HIVs ability to many cellular responses. In addition tural ones. Viral replication would be turn off its own growth and lie utterly the nef protein is itself a protein ki switched on. dormant. The nef protein's target se nase and can be modified by a cellu This picture of three regulatory quence, found at the start of the viral lar protein kinase. All these proper pathways interacting to set the level of genome in the long terminal repeat, is ties suggest that the nef protein acts viral growth may soon be complicated known as NRE (negative-regulatory ele by affectingcellular factors that ulti further. HIV contains two newly identi ment). The NRE sequence represses mately carry its message to the NRE fied genes, vpr and vpu, that are active transcription even on its own; when sequence in the nucleus. in the course of infection. Perhaps the the viral LTR is transferred into un- The repressive effect of nefis inter- vpr and vpu products also regulate

~~SCIENTIFIC AMERICANOctober 1988 57~~

© 1988 SCIENTIFIC AMERICAN, INC viral replication. Studies of these two the RNA initiation site: the starting The activation of this protein, then, proteins and their possible interac point for the copying of viral genes may be one means by which T-cell tions with known regulatory factors into mRNA The sequences resemble stimulation precipitates viral growth. are at an early stage, however. those found at the initiation sites of Not all the cellular proteins that act cellular genes, and at least eight pro on the viral genome are stimulatory; hese intricate mechanisms for teins that are normally engaged in some must repress gene expression. controlling HN growth do not cellular transcription bind to the viral The virus's nef protein, for example, operate in isolation; they are in genome at or near the initiation site. which acts from a distance to slow the timatelyT intertwined with the physiol One probably serves to position the expression of viral genes, relies on ogy of the host cell. For one thing, the RNA polymerase (the cellular enzyme cellular intermediaries to carry its sig virus depends on cellular machinery that copies genes into mRNA) as tran nal to the NRE sequence in the nucleus. to transcribe its genes and convert scription begins, and several other That sequence's ability to slow tran them into protein. More specifically, proteins are believed to speed the rate scription even in the absence of nef, cellular factors surely contribute to of RNA initiation. moreover, probably reflects an inde the tat-driven burst of HN replication One protein that recognizes the HN pendent interaction with inhibitory that ensues when an infected T cell is initiation sequences has a specific role factors made by the cell. stimulated by antigen. Differencesin in the physiology of T cells and other The constellation of cellular factors the host molecular climate must also lymphocytes. The protein, designated acting on the viral genome presum play some part in the varied levels of NF-K B, is activated when lymphocytes ably varies depending on both the growth seen in different cell types. are stimulated by an antigen and be condition and the kind of host cell. What is the basis of these influences? gin to multiply, and it is thought to Some resting cells may simply lack the One key phenomenon may be the contribute to cell growth by increasing proteins needed for RNA initiation, so interaction of cellular proteins with transcription. It turns out that stimu that the infection remains quiescent. the LTR at the beginning of the viral lation of infected T cells increases the In other cells the rate of viral growth genome. Sequences in the LTR define binding of NF-K B to the viral genome. may be constrained by a low con centration of initiation factors or by an abundance of proteins that inhibit REPRESSION mRNA synthesis. Thus the host cell, through its array of transcription fac tors, creates a molecular environment that influences the working of HIVs own regulatory mechanisms.

REPRESSION ter those mechanisms trigger �the production of infectious virus particles, a final gene comes into play. Called vif,for virion [:>------(--�� ENVELOPE infectivity factor, the gene encodes a small protein that is found in the { cytoplasm of infected cells, in the )--- PROTEIN fluid surrounding them and perhaps z � _---',.._------TAT, REV w� also in free virus particles. The vif f-f- Oz protein somehow enhances the abili g: >------NEF V1 ty of virus that has budded from one cell to infect another; HIV strains car rying mutations that inactivate vif make normal-looking virions that car CORE AND ry a full complement of RNA and en ENZYMES V1 zymes but infect cells less efficiently. ZVi WJ:c REPRESSION In the absence of vif the initial step f-f �z in infection occurs just as readily: Cl..> V1 gp120, the outer part of the envelope �V- PROTEIN ENVELOPE � REV protein that studs the virion surface, binds to a speCific protein on the sur J face of an uninfected cell. This recep REPRESSION tor molecule, known as CD4, is abun ------dant on the surface of T4 cells but is TAT, REV also present in at least trace amounts on every kind of cell infected by the ------NEF virus [see uHN Infection: The Cellular Picture," by Jonathan N. Weber and GENETIC SWITCH for viral growth is embodied in the rev pathway. The pathway Robin A Weiss, page 100]. includes two nucleotide sequences designated CRS and CAR, which are found in the Next, in the ordinary course of messenger RNA's (mRNA's) for components of the virus core and envelope. In the absence of rev protein (top), CRS represses the synthesis of protein from these events, one end of gp41, the part of mRNA's, and the elements of new virus are not made. Only the short mRNA's for the envelope protein that is embedded regulatory proteins (the rev, tat and nef products), which lack CRS, are made into in the viral membrane, pierces the protein. When the rev protein is present (bqttom),it interacts with CAR to override the membrane of the target cell and initi repressive effect of CRS; virion proteins are made and viral growth is switched on. ates fusion. (An unidentified cell-sur-

~~58 SCIENTIFIC AMERICANOctober 1988~~

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© 1988 SCIENTIFIC AMERICAN, INC face component known as fusion fac What is the molecular basis for the C04 molecules on the surrounding tor, the absence of which prevents cellular devastation that accompa cell membrane, tearing holes in it. The infection of certain cell lines even nies this intricately controlled cycle of punctured cell swells and dies. Prolific though they are rich in C04, must also growth and dissemination? HIV infec viral replication and a high concentra be present.) The core of the virus then tion practically eliminates the entire tion of surface C04 are both needed enters the cell, and the viral genome is population of T4 cells and may also for this means of killing cells. Infect copied into DNA and integrated in the kill their precursors in the thymus ed T cells meet both criteria; infect cell nucleus. gland and the bone marrow. It does so ed macrophages, monocytes and mi In vif-defectivevirus one of these even though the number of infected T croglial cells (structural cells in the later steps apparently takes place very cells at any given time is quite low. brain and spinal cord) produce virus inefficiently. The absence of the vir Moreover, the virus is just as common slowly and display little C04. They product hampers only the transmis in other cell populations, such as mac generally escape destruction by this sion of free virus,however. The virus rophages and monocytes, and yet it mechanism. can still spread by cell-to-cell trans kills relatively few of those cells. The envelope protein can also killT4 mission, in which viral envelope pro cells in quantity by another means: the tein on the surface of an infected cell he properties of the viral enve same process of cell fusion that is , binds to the C04 receptor on an unin lope protein explain much of responsible for cell-to-cell transmis fected cell and the cell membranes this pattern of cell death. The sion of the virus. Beginning witha fuse, allowing virus cores that have envelopeT protein kills cells directly in single infected cell, the process of fu formed but not yet budded from the at least two ways. As virus particles sion, mediated by gp120 and the C04 infected cell to pass into the new cell bud from an infected cell, the protein molecule, can continue until as many and infect it. on the departing virus may bind to as 500 uninfected cells have combined into a giant, moribund mass called a syncytium. The ability of this process to multiply the cell-killing effect of infection may explain how T4 cells AIDS SPLICING become drastically depleted in patients even though at any given in �I stant fewer than one in every 1,000 T t ---7t cells harbors the virus in active or latent form. tt In a third process of cell killing, carried out by the immune system TI �t\REGULATORY itself, the envelope protein has an in � PROTEIN direct role. The immune system of a �: person infected with HIV makes anti bodies to the envelope protein as well DEGRADATION 1 i NUCLEUS I as to other viral proteins, yet this im u-i(:RS �--1CARI--- : mune response does not eliminate or I inactivate the virus. Important func tional sites on the envelope protein, in particular, seem to be mostly protect ed from antibodies by its shape, its shroud of sugar molecules and the continual variation that results from � REV PROTEIN mutations in the gene encoding it [see "AIDS \0 Vaccines," by Thomas J. Mat I thews and Oani P. Bolognesi, page 120]. � I ) I Not only does the immune response I to the envelope protein fail to check the disease but also it may be fatal to / the patient's own cells-cells such as macrophages and monocytes, which HIV does not killdirectly. Antibodies that have bound to the envelope pro tein (routinely displayed on infected cells) may activate a set of blood pro teins known as complement, which lyses, or ruptures, the antibody-coated cells. A subset of lymphocytes known as killer T cells may also respond to POSsmLE MECHANISM of the rev switch depends on the selective transport of the envelope protein by destroying mRNA's. In the absence of the rev protein (top)any mRNA's that include the CRS infected cells. The viral protein could sequence are held in the nucleus in a hypothetical subcompartment, where they are either degraded or spliced to remove CRS. Spliced transcripts can then be transport make even uninfected cells into tar ed into a second subcompartment, where they are stable, and ultimately made into pro gets for immune-mediated killing. In tein; because of the splicing, however, they yield only regulatory proteins. The rev fected cells readily shed gp120; the protein interacts with CAR to override CRS (bottom). Full-length mRNA's can now be free protein can then bind to C04 on transported into the second subcompartment and then made into virion proteins. healthy cells, subjecting them to at-

~~60 SCIENTIFIC AMERICANOctober 1988~~

~~A 1\1 ERIC A N F () l' ;\; D A T I();\; F () R A IDS RES EAR C II~~

rules about how quickly HIV disease pro gresses. By and large, most patients and Medical Research their families have time to consider their options carefully. It is crucial to seek thoughtful medical advice from a personal physican they trust. inAIDS Beware of extravagant claims or prom ises of miraculous results concerning any treatment. Should a new treatment be proven to be effective, it will not remain s with so many illness, there accelerates research because it minimizes a secret for very long. Exorbitant fees or is no cure today for AIDS or bias-thereby improving the value of trial "expenses" for any experimental treat HIV disease. But there is an results. Phase III trials may include ment should make you suspicious. In gen Aaccelerated, worldwide effort thousands of volunteers at multiple re eral, experimental drugs are provided at to develop effective treat search centers. They help to further de no cost, and no ethical medical practi ments --an effort that is producing en fine--under carefully controlled condi tioner would seek to charge more than couraging early results. A variety of new tions-how and when a drug is optimally standard fees for caring for you. What drugs have been identified that have safe and effective. about alternative therapies? Balanced nu promise because--in the test tube--they Volunteers are protected by certain trition, low-dose vitamins, meditation, or can suppress HIV or fight one of the mi laws and regulatory agencies such as the mental imaging may all play a role in crobes that cause the opportunistic infec Foodand Drug Administration. In the healing for many individuals. But, here tions seen in AIDS. U.S., the law requires review and ap again, be suspicious of extrayagant Many of these new drugs are now being proval of each clinical trial protocol by an claims, excessive cost or extreme regi tested in hwnanvolunteers with various Institutional Review Board concerned mens. As more promising drugs become stages of HIV disease. Such medical re with the safety of volunteers and adher available for study in hwnans, the part search is essential to the development of ence to strict ethical standards by inves nership between investigators and volun treatments that will be safe and optimally tigators. Study volunteers must receive teer subjects becomes ever more impor effective. But it also poses certain risks. It complete written and oral disclosure--in tant. Ultimately , their research will is important to both the quality of the terms that are clearly understandable to provide enduring medical answers to this research and the safety of volunteer study them--of all benefits and risks in a par global health crisis. subjects that they be fullyinformed before ticular drug trial. This permits subjects enrolling in any drug trial. They must un to provide "informed consent" before par derstand the methodology of clinical ticipation. Volunteering as a study subject Adapted from the AIDS/HIV Experi trials, the requirements for participation, is not only a valuable public service, it mental Treatment Directory, published and any risks that may be entailed. also represents a way to access forms of quarterly bythe American Foundation for Trials of new drugs in humans involve anti-HIV treatment that are still under AIDS Research (AmFAR). The directory in three phases of testing. Phase I trials are investigation. cludes detailed background inforfl'l4tionon clin of short duration and involve a small ical trial procedures and the drug approval nwnber of patients. Their goal is to de A NOTE TO THOSE WITH process. Toorder a copy, call1-800-992- termine the safe dose range of a new drug HIV INFECfION 2873. Tofind out more about AmFAR and and how it is dealt with by the body. If you are told, after carefuland com its research and prevention grant programs, see Phase II trials aim at determining petent medical evaluation, that you are the Reader Servicecard. whether a new drug has therapeutic effi HIV-infected or that you have AIDS, try cacy. These usually involve several to keep the following information in AMERICAN FOUNDATION hundred volunteers and are "c on mind: Although a diagnosis of AIDS or trolled"-the efficacy of the drug is com HIV infection is nobody's idea of good FOR AIDS RESEARCH pared to a placebo or to another drug. news, it is not-repeat, not--aninstant 1515 Broadway 36th Floor Neither doctors nor patient� know who "death sentence." In some individuals, New York, NY 10036 receives the experimental drug or the con even full-blown AIDS has not proved fatal (212) 333-3118 trol preparation. The use of these controls for many years. There are no hard-and-fast

© 1988 SCIENTIFIC AMERICAN, INC mutations affecting genetic regulation NEF PROTEIN do not seem common in natural infec tions; nearly all patients make anti bodies to the nefprotein, for instance. t That is not to say that mutations CELLULAR SE COND MESSENGERS play no role at all in the pathology of t AIDS. TRANSCRIPTION The advent of variants carrying FACTORS �------r------/ mutations in the envelope gene in par ticular may well affect the progres t NUCLEUS CELLULAR sion of the disease in an individual. GENE Changes in an exposed part of the envelope protein called the hypervari able loop, for example, may enable the virus to evade an immune response directed at the protein and so would be favored by natural selection. Muta ACTION AT A DISTANCE characterizes the nefpathway, which represses HIV growth. The protein encoded by nefis found in the cell cytoplasm, probably attached to the tional change in other parts of the inside of the cell membrane. Yet it seems to exert its effects by way of NRE, a se protein may alter the virus's ability to quence in the viral genome, in the nucleus. It is thought that cellular signaling sys bind to or fuse with a speCifickind of tems and factors probably carry the nefprotein's message to the nucleus. By affect cell. As one population of cells be ing the cell's own biochemistry, nefmight also alter the expression of cellular genes. comes depleted, HIV variants with an increased affinity for another cell pop ulation might have the advantage. tack by agents of the immune system. the source of this striking variability? The envelope protein is the only HlV HlV replication includes three steps his is the molecular character of component whose role in cell killing at which mutations are likely. The viral the opponent facing clinicians has been documented. Yet the regula DNA polymerase lacks the error-cor and workers in drug and vaccine tory proteins may also contribute to recting feature that analogous cellu development.T The picture is a daunt cell death or dysfunction, by altering lar enzymes have, and so the copying ing one. HIV is able to slip into cells the expression of cellular as well as errors it makes in converting viral and remain there for life. Its elaborate viral genes. The nefprotein, for exam-· RNA into a single DNA strand and genetic regulation enables it to lie low, pIe, relying as it does on cellular fac then synthesizing the complementary hidden from immune surveillance; to tors to carry its message of repression strand go uncorrected. The cellular replicate slowly, possibly deranging to the viral genome, is very likely to RNA polymerase that makes the genet the host cell's own genetic controls as have broader effects on the cell; tat, ic material for new virions also does it does so, or to initiate a burst of rev and perhaps other HlV genes may not correct its own errors. These three growth that kills the infected cell. Even also disturb the cell's genetic control. steps are common to all retroviruses; when HIV is active, the design of its Among the cellular genes thus affect in a bird retrovirus they-together envelope protein and the variability ed might be those that direct the pro with other, less problematic events in that results from its error-prone repli duction of diffusible factors that help replication-have been found to pro cation mechanisms make it a difficult to maintain immune-system function. duce an average of about one muta target for an immune response. For example, macrophages and tion per replication cycle. A molecular description of HIV, monocytes release protein factors, At that rate new HlV variants can then, reveals the full dimensions of such as interleukin- l and interferons, develop during a single infection. And the challenge presented by AIDS.Yet that activate other cell populations in yet if one sets aside differences in it also sets out the vital features of the immune system. Abnormally high the disease's course and transmission the virus, some of which can serve as or low levels of these factors could properties that can be ascribed to en the focus of control strategies. Surely alter the behavior of the target cells or vironmental or social factors, AIDS this description contains the seeds even kill them. Cells in the central shows a remarkably consistent face of HIVs eventual defeat. nervous system require similar diffus throughout the world. Why is the vari ible proteins for their survival, which ability of the virus not reflected in the FURTHER READING raises the possibility that altered mac nature of the disease? STRUCTURE AND FUNCTION OF HUMAN rophage and monocyte function un Many mutations leave HIV unable to PATHOGENIC RETROVIRUSES. William A derlies some of the neurological de survive and so are eliminated. The Haseltine, Ernest F. Terwilliger, Craig A terioration seen in AIDSpatients. many other mutations that persist are Rosen and Joseph G. Sodroski in Retro concentrated in parts of the genome virus Biology: An Emerging Role in Hu man Diseases, edited by Robert C. Gallo he viral genetic blueprint that that are thought to have little func and Flossie Wong-Staal. Marcel Dekker, specifies these events, from in tional role. Most mutations, then, are Inc., 19 88 fection through replication to not likely to affect the structure and Os- AND TRANS-ACTIVATION OF HlV. Jay cellT killing, is remarkably changeable. life cycle of the virus, and so strains Rappoport and Flossie Wong-Staal in The complete sequence of nucleotides that are rather different genetically Concepts of Viral Pathogenesis, edited has been determined for a number may have similar pathogenic proper by Abner Notkins and Michael Old of HlV samples, isolated at different ties. In virus that has been maintained stone. Springer-Verlag, in press. THE CONTROL OF HUMAN RETROVIRUS times and places. Some pairs of iso in culture, mutations do appear in the GENE ExPRESSION, edited by B. Robert lates differ in no more than 1 or 2 regulatory genes; such mutations can Franza, Jr., Bryan R. Cullen and Flossie percent of their nucleotides, but for increase a cultured strain's growth Wong-Staal. Cold Spring Harbor Labo other isolates the differences amount rate by, for example, incapacitating ratory, in press. to more than 25 percent. What is the negative-regulatory gene nef Yet

~~62 SCIENTIFIC AMERICANOctober 1988~~

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The cias8ic te:xt8 are convenient A comprehen8ive, �,300-page text in two 1008e-leai volume8, reierence8-hut the iniormation they incorporating the late8t advance8 in medical practice as oi the contain i8oh80lete heiore puhlication. month you 8uh8crihe. Like many physicians, you probably rely on This superbly designed, heavily illustrated resource, called "the best the texts you first used in medical school. But written of all [the internal medicine) books" by JAMA (251:807, 1984), even using the most recent editions, you find provides a practical, comprehensive description of patient care in 15 material that no longer reflects current clini subspecialties. And, because the text is updated each month, the cal thinking-and they lack the latest informa clinical recommendations reflect all the current findings. A tion on such topics as herpes, oncogenes, practice-oriented ind.ex and bibliography of recent articles further AIDS, and photon imaging. enhance the efficiency ofthe text.

Reading 8tack8oi journal8 a1ert8 you to Each month, 8ix to nine replacement chapter8 to update recent development8-hut can't giveyou your text plus new reierence8, an eight-page neW8 qnick aD8Wer8 on patient management. bulletin, and a completely new index. Struggling through the hundreds of journal You'd have to read hundreds of journal pages each month-and pages published each month-even on only memorize the contents-to get the same information SCIENTIFIC the really significant advances in the field-is AMERICANMedicine contains. With our updated text, you read only arduous and memory-taxing. And it's a task the information you really need. Our authors, largely from Harvard that costs physicians valuable time-their and Stanford, sort through the literature and monitor develop most precious resource. ments, incOIporating the significant advances into our chapters.

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© 1988 SCIENTIFIC AMERICAN, INC The Origins .of the AIDS Virus The AIDS virus is not unique. It has relatives in man as well as other primates. Studies of related viruses indicate that some have evolved disease-free coexistence with their animal hosts

~~by Max Essex and Phyllis J. Kanki~~

he sudden appearance and rapid something about how they cause dis The genetic material of STLV was or spread of a previously unknown ease. Evolutionary selection tends in ganized much like that of HTLV and Tinfectious disease such as AIDS the long run to favor the survival of the sequence of its component nucle raises a series of compelling ques both a virus and its host. Over decades otides was between 90 and 95 percent tions. What is the causative agent, or millenniums a virus-host relation homologous to, or identical with, that what is its structure and how does it can change; a lethal disease caused by of HTLV. Besides these virological sim function and-in the case of a previ a virulent pathogen in a susceptible ilarities, the monkey and human virus ously unknown agent-where did it host tends to give way as less viru es had similar biological properties. come from? lent viruses and more resistant hosts When we studied Asian macaques at Our own work has addressed the emerge. Understanding how this may the New England Regional Primate Re third problem, that of the origin of the have happened in the case of other search Center in Southborough, Mass.,

AIDS virus, HIV. The object of these viruses may reveal ways to control the we found that monkeys with malig studies, we should make clear, is not AIDS virus and its disease. nant lymphoma (a cancer of lymphoid to identify a particular site or group of cells) showed much higher rates of people that harbored a particular an ne way to begin searching out STLV infection than healthy macaques. cestral virus and trace a path that led the origin of HIV is to look for It appeared, then, that STLV was capa to the AIDS pandemic. Rather, the ob Osimilar viruses in nonhuman ble of inducing a lymphoid cancer in ject is to learn more about viruses primates. Monkeys and apes are often monkeys similar to the HTLV-induced related to HIV and so understand how the only animal species other than lymphoid cancer in people. HIV has evolved the unique and deadly human beings that are infected with The discovery of STLV prompted a properties that lead to AIDS. important human viruses such as yel number of studies aimed at determin These questions are of more than low fever and Marburg virus; in certain ing its distribution in various primate historical interest. Within the past cases it is even thought that wild mon species worldwide; the hope was to three years we and others have iden keys harbor the pathogens and can be find clues to the geographic and evo tified retroviruses related to HIV in the source of human infections. lutionary origin of HTLV. The simian monkeys and in human beings. The The search for monkey viruses relat virus was found to infect both Asian different biological properties of the ed to HIV had a precedent in the dis and African Old World monkeys and viruses in various hosts can reveal covery of a primate counterpart of apes; in various serological studies (in another human retrovirus. The first which blood samples are analyzed for retroviruses shown to infect human the presence of speCific antibodies) MAX ESSEX and PHYLUSj. KANKI work beings (in 1980, by Robert C. Gallo of the rate of STLV infection in these together at the Harvard School of Public the National Cancer Institute) were species varied from 1 to 40 percent. Health, where he heads the department two human T-Iymphotropic viruses: Genetic studies of STLV's from Asian of cancer biology and is chairman of HTLV-I (the cause of a rare form of and African primates showed that the the new Harvard AIDSInstitute and she is a research scientist in the institute. T-cell leukemia/lymphoma in people) human virus was more closely related Essex has a doctor's degree in veterinary and the very closely related HTLV-II. to the simian virus seen in the African medicine from Michigan State Univer Two years later Isao Miyoshi of Kochi chimpanzee or the African green mon sity and a Ph.D. from the University University described a related virus in key (95 percent homology) than to the of California, Davis. His laboratory dis a monkey, the Japanese macaque. The virus seen in the Asian macaque (90 covered the human-retrovirus envelope virus was remarkably similar to the percent), indicating that African STL V proteins, which are major candidates HTLV's and was designated the simian might have played the more important for future AIDS vaccines. In 1986 Essex T-Iymphotropic virus, STLV. role in the origin and evolution of shared the Lasker Award in clinical med ical research with Robert C. Gallo and Both the HTLV's and STLV were ca human HTLV's. Luc Montagnier. Kanki has a doctor's pable of inducing immortality (one One hypothesis regarding the ori degree in veterinary medicine from the characteristic of cells transformed to gin of HTLV relied on the premise that University of Minnesota and a D.Se. from the cancerous state) in Tlymphocytes the 5 percent difference in the genet the Harvard School of Public Health. grown in the laboratory. The proteins ic sequences of the African STLV and After working at the New England Re of the two types of viruses were very HTLV was so great that it ruled out any gional Primate Research Center, she similar: antibodies elicited by either possibility of a monkey-virus transfer joined Essex' laboratory in 1983. Kanki is currently leading an investigation of virus in its host could recognize the to human beings any time after New the biology of HlV-2 in West Africa. proteins of the other virus-a phe World primates diverged from the Old nomenon known as cross-reactivity. World primate lineage during the Eo-

64 SCIENTIFIC AMERICAN October 1988 © 1988 SCIENTIFIC AMERICAN, INC AFRICAN GREENMONKEY is a major reservoir of the simian the animals are infected_ Yet SlY does not cause disease in the immunodeficiency virus (SlY), a relative of the AIDS virus; in infected green monkeys-whereas it causes simian AIDS in, for various green-monkey populations from 30 to 70 percent of example, Asian macaques in primate research centers. Why?

~~SCIENTIFIC AMERICAN October 1988 65~~

© 1988 SCIENTIFIC AMERICAN, INC HTLV HIV-l HIV-2 cene epoch, about 40 million years ago. lITLV, then, would have evolved D D very long ago, from a virus infecting �,. the primate ancestor that gave rise to the great apes. HUMAN If that were the case, however, the

SIV parallel evolution of STLV and HTLV within their respective hosts would need to have been virtually identical, considering that at the present time the two viruses differ by less than 5 GREAT percent Many of us thought it unlikely APES that retroviruses could maintain such similarity after millions of years of evolution in various host species that were themselves evolving. • This suggested that primates could have infected human beings with a version of STLV in more recent times, GORILLA within the past 40 million years. In deed, Gallo has proposed that HTLV originated in Africa, where both peo ple and African primates were infect II ed, and was spread to the Americas by the slave trade and to the southwest

GIBBON ern islands of Japan (the virus's other endemic area) by oceangoing Portu guese traders_ Regardless of just how I STLV and HTLV entered their respec tive host species, the available data made it clear that their origins were inextricably linked. BABOON his background provided the im petus, after the AIDS virus had Tbeen characterized, for us to un dertake a search for a monkey virus • related to HIV. In 1984 we set about I examining large numbers of primates OLD WORLD MACAQUE MONKEYS by serological testing. Any virus in fecting these primates that was relat ed to HIV would share with HIV some � sites (called cross-reactive epitopes) �;"1t�:. \:\i on its viral proteins. When an HIV 'Y .T . � • D related protein was present in an in "� ...... fected animal, it would elicit cross AFRICAN GREEN reactive antibodies to these epitopes, MONKEY and we could detect the antibodies in the monkeys' blood_ Soon we succeed ed in findingsuch antibodies-and hence evidence for the presence of a • monkey virus related to HIV-in blood samples from Asian macaques (Maca- COLOBUS

- PRIMATES AND RETROVIRUSES that in fect them are related as shown_ (The diagram is not drawn to reflect the pre cise sequence or dating of the evolu tionary branching.) STL V, the first mon NEW WORLD key retrovirus discovered, is not seen MONKEYS in New World monkeys; presumably it originated after they diverged from the main primate lineage. SIV infects Af rican green monkeys in the wild. The • hatched symbols indicate primate spe cies that have been infected experimen tally. HIV-I and HIV-2infect humans and, in the laboratory, certain primates.

~~66 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC ca spp.) housed at the New England ANTIBODIES FROM PERSON ANTIBODIES FROM PERSON INFECTED WITH VIRUS X INFECTED WITH VIRUS Y primate center. At about that time veterinary pa thologists at several primate research centers in the U.S. were reporting out YYII IIII breaks of AIDs-like disease in captive macaque monkeys. The illness (called SAIDS, for simian AIDS) was seen only � in Asian macaques. We were able to identify HN-related antibodies in the SAIDS macaques. Then, in collabora tion with Norman L. Letvin, Ronald C. VIRUS X Desrosiers and Muthiah D. Daniel of the New England center, we isolated and characterized the virus infecting them, which is now designated the simian immunodeficiency virus (SIV). GROUP-SPECIFIC It was clearly related to HIV, as the PROTEIN antibody studies had suggested it TYPE-SPECI FIC would be. It infected the same CD4 TYPE·SPECIFIC PROTEIN PROTEIN subset of lymphocytes the human vi rus infects. The biochemical and bio CROSS-REACTIVTIY is displayed by related viruses. Each virus has on its surface physical properties of the SIV proteins type-specific proteins that are uniquely its own and group-specificones that it were very similar to those of the HN shares With related viruses. Some antigenic sites (epitopes) on group-specificpro proteins. Antibodies from AIDS pa teins are common to both viruses. A person infected by virus X Will have developed tients recognized cross-reactive epi cross-reactive antibodies that recognize cross-reactive epitopes on related virus Y. topes on the SIV proteins, just as the monkey antibodies had recognized HIV proteins. The human antibodies whether the geographic distribution monkeys, including macaques, failed were highly reactive with the major of the monkey virus might provide to find evidence of an SIV- or HIV-like core protein of SIV but only minimally clues to the origin of the human AIDS agent. Studies by many investigators cross-reactive with the envelope gly virus. The mere existence of a related confirmed that SIV infection in the coproteins on the surface of the mon virus in captive immunosuppressed Asian macaque was limited to small key virus. It is characteristic of retrovi monkeys maintained in a U.S. primate numbers of monkeys in captivity, ruses that the internal core proteins facility did not provide much informa where it was highly associated with are the most conserved, or "group tion in that respect. The monkey virus SAIDS. The data suggested that SIV did specific": they tend to be common to could have been transmitted to the not naturally infect Asian monkeys the members of a group of viruses. macaques from another monkey spe in the wild. It seemed quite possible The envelope glycoproteins, on the cies housed in the same facility or that the primate-center macaques had other hand, are the least conserved even by experimental manipulations. been exposed to SIV in captivity. they are more "type-specific," or dis We therefore investigated the pos If the Asian macaque monkey was tinct for each virus in the group. sibility that wild Asian macaques not the natural host for SIV, then what also harbored SIV. Seroepidemiologi was? And how (if at all) were the pri ubsequent genetic studies have cal studies of wild and captive Asian mate viruses related to the observed shown that SIV is approximately 50 percent related to HN at the S HIV·l nucleotide-sequence leveL The organi AIDS zation of structural and regulatory PATIENT MONKEY genes is virtually identical in SIV and HIV. The notable exceptions are the GP160 vpx gene of SIV, which is not found in GP120 HIV, and the vpu gene of HIV, which is not found in SIV. Like humans infect ed with HIV, Asian macaques infect ed with SIV suffered a decrease in T4 P55 lymphocytes withensuing immuno P55 suppression; the animals died of op portunistic infections very similar to those seen in human AIDS. These fea tures of SIV provide striking parallels P24 P24 to those of HN. SIV therefore repre sents a system in which drugs and vaccines aimed at HIV can be subject SlY was discovered by serological testing. AIDS patients have antibodies that rec ed to preliminary testing. ognize HIV-lenvelope proteins (gp120 and its precursor gp160) and core proteins As we studied SIV in 1985, the simi (p24 and its precursor p55). Both Asian macaques that had simian AIDS and African larities between the simian virus and green monkeys were found to have antibodies that recognized the HIV-l core pro the human virus suggested that the teins (which are generally the more cross-reactive proteins in a retrovirus). The anti two must be related, and we wondered body response showed the monkeys had been infected With a virus related to HIY-l.

~~SCIENTIFIC AMERICAN October 1988 67~~

© 1988 SCIENTIFIC AMERICAN, INC emergence of HIV in people? In 1985 monkeys (Erythrocebus patas). The not been exerting long·term adverse the highest rates of HIV were reported samples were analyzed for the pres selection pressure on the species. in the U.S. and Europe, but disturbing ence of antibodies that reacted with Why SIV is endemic in these wild reports from central Africa indicated proteins of the SIV virus from ma African monkeys but seems to do that high rates of HIV infection and of caques. We found no evidence of SIV them no harm, and is also found in AIDS prevailed there, at least in some infection in the chimpanzee, baboon the captive Asian macaques, where it urban centers. The reported rates of or patas monkey-but more than 50 causes disease, was (and still is) an infection were so high that many percent of the wild Africangreen mon enigma, but the puzzle pointed to a workers thought the AIDS epidemic in keys studied in our first survey did line of investigation. It seemed quite central Africa might have predated the show evidence of an SIV infection. possible that the captive Asian mon emergence of the disease elsewhere We have since analyzed samples keys might first have been infected in the world. On the assumption that from several thousand African green when they were accidentally exposed the distribution of HIV in human pop monkeys caught in various regions of to African monkeys in holding facili ulations might be correlated with the sub-Saharan Africa and from many ties. The fact that a virus that seemed distribution of related viruses in mon others housed in research facilities to be quite harmless in African mon keys, it seemed to us to be important throughout the world. We find SIV in keys was wreaking havoc in the newly to determine whether HIV-related vi fection in from 30 to 70 percent of exposed Asian monkeys indicated that ruses were present in primate species them. Yet they show no sign of im at least some strains of SIV still had in Africa. munosuppression or of SAIDS. More a potential for great virulence. The We therefore obtained blood sam· over, in spite of their having the high infected African species must have pIes from representative African pri est rates of SIV infection, the various evolved mechanisms that kept a po mates, including wild-caught chim green-monkey subspecies are among tentially lethal pathogen from caus panzees (Pan troglodytes), African the most ecologically successful Afri ing disease. Indeed, some SIV strains green monkeys (Cercopithecus aethi· can primates, suggesting that the high might also have evolved toward coex ops), baboons (Papio spp.) and patas infection rate in these monkeys has istence with their monkey hosts.

~~VIRULENT LESS VIRULENT LESS SUSCEPTIBLE ®®®®®®®®®@ � � SUSCEPTIBLE LESS SUSCEPTI BLE (Ilv � � � �� § �§� �� ~~

~~VIRULENT LESS VIRULENT �® ® @@@ �� § § § I � I I RESISTANT~~

~~LEAST VIRULENT LESS VIRULENT @tQ(@@@@@@@@ I i I I 1 I IIII III s � i I I I~~

CASE OF THE RESISTANT RABBITS illustrates the mutual evolu virulent viruses eventually killed them, but a few truly resis· tion of a virus and its host. Myxoma virus was introduced into tant rabbits were spared. Meanwhile natural selection favored Australia in an effort to get rid of wild rabbits. Virulent virus the evolution of avirulent virus strains (because a virus does es killed most of the rabbits, but a few animals happened to best if its host survives). Eventually a resistant rabbit popula· be less susceptible; they survived (right) and multiplied. The tion was established, coexisting with a largely avirulent virus.

~~68 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC There is a rough parallel between u.s. AIDS WEST PATIENT MONKEY AFRICAN the differential SAIDS susceptibility of green monkeys and macaques and the GP160 very different susceptibility to AIDS SIV ENVELOPE PROTEINS GP120 of chimpanzees and human beings. Chimpanzees are the only animals that can be experimentally infected with the HN isolated from AIDS pa P55 P55 tients. Yet the virus does not appear '--_-""- to cause lethal disease in chimpan zees as it does in people. Might it be, SIV CORE PROTEINS we wondered, that chimpanzees have somehow acquired resistance to the P24 t----j...r P24 AIDS virus? If they have, could it be because wild chimpanzees have had earlier evolutionary experience with lllV-2 was discovered by serological testing with SIVproteins. The blood of u.s. some close relative of HN-a relative AIDS patients had antibodies only to the core proteins, in keeping with the rough that might, in fact, be an immediate ly 50 percent relation of SIVto lllV-l. As one might expect, SIV-infected monkeys evolutionary precursor of HN? had antibodies to both core and envelope proteins of SIV. People in high-risk groups in West Africa turned out also to have antibodies that reacted with both the etroviruses (like other intracel core and the envelope proteins, indicating that they were infected by a human lular parasites) tend to coexist virus more closely related to SIV than to lllV-l. The virus is now designated lllV-2. Rwith their natural host species in some way that allows both to sur vive. In the case of some retroviruses of myxomatosis? Might the African travenous drug abusers and hemo of rodents and chickens, there has monkeys be analogous to the later, philiacs, either are rare or are difficult been mutual adaptation to the extent myxoma-resistant generations of rab to identify in much of Africa. that the complete viral genome, inte bits? Knowing what mechanisms of In early 1985 we found evidence for grated into the host genome, is regu immune resistance have evolved natu such an SIV-related virus in Senegal larly inherited in all members of the rally in SIV-infected African monkeys, in West Africa. With our collaborators host species. Such genetically inherit one could try to mimic such mecha Souleymane M'Boup of the University ed "endogenous" viruses have also nisms in people exposed to HIV. The of Dakar and Francis Barin of the Uni evolved to become totally nonpatho analogy between myxomatosis and versity of Tours, we had tested blood genic. The human and simian retro SAIDS might extend to the viruses. Like serum samples from prostitutes with viruses we are discussing, however, the myxoma virus, HIV and SIV can antigens from both HIV and SIV. HIV are "exogenous": they are transmitted mutate rapidly. Perhaps some strains positive serums (samples known to horizontally, from individual to indi of SIV, including the one that infects have antibodies to HIV) from both cen viduaL It seems logical that retrovirus Asian macaques in captivity, are high tral Africa and the U.S. were tested es, like other infectious agents, may be ly virulent and others are much less with the same antigens. About 10 per most pathogenic when they first enter virulent. Identifying and comparing cent of the samples from prostitutes a new species. Selection for survival such strains could contribute to the had antibodies that reacted with both on the part of both the virus and the understanding of HIV and the devel HIV and SIV. Surprisingly, the antibod host species might then ensue. opment of effective vaccines. ies reacted much better with SIV anti A classic example of rapid evolution Clearly SIV is the closest known ani gens than with those of HN, particu of the virus-host relation resulted mal-virus relative of HIV. Yet it is only larly with SIV's type-specific external from the introduction of myxoma, a about 50 percent related on the ba envelope glycoprotein and envelope lethal virus of rabbits, into Australia sis of sequence analysis-not close transmembrane protein. In contrast, several decades ago. It was done delib enough to make it likely that SIV was the HN-positive serums from central erately, in an effort to get rid of wild an immediate precursor of HN in Africa and the U.S. did not react very rabbits that had become agricultural people. Postulating that various HIV's well with the SIV envelope antigens. pests. At firstthe virus killed most and/or SIV's might exist as a spec exposed rabbits, but soon populations trum of viruses in different monkey �l in all, the reactivity of the of rabbits emerged that were able to or human populations, we expanded prostitutes' antibodies to SIV an survive infection by the virulent myxo our serological studies. Perhaps, we tigens was indistinguishable ma virus and in the process to become thought, one could find such a virus from that of antibodies in the blood immune to it. Less virulent strains of an intermediate between SIV and of SIV-infected macaques and African the virus also emerged; their hosts HN-in human beings. green monkeys. This clearly suggested tended to survive, giving them a selec To address the possibility that there that people in West Africa were infect tive advantage over the lethal strains. might in fact be such a human virus, ed with a retrovirus different from the Within a few years the rabbit popula we examined high-risk people from one infecting people in central Africa, tion was restored to its original size diverse parts of Africa where we had Europe and the U.S., and that the West and the virus-host relation was com earlier identified SIV-infected mon African virus was more closely related pletely changed. keys. We included female prostitutes, to SIV than to HN. Because the puta Could the Asian macaques be analo because they are at elevated risk for tive West African human virus respon gous to the first generation of Austra infection with sexually transmitted vi sible for these serological findings lian rabbits, which were exposed to ruses; the groups that are at risk for was clearly distinct from the AIDS vi the myxoma viruswithout prior evolu HIV infection in industrialized coun rus (which in 1985 was still called tionary experience and therefore died tries, such as male homosexuals, in- HTLV-Ill or LAy)and would be a fourth

SCIENTIFIC AMERICAN October 1988 69 © 1988 SCIENTIFIC AMERICAN, INC human retrovirus, we suggested that have been from a cell culture that was the development of AIDS to only a it be designated HTI.V-IV; now the contaminated with the monkey virus fraction of the infected people. original AIDS virus is called HIV-l and itself. This suspicion is based on the One could address the question of the West African human virus is HIV-2. assumption that there cannot have the degree of HIV-2's virulence in West Soon Francois Clavel and Luc Monta been any interspecies transmission of African people in several ways. Clavel gnier of the Pasteur Institute also SIV to people. It is still not possible to and Montagnier and their colleagues showed that West African people were say with certainty how these highly had isolated HIV-2 from West African infected with a virus very similar to related viruses came to infect their AIDS patients who had been referred SIV. Their studies and ours showed respective hosts. to Europe for treatment, suggesting that people infected with HIV-2 have Our early studies showed HIV-2 was that at least some strains of HIV-2 antibodies entirely cross-reactive with endemic in West Africa-where there could cause AIDS. Yet the isolation SIV antigens; in fact, it is impossible to did not appear to be any clinical epi from AIDS patients was not enough distinguish between SIV and HIV-2 on demic of AIDS. This raised new ques evidence to establish HIV-2 as a cause the basis of serological criteria. tions. Was HIV-2 minimally pathogenic of AIDS. To determine whether HIV-2 When the genetic material of the in humans, as SIV seemed to be in strains in general were as virulent as two viruses was examined, the nucle African monkeys? HIV-2 might cause a strains of HIV-l, the epidemiology of otide sequences too were found to different syndrome, one that is less HIV-2 had to be assessed in a number be closely related. All of this suggests severe and not as regularly lethal as of African populations; the extent to at least that the primate and human HIV-l. It is also possible that AIDS which AIDSwas associated with HIV-2 viruses share evolutionary roots and cases were present in West Africa but infection could help to establish the at most that there may have been in were missed because of inadequate virulence of the virus. terspecies infection-that SIV-infect clinical diagnOSis. Still another expla ed monkeys transmitted the virus to nation for the seeming absence of an e undertook extensive sero humans or vice versa. The sequence epidemic is the possibility that a mix epidemiological studies in 14 studies also pointed to a possibility ture of HIV-2 strains was present in WAfrican countries in order that one of the early isolates of HIV-2 the population; differences in viru to determine the rates of HIV-2 and reported from our laboratory might lence among the strains might limit HIV-l infection, examining more than 10,000 people in three groups: female prostitutes, patients with severe infec tious diseases (such as systemic tu berculosis) that might signal an AIDS 0% 0% like immune deficiency,and healthy control adults. In the controls, rates of HIV-2 infection ranged from less than 1 percent to more than 15 percent depending on location. The rates were from five to 10 times higher in female prostitutes, indicating that HIV-2, like HIV-l, is transmitted sexually. To our surprise, individuals with tuberculosis or other severe infectious diseases did not have significantly higher HIV-2 rates than the controls. We found only very low rates of HIV-l in the West African countries, where HIV-2 was most prevalent. On the other hand, HIV-2 was virtually absent in the cen tral-African countries we studied. Prostitutes who tested positive for HIV-2 in 1985 were subsequently fol lowed and examined carefully for ab normal clinical signs and symptoms. In contrast to prostitutes in other parts of Africawho are positive for HIV-l, they showed negligible rates of generalized lymphadenopathy (en largement of the lymph nodes); none have shown signs or symptoms of AIDs-related complex or AIDS itself. All in all, the data suggested that West Africans infected with HIV-2 were at LILONGWE, MALAWI substantially lower risk for the devel opment of AIDS than individuals in fected with HIV-l. DISTRIBUTION OF HIV-2 in Africa was established by serological testing of female Whether the differenceis due to prostitutes, who constitute a high-risk group. The seroprevalence rates (the fraction the widespread distribution of less of individuals who tested positive for HIV-2) are given for 15 cities in 14 countries virulent strains of HIV-2 in West Af where the test was administered. The virus appears to be limited to West Africa. ricans remains to be determined. One

~~70 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC should also consider the possibility REV --E-NV---' that HIV-2 infection of human beings ID I Ir-I I is simply too new for AIDS to have r POL DVPR 1 NEFI developed after a long period of latent I I I I I I infection. Several observations seem I CAC I 2: V'FD D l vPU I to argue against that possibility. One I I TATI I is the fact that older prostitutes have I I I higher antibody rates than younger •LTR I • I LTR ones. This could simply reflect an in I I crease in the total number of expo I Sures to the virus with increasing age. 1

The age effect also suggests, howev I I I I I I I I I er, that the women who had been ex : : ! : I I : posed for a long time were not being I I NEF eliminated from the population pool > VPX 1 1 I I DT��I I Vi ______� �'I I by illness (as they would be by HIV-l -..... ,-� : infection), and therefore that HIV-2 N POL 1 I, DREV : 2: !--____� __ ---:- , ...J I I l has been present in West African pop I ulations for a longer time but has not r--CA -C--'----i VIF D 0 ;"'1 ---E-N-V�--""" been very efficientat causing disease. VPR We also analyzed blood from pa • 1 • LTR tients who were in Dakar hospitals LTR with AiDs-like illnesses, looking for GENETIC ORGANIZATION of HIV-2 and SIV is compared with that of HIV-l (top). The evidence of infection with HIV-2 or genes are arranged along the strand of proviral DNA as is shown. The gag gene HIV-l. Most patients had type-specif encodes the core proteins, env the envelope proteins and pol the enzymes needed for ic antibodies to HIV-l rather than to replication. Sequences constituting some genes overlap or are noncontiguous. The HIV-2, in spite of the much lower back two genes that are not common to both genomes are shown in color. Knowledge of ground rates of HIV-l infection in Da their function might help to show why HIV-l causes lethal disease but HIV-2 may not. kar's population-a finding compati ble with HIV-l's being more patho genic than HIV-2. Although about 20 Prostitutes from West Africa who lutionary immunoselection. Thus the percent of the AIDS patients did ap have been infected by HIV-2 are now origin and history of the AIDS viruses pear to have been infected with HIV-2 beginning to be exposed to HIV-l, par themselves may provide the very in rather than HIV-l, the disease seen in ticularly in countries such as Ivory formation that is critical to the pre HIV-l-positive patients was severer Coast and Burkina Faso, to which vention and control of AIDS. and fitteda more stringent definition HIV-l seems to be moving from cen of AIDS. For the known human lym tral Africa. We and others will be FURTHER READING photropic retroviruses, then, there ap watching to see whether or not people SEROLOGIC IDENTIFICATION AND CHAR pears to be a spectrum of pathogenici previously infected by HlV-2 show de ACTERIZATION OF A MACAQUET-LYM ty. HIV-l causes lethal disease in most creased rates of infection with HlV-l. PHOTROPIC RETROVIRUS CLOSELY RE infected people, whereas HTL V causes (Such resistance might be brought LATED TO HUMAN HTLV-III.P. J. Kanki, M. F. Mclane, N. W. King, Jr., N. L Letvin, leukemia in only a few. The disease about by a number of mechanisms, R. D. Hunt, P. Sehgal, M. D. Daniel, R. C. inducing potential of HIV-2 may fall including the elicitation by HIV-2 of a Desrosiers and M. Essex in SCience, Vol. between the two. protective immune response to both 228, No. 4707, pages 1199-1201; June viruses.) If individuals previously in 7,1985. eal difference in pathogenicity fected with HlV-2 nonetheless become ISOLATION OF T-LYMPHOTROPIC RETROVI � RUS RELATED TO HTLV-IIl/lAV FROM between HIV-l and HIV-2 could infected with HIV-l, will HIV-l then be significant, and it would be cause disease as relentlessly as it does WILD-CAUGHT AFRICANGREEN MON KEYS. important to determine its molecular in previously uninfected people? P. ]. Kanki, ]. Alroy and M. Essex in Science, Vol. 230, No. 4728, pages basis. The two viruses infect the same Answers to these questions are like 951-954; November 22, 1985. populations of cells, binding to the ly to yield information that will help in SEROLOGIC EViDENCE FOR VIRUS RELATED same CD4 receptor, but there are the design of vaccines to preVent in TO SIMIAN T-LYMPHOTROPIC RETROVI some differences in their genetic ma fection with HlV's. Although progress RUS IIIIN RESIDENTS OF WEST AFRICA. terial and therefore in their proteins. toward a vaccine against HIV-l may F. Barin, S. M'Boup, F. Denis, P. Kanki, One of the most obvious is the pres have seemed to be disappointing, it ]. S. Allan, T. H. Lee and M. Essex in ence in HIV-l of the vpu gene, which appears likely that some species of The Lancet, Vol. 2 for 1985, pages 1387-1389; 21/28,1985. is absent in HIV-2 (and in SlY, for monkeys, and perhaps some people, December HUMAN T-LYMPHOTROPIC VIRUS TYPE 4 that matter). Perhaps the product of have already evolved protective mech AND THE HUMAN IMMUNODEFICIENCY VI this gene, a small 16-kilodalton pep anisms that keep certain HlV's and RUS IN WEST AFRICA. Phyllis J. Kanki et tide, enhances pathogenicity. Similar SlY's from causing lethal disease. Ob al. in SCience, Vol. 236, No. 4803,pages ly, HIV-2 and SlYcontain the vpx gene; viously one cannot simply wait for 827-831; May IS, 1987. HIV-l does not. If this gene's 12-kilo natural selection to respond (as in the CLINICAL, HEMATOLOGIC, AND IMMUNO dalton product somehow slows the case of the Australian rabbits) with LOGIC CROSS-SECTIONAL EvALUATION proliferation or spread of the virus or the advent of more efficient immune OF INDIVIDUALS ExPOSED TO HUMAN IM MUNODEFICIENCY VIRUS TYPE-2 (HIV-2). reduces its ability to kill cells, that too mechanisms in people or of less viru Richard G. Marlink et al. in AIDS Re could help to explain why HlV-2 and lent viruses. The challenge, then, is to search and Human Retroviruses, Vol. 4, SlY appear to be less regularly patho understand the mechanisms that may No.2, pages 137-148; April, 1988. genic than HlV-l. have been involved in successful evo-

SCIENTIFIC AMERICAN October 1988 71 © 1988 SCIENTIFIC AMERICAN, INC The Epidemiology of AIDS • In the u.S . In 1981 Federal officials noted that a rarely prescribed drug was being dispensed more often. It was the first sign of the AIDS epidemic. By 1992 there willprobably be 365,000 cases in the U.S.

~~by William L. Heyward and James W. Curran~~

oday AIDShas become a major enumeration of the varied manifesta caused by the protozoan Pneumocys cause of morbidity and mortal tions of HIV infection and the analysiS tis carinii had been diagnosed in the ity in the u.s. Indeed, it has of the circumstances that made it pos Los Angeles area. (Protozoans are a becomeT the leading cause of death sible for such an infection to spread type of primitive microorganism.) This in the country among people with have been missions assigned to epide pneumonia is characteristically an op hemophilia and users of illegal intra miology: the study of the occurrence portunistic infection, occurring in peo venous (IV) drugs. Moreover, nation and distribution of disease as well as ple whose immune system has been wide morbidity and mortality rates its control in a given population. Epi profoundly impaired by cancer or by will increase in the next few years as demiologists monitor mortality and powerful immunosuppressive drugs. some of the one to I.S million Ameri morbidity rates associated with HIV The disease was so uncommon that cans who are already infected with the infection and AIDS;they also make the drug given to treat it, pentamidine human immunodeficiency virus (HIV) predictions of likely changes in HIV isethionate, was considered investiga develop AIDS. Most of those affected in infection rates in the course of time. tional (experimental) and could be dis the near future will be either homo Most important, by carrying out pensed solely by the CDC. Records at sexual men or IV drug abusers, and studies to define the ways HIV is trans the CDC showed that between Novem a significant proportion of them will mitted from person to person, epide ber, 1967, and December, 1979, there be blacks and Hispanics. Yet, given miologists can identify the popula had been only two requests for pent the fact that the virus is transmitted tion groups that are at greatest risk of amidine isethionate to treat adults through sexual contact, through the acquiring AIDSand thereby develop who had contracted P. carinii pneumo traces of blood in needles and oth strategies for the prevention and con nia without an underlying disease. Yet er drug paraphernalia and from moth trol of the disease-strategies that are in these fivenew cases the pneumonia er to newborn infant, one can envi independent of the development of an had struck young homosexual men sion many possible chains of infec effective vaccine or therapy. Indeed, whose immune system had no appar tion, which leave no segment of the determining the risk factors for AIDS ent reason for malfunctioning. u.s. population completely unaffected enabled the U.S. Public Health Service At about the same time the CDC by the threat of AIDS. and other groups to issue recommen received reports of an increase in the The discovery of the epidemic, the dations for the prevention of AIDSas incidence of a type of cancer known early as 1983, a full year before HIV as Kaposi's sarcoma. The cancer had was firmly identified and two years been seen only rarely in the u.S. be WIlllAM LHEYWARD and JAMES W. CURRAN are colleagues in the AIDSPro before laboratory tests to detect the fore-predominantly in elderly men gram at the Centers for Disease Control presence of the virus became widely and patients receiving immunosup (CDc) in Atlanta. Heyward is chief of in available. pressive therapy. Yet in a 3D-month ternational activities for the program. To carry out all these tasks epidemi span 26 cases of Kaposi's sarcoma had He was working in a CDC laboratory in ologists depend on surveillance: the been diagnosed among young homo Alaska in 1985 when the first AIDS case gathering of high-quality, consistent sexual men in New York and Califor was diagnosed in that state. Since then and interpretable data on a disease or nia. Several of these patients had also his involvement in AIDSresearch has an infection. Surveillancedata are rou experienced P.carinii pneumonia and increased steadily; he moved to Atlanta in 1987. Curran is director of the AIDS tinely compiled from reports filed other severe opportunistic infections. Program. He was a member of the CDC with state and local health depart Not long afterward clinicians and task force that was organized after the ments that are then forwarded to the epidemiologists noted an increased first AIDScases were diagnosed in 198 1 U.S. Centers for Disease Control (CDC). occurrence among homosexual men to help make investigators aware of the of two unexplained conditions: chron disease and to stimulate the research t was just such a report, in June ic lymphadenopathy (a condition char that led to the discovery of its cause. of 1981, that first alerted the CDC acterized by enlarged lymph nodes) The authors would like to note that the to AIDS.The report described how and a relatively rare malignancy called photographs accompanying this article I were not provided by the CDC. in the past eight months five cases of diffuse, undifferentiated non-Hodg an extremely rare type of pneumonia kin's lymphoma. Once again, the only

~~72 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC INTRAVENOUS (IV) DRUG ABUSERS share hypodermic needles blood, they may become infected. IV drug abuse is directly or and other paraphernalia that can be contaminated with blood indirectly responsible for most of the HIV infections in the U.S. infected with HIV. If they inject themselves with traces of the among heterosexual men and women as well as among infants.

~~SCIENTIFIC AMERICANOctober 1988 73~~

© 1988 SCIENTIFIC AMERICAN, INC ed risk factors. Such cases were con 12,000 33% firmed first among people with hemo 11,000 47% philia and then among blood-transfu 10,000 sion recipients as well as people who had shared hypodermic needles to in 58% 9,000 ject themselves with illicit drugs. Vl UJ 8,000 In July, 1982, three patients with Vl 70% « hemophilia from three differentstates u 7,000 u.. were confirmed as having P. carinii 0 6,000 77% pneumonia. In December of the same ex: UJ year an unexplained immunodeficien "" 5,000 80% ::;: P. carinii w � cy with fatal pneumonia as z 4,000 83% reported in a 20-month-old baby who 3,000 PERCENT DECEASED 83% at birth had received a blood-plate let transfusion from a man who sub 2,000 89% 90% sequently had died of AIDS. These re 1,000 89% ports convincingly supported the hy 92%I 93% 89% 0 pothesis that the disease was caused L-1981� L-1982� l-1983� l-1984� l-198S� l-1986� l-1987� by an infectious agent in the blood and perhaps in other body fluids. The NUMBER OF REPORTED CASESof AIDSin the U.S. has increased each year since the reports also bolstered the evidence disease was first recognized in 1981. The two bars for each year represent the that the period between HIV infection number of cases diagnosed respectively in the firstand second half of the year. The and AIDS could be quite long. dark part of each bar corresponds to the fatality percentage among the cases. Most During the following months several of the patients who were diagnosed before 1986 as having AIDShave already died. additional reports were received de scribing cases of AIDS in people who had received blood transfusions an common underlying factor among the people free of the disease (controls). average of two years before the onset new findings and the previously reo The first national AIDS case-control of the symptoms. In each case at least ported cases of opportunistic infec· study, done in 1981 among homosex one individual who had donated the tion and Kaposi's sarcoma was a se· ual men, indicated the variable that blood for the transfusions was iden verely impaired immune system. This most clearly distinguished patients tified as being in a group at high risk collection of clinical conditions was with the disease from homosexual for AIDS (such as homosexual men or recognized as an entirely new syn· controls was the number and frequen IV drug abusers). These reports not drome that became known in 1982 cy of sexual contacts. only reconfirmed the transmissibility as acquired immunodeficiency syn· Another study, done in June of 1982, of the putative AIDS agent through drome, or AIDS. provided further evidence that there blood but also emphasized the urgent Because the patients exhibited var was an AIDS agent and that it was need for preventing high-risk people ious common characteristics (such as transmitted through sexual relations from donating blood and for the de age, race, city of residence and sexual among homosexually active men. In velopment of laboratory tests that orientation), it was suspected that the that study data were obtained on the could detect the AIDS agent in donat wide range of clinical conditions had sexual partners of 13 of the first 19 ed blood. the same underlying cause. Moreover, cases of AIDS among homosexual men In January, 1983, two well-docu laboratory tests indicated that many in the Los Angeles area. Within five mented AIDS cases among heterosex patients with mild lymphadenopathy years before the onset of their symp ual partners of male IV drug abusers who did not exhibit any other signs of toms, nine of them had sexual contact were reported, indicating that the AIDS disease nonetheless had an abnormal with people who later developed Ka agent could be clearly transmitted to immune status, suggesting there was posi's sarcoma or P. carinii pneumo an infected man's heterosexual part an asymptomatic period in the pa nia. The nine were also linked to an ners as well as his homosexual ones. tients between initial infection and other interconnected series of 40 AIDS Later that year AIDS cases were first the eventual development of AIDS. Dur cases in 10 different cities by one recognized in people from central Af ing this so-called latency period a per individual who developed lymphade rica and Haiti who had no history son might not be ill and yet might be nopathy and was later diagnosed with of homosexuality or IV drug abuse. It capable of transmitting the disease. Kaposi's sarcoma. Overall, investiga became increasingly evident that AIDS This in turn meant that the pool of tion of these 40 cases indicated that was a sexually transmitted disease people who might be capable of trans 20 percent of the initial AIDS cases in and that the most important risk fac mitting the AIDS agent was significant the U.S. were linked through sexual tor was the relative number of differ ly larger than the number of cases of contact-a statistical clustering that ent sex partners-not necessarily sex AIDS reported to the CDC. AIDS was was extremely unlikely to have oc ual preference. It was also evident that only the tip of an epidemic iceberg. curred by chance. Still, many doubted the extent of homosexual transmis that AIDS could be caused by a trans sion of AIDS in relation to its hetero he method commonly employed missible agent. sexual transmission varied from coun by epidemiologists to determine Then came the first significant evi try to country. Trisk factors for a particular dis dence that other modes of transmis ease is the case-control study. In this sion were possible. In 1982 AIDS cases ecause the disease appeared to type of study people with the disease were described among people who be transmitted through the ex of interest (cases) are systematical had been injected with blood or blood change of blood or by sexual ly compared with a similar group of products but had no other expect- contact,B most investigators were con-

~~74 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC vinced by late 1982 that the cause of that the national supply of donated vidual patients, to the CDC. The pri AIDSwas an infectious agent (most blood could now be screened, so that mary sources of surveillance data likely a virus) and not the result of additional cases of AIDS due to blood on AIDS therefore include hospitals, exposure to toxicsubstances or other transfusions and contaminated blood clinics, physicians and medical-record environmental or genetic factors. The products could be avoided. systems (which handle such matters infectiqn hypothesis was finally con Serological studies among high-risk as death certificates, tumor registries, firmed when HIV was isolated by Luc groups soon confirmedwhat had orig communicable-disease reports and Montagnier and his colleagues at the inally been suspected: the AIDS cases hospital-discharge summaries). Pasteur Institute in Paris and by Rob recorded so far constituted just a frac The main concern about any surveil ert C. Gallo and his colleagues at the tion of the total number of people lance system is the completeness of National Cancer Institute. infected with HIV. These studies made the reporting. One way to measure Soon after the discovery of the AIDS possible a clearer definition of the this is to compare reports from vari agent a laboratory test was developed disease's modes of transmission, the ous surveillance sources. Recent stud to detect antibodies to HIVin the factors affecting the risk of infection ies in five major cities showed that blood. A positive result in a test of a and the specificpopulation groups at least 90 percent of the diagnoses person's blood sample was a reliable that should be targeted for prevention meeting the AIDScase definition were sign that the person was infected with and control measures. The serological in fact reported. This rate of reporting the virus. Such a serological test made test also clarified the clinical spec is extraordinarily high compared with it possible to detect HIVinfection in trum of the disease and enabled the that for most other diseases, for which people who showed no clinical symp CDC to formulate a more precise "case only between 10 and 25 percent of the toms, and to confirm clinical diag definition" of AIDS that made the di cases are typically reported. noses of AIDS and other HIV-related agnosis and reporting of AIDS cases conditions. It also made it possible more consistent nationwide. Of July 4 of this year, a total of to measure directly the prevalence of AIDS cases (along with cases of other �66,464 adults and children have HIVinfection (the number of infected diseases or health conditions) are re been reported as AIDScases to people in a given population at a given ported to state or local health agen the CDC. Of these, 37,535-more than time) and its incidence (the number of cies. Currently all 50 states, the Dis half-have died, including more than new infections occurring within a de trict of Columbia and Puerto Rico re 80 percent of the patients diagnosed fined period in a speCific population). quire that all such reports be passed before 1985. Since 1981, when report Most important, perhaps, was the fact along, without identifying the indi- ing of AIDS cases began, 63 percent

~~WASH. N. MICH. MONT . OAK. MINN.~~

~~ORE. S. OAK. IDAHO WYO.~~

~~NEBR.~~

~~COLO. KANS. MO.~~

~~OOTO.S ALASKA HAWAII 0.51 TOI • • •• 01.01 to 2~~

~~PUERTO RICO .2.01 TOS .MORETHAN 5~~

GEOGRAPHIC DISTRIBUTION of AIDSshows that the Northeast ported cases of AIDSper 10,000 population for each state, has been most affected.The map displays the cumulative re- the District of Columbia and Puerto Rico as of March 28, 1988.

SCIENTIFIC AMERICAN October 1988 75 © 1988 SCIENTIFIC AMERICAN, INC © 1988 SCIENTIFIC AMERICAN, INC © 1988 SCIENTIFIC AMERICAN, INC of the victims of the disease in the means, such as IV drug abuse and AIDScases among blacks and His u.s. have been homosexual or bisexu homosexual contact. It is also possi panics largely reflects higher reported al men without a history of IV drug ble that male-to-female transmission rates of AIDSin black and Hispanic IV abuse, 7 percent were homosexual or is more efficient than female-to-male drug abusers, their sex partners and bisexual men with a history of IV drug transmission. their infants. Because of the high con abuse and 19 percent were hetero The members of the fastest growing centration of IV drug abuse in the sexual men and women who were IV group of reported AIDSpatients are Northeast, the risk of contracting AIDS drug abusers. In addition almost 3 not adults; they are children. In the is between two and 10 times high percent of all the recorded AIDScases past 12 months 502 cases of AIDShave er for blacks and Hispanics living in were associated with transfusions been reported in children under 13 that region than it is elsewhere in the of contaminated blood, nearly all of years old-a 114 percent increase over country. Rates for transfusion-associ which had been received before 1985 the previous 12-month period. A total ated AIDS do not differ significantly (when serological screening of blood of 1,054 such pediatric cases have when they are divided by race or eth donors was instituted); roughly 1 per now been recorded. 1n 78 percent of nicity for adult cases, although the cent of the adults who contracted them the HIV infection was acquired rates are Significantly higher for black AIDSwere hemophiliacs. The means perina tally (before, during or soon af infants-perhaps owing to a greater by which the HIV infection was ac ter birth). Most of these pediatric cas need for transfusions to manage low quired was undetermined in only 3 es can be traced to IV drug use by the birth weight in black newborns. percent of adults with AIDS,generally child's mother or her sexual partner. because of incomplete information on In 19 percent of all pediatric cases the he human immunodeficiency the frequency of their sexual contacts, source of HIVinfection was either a virus is transmitted primarily among other factors . blood transfusion or treatment for through sexual contact, expo Of the 2,702 AIDScases attributed to hemophilia. sureT to blood and blood products and heterosexual transmission (represent In the u.s. 59 percent of the reported from mother to child during the peri ing 4 percent of the total), 1,643 (367 AIDScases among adults and 23 per natal period. In the u.S. most sexual men and 1,276 women) had a history cent of the cases among children have transmission of HIV has been among of sexual contact with a person docu been white; blacks have accounted for homosexual men. The risk of infection mented as having been infected with 26 percent of adult cases and 53 per in these men increases with the num HIV or with a person in another risk cent of pediatric cases, and Hispanics ber of sexual partners and the fre category. Another 1,059 were born in for 14 percent of adult and 23 percent quency with which they are the recep countries where heterosexual contact of pediatric cases. Such figures are in tive partner in anal intercourse. The is the major mode of transmission. striking contrast to the respective per insertive partner in anal intercourse, The 1: 3.5 ratio of male to female centages of blacks (11.6 percent) and however, has also been known to be cases of heterosexually transmitted Hispanics (6.5 percent) in the general come infected with HIV, and one re AIDSin the u.s. is probably due to a U.S. population. port has described infection in the larger pool of men infected by other The disproportionate percentage of receptive partner in orogenital inter course. The relative efficiency of trans mission for differenttypes of sexual practices is difficultto determine pre 63% 78% Cisely, because most homosexual men in studies have engaged in multiple practices. As in the case of other sex ually transmitted diseases, the fre quency of female-to-female transmis sion is very low, although at least one such case (involving the tearing of skin and mucous membranes) has been reported. Syphilis and genital herpes, as well as other causes of genital or anal ul cers, have been associated with HIV infection in homosexual men in the U.S. and in heterosexuals in central Africa. It is supposed that the dam age done to the genital skin and mu D HOMOSEXUAL OR BISEXUAL MEN D HETEROSEXUAL MEN AND WOMEN cous membranes by these infections may facilitate HIV acquisition or trans RECIPIENTS OF BLOOD HETEROSEXUAL IV DRUG ABUSERS . OR BLOOD-PRODUCT TRANSFUSIONS mission. If sexually transmitted gen D ital-ulcer diseases increase the trans HOMOSEXUAL OR BISEXUAL CHILDREN OF MOTHERS WITH AIDS IV DRUG ABUSERS OR AT INCREASED RISK FOR AIDS mission rate of HIV, then populations D D with high rates of venereal disease PEOPLE WITH HEMOPHILIA OR OTHER OR UNDETERMINED are likely to be at increased risk for • OTHER COAGULATION DISORDERS D HIV infection. Prevention and prompt POPUlATION GROUPSaccounting for the adult (left) and pediatric (right) cases of treatment of sexually transmitted in AIDSas of July 4, 1988, are indicated by these pie charts. As can be seen, homosexual fections could potentially slow the or bisexual men and IV drug abusers together account for 89 percent of all adult spread of HIV among sexually active cases. More than three-fourths of the children with AIDSacquired the disease from a men and women. mother who either had AIDSor was a member of the group at increased risk for AIDS. Although there have been many doc-

~~78 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC umented cases of male-to-female as well as female-to-male sexual trans mission of HIV, the study populations have been too small to allow a com parison of the relative efficiencies of transmission in the two directions. Most heterosexual transmission of HIV occurs during vaginal intercourse, but two small studies have suggest ed that anal intercourse increases the risk of infection in women. The cu mulative rate of infection has been . reported to be significantlyhigher among the female partners of infected male IV drug abusers and men from Haiti or countries in central Africa than it is among female partners of infected men in other risk groups (in cluding bisexual men, hemophiliacs and transfusion recipients). Among heterosexual couples in which one partner (the "index" case) is infect ed with HIV, from 10 to 70 percent of the other partners have become in fected through sexual intercourse. This variability in infection rate is not fully explained by the frequency of sexual contact; it may have something FIVE-Y£AR-OLD AIDS PATIENT is one of the increasing number of children who to do with how long the index case has have become infected withlllV perinatally: before, during or soon after birth. been infected. Recently it has been Reports of such pediatric cases doubled in number in a recent 12-month period. shown that people with AIDS or symp tomatic HIV infection are more likely to transmit HIV infection than those the major source of HIV transmission of 870 health-care workers who had who are asymptomatic or at an earli� in heterosexual men and women and, accidentally punctured their skin with stage of infection. Nevertheless, part consequently, of perinatal transmis needles contaminated with the blood ners in some such couples have man sion as well. of HIV-infected people developed HIV aged to remain uninfected, in spite of The possibility that one can become infection, but none of the 104 work the fact that the couples had long infected with HIV if contaminated ers whose mucous membranes or skin standing sexual relations and took no blood penetrates the skinor mucous had been exposed to blood became precautions against infection. membranes also represents a small infected. In another study of health These findings suggest that, in addi but definite occupational risk for care workers at the National Institutes tion to behavioral factors, biological health-care workers. In a national col of Health, no HIV infections occurred factors often contribute to HIV trans laborative study done by the CDC, four among 103 workers with needle-stick mission. It also appears that some infected individuals may be more ef ficient transmitters of HIV than oth 3,500 ers and that a person's infectiousness may vary with time. 3,000

ransfusion of a single unit of 2,500 HIV-contaminated blood is very V'l likely to result in infection; be � 2,000 u tweenT 89 and 100 percent of recipi ents of contaminated blood are re 01,500 � ported to become infected. Fortunate w � 1,000 ly transfusion of HIV-infected blood in ::::l U.S. the is now rare, since high-risk Z 500 people are discouraged from donat ing blood and all donated blood is O�--��lili��-'--r-l screened for HIV antibodies. Because 500� the sharing of needles and other drug FEMALE related paraphernalia also provides a o I I I I�III I I I I I I way for contaminated blood to be in o 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 AGE AT DIAGNOSIS jected into the body (in amounts sub stantially smaller than those involved in transfusions), that activity can re AGE DISTRIBUTIONS for male and female AIDSpatients in the U.S. indicate that most sult in HIV transmission as well. In patients are males between the ages of 25 and 45. The distinct peaks at the left ofthe deed, in the U.S. IV drug abuse is now distributions represent the small but increasing number of pediatric AIDS cases.

~~SCIENTIFIC AMERICAN October 1988 79~~

© 1988 SCIENTIFIC AMERICAN, INC injuries, nor were there any HIV infec ing HIV infection in these newborns. even lower than in household settings. tions among 691 workers who had a Currently all infants born to infected Epidemiological studies in the U.S. total of more than 2,000 reported skin mothers must be followed closely for and other countries throughout the and mucous-membrane exposures to at least 12 months to see whether world show no patterns of HIV infec blood or body fluids of AIDSpatients. there is any clinical or laboratory evi tion consistent with transmission by These studies are consistent with oth dence of HIV infection or AIDS. insect vectors. If HIV were transmitted er data indicating that the occupation by insect vectors, additional cases of al risk of acquiring HIV infection in here has been considerable con infection would be seen in people who health-care settings is low and is most cern that in rare circumstan share environments with infected in often associated with percutaneous ces other types of transmission dividuals. Such evidence is lacking, in inoculation of blood from an infected mightT occur-particularly through ca spite of extensive surveillance efforts. patient. sual contact with HIV-infected people In addition there is a relative absence HIV is also transmitted from an in or by way of insect vectors. Although of HIV infection in African preado fected mother to her newborn child, HIV has been recovered from the sali lescent children-another fact that ar but the extent of transmission that va of infected individuals, the virus gues against insects as an important takes place respectively during preg concentration is much lower in saliva mode of transmission. Although HIV nancy, at birth or soon afterward is as than it is in blood. In a CDC study not can survive for from several hours to yet unknown. Detection of HIV in fetal one of 48 health-care workers became several days in insects artificially fed tissues supports the hypothesis that infected after skin or mucous-mem blood with high concentrations of the infection occurs in utero, and case brane exposure to the saliva of HIV virus, there is no evidence that HIV reports of women who became infect infected people. actually grows in insects. Such a bio ed with HIV immediately after giving To evaluate the risk of HIV transmis logical event is important in most viral birth, and subsequently infected their sion through other casual contacts, diseases transmitted by insects. infants, suggest that the virus may be several prospective studies (which are To be sure, the existence of other transmitted through breast-feeding. carried out over several years) have unrecognized modes of HIV transmis Studies of such perinatal transmis been done of the families of infected sion can never be entirely excluded, sion are greatly complicated by the adults and children. In spite of tens of but if they do exist, they appear to be lack of a reliable diagnostic test to thousands of days of household con extremely rare. determine HIV infection in newborns. tact with infected individuals, not one As is the case with other infections, of more than 400 family members has athematical models have been infants born to HIV-infected mothers been infected with HIV-except for developed to predict the fu have maternally derived HIV antibod sexual partners of the infected person ture course of HIV infection ies circulating in their blood-regard. and children born to infected mothers. andM AIDSin the U.S. These models, less of whether or not they have been In these studies the documented risk which are useful for planning public infected. The maternal HIV antibodies of household transmission was zero, health programs, take into account may persist for as long as 12 months and therefore the actual risk must the natural history of HIV infection and cannot be distinguished from an be extremely low, even in crowd and make certain assumptions about tibodies that may be present in an ed households. The risk of transmis the size of the population groups at infant infected with HIV. Other tests sion in other social settings, such risk, diagnostic and reporting practic are under development for identify- as schools and offices, is presumably es and the incidence of infection. The projections must also adjust for the prolonged latency period of AIDS.(It is now estimated that about half of the people infected with HIV will develop 80% AIDSin 10 years.) The Public Health Service estimates that currently a total of between one and 1.5 million people in the U.S. are infected with HIV. Yet since the epi demic of HIV infection in the U.S. is actually a composite of many partial ly overlapping epidemics, each with its own rate of spread, there must be estimates of incidence in each of the groups at risk for AIDS in order to predict accurately the future course of the overall epidemic. Unfortunately the accurate data necessary for de AIDS PATIENTS U.S. POPULATION (1980) tailed estimates of the incidence and prevalence of HIV infection in most speCific groups and geographic areas are not currently available. Obtaining DWHITE D BLACK DHISPANIC OTHER the data is therefore a priority of the Public Health Service as well as state RACIAL AND EruNICClASSIFICA nON of the adult AIDScases shows a disproportion and local pUblic-health departments. ate fraction of them are among blacks and Hispanics. The figures reflect the higher At least two methods have been uti reported rates of AIDSin black and Hispanic IV drug abusers and their sex partners. lized to forecast short-term future

~~80 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC trends of AIDSin the U.S. One method, 30,000 employed by W. Meade Morgan and John Karon of the CDC, involves fitting a curve to the cases of AIDS reported in 25,000 the past and extrapolating it into the future. Another approach, called the back-calculation method, is used by � 20,000 Vl Ronald Brookmeyer and his collabora « u tors at the Johns Hopkins University o 15,000 68% CONFIDENCE BOUNDS-,,'.' School of Hygiene and Public Health. c:: LIJ This method makes use of current UNITED STATES: A REvIEW the recent decrease in incidence rates ing people on how to avoid behavior Of CURRENT KNOWLEDGE. Timothy J. for homosexual men is not uniform that results in the transmission of HIV. Dondero and the HIV Data Analysis and certainly the risk of HIV infection Counseling people found to be infect Team in MMWR (Morbidity and Mortali for homosexual men remains high. In ed with HIV involves not only advising ty Weekly Report), Vol. 36, Supplement contrast, since the screening of blood them and their sexual partners on how No. S-6; 1987. REpORT Of THE PRESIDENTIAL COMMIS and blood products for HIV antibodies to avoid HIV transmission but also SION ON THE HUMAN IMMUNODEfICIEN was instituted, the incidence of HIV providing them with medical care, so CY VIRU� EPIDEMIC. U.S. Government infection among people with hemo cial services and perhaps treatment Printing Office,1988. philia and among blood-transfusion for drug addiction. Indeed, the treat-

~~SCIENTIFIC AMERICAN October 1988 81~~

© 1988 SCIENTIFIC AMERICAN, INC The International Epidemiology of AIDS Reports to the World Health Organization suggest that at least five million people worldwide are infected by the AIDS virus and a million new cases of AIDS are likely within the next five years

~~by Jonathan M. Mann, James Chin, Peter Piot and Thomas Quinn~~

ver since the AIDSpandemic was ness of AIDSreporting vary in different from an infected mother to her infant. initially recognized in 1981 it areas of the world. In the U.S., valida There is no evidence to support trans has been met by denial and a tion studies by the Centers for Disease mission by food or water, by biting grossE underestimation of its potential Control in Atlanta have indicated that insects or by coughing or sneezing. magnitude. The pandemic is still in its from 80 to 90 percent of diagnosed Most important, there is no evidence early stages and its ultimate dimen cases are in fact reported. In most for casual transmission between peo sions are difficult to gauge, but by now developed countries, it is thought that ple in schools, in the workplace or it is apparent that AIDSis an unprece the majority of diagnosed cases are other such social settings. Individual dented threat to global health. From reported to national health authori reports and rumors to the contrary our current knowledge of the disease, ties. On the other hand, it is thought should not be allowed to distort the we estimate that over 250,000 cases that in most developing countries the basic facts about transmission, be of AIDShave already occurred, that majority of AIDScases to date have not cause an understanding of how HIV is between five and 10 million people been reported to the WHO because of spread and not spread is central to the worldwide are infected with the AIDS significant underrecognition, underdi development of appropriate and ef virus and that within the next five agnosis and underreporting. fective control measures. years about one million new AIDScas After infection a person may remain es can be expected. In short, the global he thousands of AIDScases now symptom-free for years. Anunknown situation will get much worse before it being reported every year are proportion of infected people do ex can be brought under control. Tdue to HIV infections that began perience an early, brief, mononucleo This grim prognosis is based on spreading silently and extensively in sis-like illness with fever, malaise and numerous epidemiological studies the 1970's, before the disease was possibly a skin rash. Such symptoms, that have clarified the current distri even recognized and before HIV was when they are present, develop at bution patterns of human immunode isolated. Although blood stored as about the time antibodies produced ficiency virus (HIV),which causes AIDS, early as 1959 in Zaire has been found by the body against HIV can first be and its various modes of transmis to contain antibodies against the AIDS detected. This usually occurs between sion. Worldwide surveillance of AIDS, virus, the actual origin of HIV is still two weeks and three months after from which the global distribution not known with any certainty; this infection, rarely later. From that point pattern is determined, is coordinated ignorance was underscored when in on an average of eight or nine years by the Global Program on AIDS (GPA) at 1987 the World Health Assembly stat may pass before AIDSis fully devel the World Health Organization (WHO) ed that HIV is a "naturally occurring oped. The fatality rate for AIDS, once it in Geneva. Reports to Geneva are re retrovirus of undetermined geograph has developed, is very high; it may ceived from the WHO'S regional offices ic origin." In 1985 a related virus was reach 100 percent. The interval be and individual countries' ministries of discovered in West Africa. The original tween diagnosis of AIDSto death var health. The accuracy and complete- virus and the newer one are now re ies greatly: in developed countries ferred to as HIV-l and HIV-2 respec about 50 percent of the patients die tively. Although preliminary observa within 18 months of diagnosiS, and 80 MANN, JONATHAN M. JAMES CHIN, tions suggest that HIV-2 infections percent die within 36 months. Sur PETER PlOT and TIIOMAS QUINNcol may be less pathogenic than those of vival times appear to be shorter in laborate on the investigation of AIDS. Mann has been director of the World HIV-l, the natural history of HIV-2 has Africa and Haiti, but this may be due Health Organization's Global AIDSPro not been fully established and for the to later diagnosis and limited medi gram (GPA) since its inception in 1986. purposes of this article the two virus cal facilities. To date no study has Chin is chief of the AIDS Surveillance es are assumed to have similar effects. found any resistance to HIV among Unit for the GPA. Piot is professor of By now a clear picture of how HIV any race group. microbiology at the Institute of Tropical is transmitted has emerged. Studies Since HIV infection precedes the de Medicine in Antwerp. Quinn is on the have consistently shown that the virus velopment of AIDS by at least several medical staff of the National Institutes is transmitted by sexual intercourse years, to get a good picture of the of Health and at the Johns Hopkins Hospital in Baltimore. (vaginal or anal), by the injection or disease's current distribution one can administration of infected blood or not rely solely on reported AIDS cases;

82 SCIENTIFIC AMERICAN October 1988 © 1988 SCIENTIFIC AMERICAN, INC FUNERALS FOR AIDS VICTIMS are daily occurrences in Kyo which causes AIDS,infects as many as 15 or 20 percent of tera, a town inUganda from which most of the merchants have certain segments of the adult urban population of Uganda, as fled and where most of the children are now orphans. HIV, well as that of the Congo, Rwanda, Tanzania, Zaire and Zambia.

~~PATTERN I~~

~~�PATTERNII r-----,PATTERN III OR '-----lNOT REPORTING~~

~~HIV-2~~

TIlREE INFECTION PATfERNSof the AIDSvirus are apparent primary mode of transmission in these regions is heterosexual worldwide_ Pattern I is found in North and South America, sex and the number of infected females and males is approxi Western Europe, Scandinavia, Australia and New Zealand_ In mately equaL Pattern ill is typical of Eastern Europe, North these areas about 90 percent of the cases are homosexual Africa, the Middle East, Asia and the Pacific (excluding Austra males or users of intravenous drugs_ Pattern U is found in lia and New Zealand); there are relatively few cases and most of Africa, the Caribbean and some areas of South America; the them have had contact with pattern- lor pattern-U countries.

it is also necessary to collect data on those used by IV drug users, are not a ern Europe, North Africa, the Middle the number or proportion of people significant factor in HIV transmission East, Asia and most of the Pacific (ex who are infected with HIV. Such "sero in pattern-I countries. cluding Australia and New Zealand). In prevalence data" indicate by the pres In pattern-I areas the male-to-fe_male pattern-III countries, HIV was probably ence in the blood of antibodies against sex ratio of reported AIDScases ranges introduced in the early to mid-1980's,

HIV, that a person has been infected by from 10 to one to 15 to one. Because and only a small number of AIDScases the virus. From analyses of both AIDS relatively few women are infected in has so far been reported. These have reports and seroprevalence data three these areas, to date perinatal trans generally occurred in people who have broad, and yet distinct, patterns of mission (transmission from mother to traveled to pattern-lor pattern-II areas AIDShave been recognized. infant) is not common. In the overall and who have had sexual contact with population of pattern-I countries, in individuals from such areas. Indige attern I is typical of industrial fection by HIVis estimated (on the nous homosexual, heterosexual and ized countries with large num basis of seroprevalence data) to be IV-drug-use transmission have only Pbers of reported AIDScases. less than 1 percent, but it has been recently been documented. Some cas These countries include the U.S., Mexi measured at more than 50 percent in es have been caused by imported co and Canada, many Western Europe some groups practicing high-risk be blood or blood products and, in a an countries, Australia, New Zealand havior: men with multiple male sex few pattern-III countries, they account and parts of Latin America. Some re partners and IV drug users who share for the largest percentage of reported gions of North Africa also exhibit pat unsterile needles or syringes. AIDScases to date. tern-I behavior, though these areas are Pattern II is presently observed in With these infection and disease not industrialized. In pattern-I coun some areas of central, eastern and patterns as a guide, we shall now ex tries HIV probably began to spread southern Africa and increasingly in amine the geographical distribution of extensively in the late 1970's. Most certain Latin American countries, par AIDSin more detail, concentrating on cases occur among homosexual or bi ticularly those of the Caribbean. Like the epidemiology outside North Amer sexual males and urban intravenous pattern-I areas, pattern-II areas proba ica [see "The Epidemiology of AIDSin (IV)drug users. Heterosexual trans bly saw the extensive spread of HIV the U.S.," by William L. Heyward and mission is responsible for only a small beginning in the late 1970's. In con James w. Curran, page 72]. percentage of cases but is increasing. trast to pattern-I areas, however, most There was transmission due to the cases in pattern-II areas occur among he continent hardest hit by the transfusion of some blood and blood heterosexuals and the ratio of infect AIDSpandemic is Africa where products between the late 1970's and ed males to females is approximately all three infection patterns can 1985, but that route has now been one to one. Transmission through ho beT found. Patterns I and II are seen in practically eliminated by convincing mosexual activity or IV drug use is South Africa. Pattern IIIprevails in people in high-risk groups not to do either absent or at a very low level, but North Africa, including most countries nate blood and by routine, effective because many women are infected, in the Sahel region. In sub-Saharan testing of blood donors for antibodies perinatal transmission is common. Africa, below the Sahel, pattern II pre against HIV. Unsterile needles, except Pattern III prevails in areas of East- vails in the large urban areas of cen-

84 SCIENTIFIC AMERICAN October 1988 © 1988 SCIENTIFIC AMERICAN, INC tral, eastern and southern Africa. In has not been documented to any ap bility to infection or the capacity to West African countries, where pattern preciable extent among AIDScases or disseminate fIIV.Neither have virolog II is also found, HIV-2 infections are HIV-infected people in sub-Saharan ical studies so far revealed any differ much more common than HIV-l infec Africa. Many epidemiological studies ence among any strains of HIV that tions. AIDScases are being increasing have shown that transfusion of HIV would result in increased infectious ly detected in West Africa; whether infected blood can account for only a capability and hence the large number HIV-2 will ultimately prove to be as small fraction of the infections in sub of infections among Africans. pathogenic as HIV-l remains an open Saharan Africa. The use of unsterile Given that the above factors do not question and is the subject of intense needles or other skin-piercing instru appear to contribute significantlyto epidemiological and clinical research. ments within the health-care system the spread of AIDSin Africa, one re AIDShas become one of the major or as part of traditional healing prac turns to what is well established: the health problems that confront the tices also accounts for only a small likelihood of sexual transmission of countries of central and eastern Africa portion of HIV infections in these are HIV appears to be governed by the in particular. In many of the urban as. Ritual surgical removal of the clito probability of exposure to an infected centers of the Congo, Rwanda, Tanza ris in females has been postulated to partner as well as the specific sexual nia, Uganda, Zaire and Zambia from S be an important factor in the spread acts performed with that partner. Al to 20 percent of the sexually active of HIV. The areas where such so-called though systematic studies of sexual age-group has already been infected circumcisions are still carried out, behavior in sub-Saharan Africa are not with HIV. Rates of infection among however, do not in general coincide yet available, investigators have gener some prostitute groups range from 27 with the areas where HIV or AIDS is ally reported a greater number of sex percent in Kinshasa, Zaire, to 66 per currently most prevalent. ual partners and/or contacts with fe cent in Nairobi, Kenya, and 88 percent Genetic differences between pat male prostitutes among African males in Butare, Rwanda. Close to half of all tern-I and pattern-II populations have who have AIDSthan among control patients in the medical wards of hos also been proposed by several Indian groups. High rates of partner ex pitals in those cities are currently in and Caribbean investigators to explain change, or the frequent exposure to a fected with HIV. So are from 10 to 2S the level and extent of heterosexual relatively small number of prostitutes percent of the women of childbearing transmission in Africa. Yet no genetic of many men who then return to their age, and that will mean an increase in basis has been identified among race spouses, could contribute to the epi child mortality by at least 2S percent; groups for either increased suscepti- demiological pattern of HIV infection the gains achieved with difficulty by child-survival programs over the past 60 two decades may be nullified. By the ,'1 early 1990's the total adult mortality I 1 " 1 rate in these urban areas will have I I AIDS. I been doubled or tripled by 50 -!. I As bleak as this picture is, the situa " 1 I 1 tion could become even worse if the " 1 AIDSepidemic spreads significantly I :AMERICAS from urban areas, where it is now focused and which contain only from 40 10 to 20 percent of the population, to the rural areas where most people live. YEARLY TOTAL The cumulative total of AIDScases in Africa by mid-1988 was estimated at 30 more than 100,000, and health-care systems in developing African coun tries are often unable to cope with the current patient load. How these health-care systems will be able to 20 AFRICA manage the additional 400,000 cases projected within the next five years in urban areas is a problem seeking solu tions; it will be a severe challenge not 10 only to the countries directly affected EUROPE but to external assistance groups. In pattern-I countries, for example OCEANIA the U.S., HIV infection is found over whelmingly among male homosexu o --=:::::::::::::::=---==;;;;;;;;;;;;;;;;:::::=:-----II!'I!!!!...! ::LASIA als and IV drug users. In contrast, the 1980 1981 1982 1983 1984 1985 1986 1987 1988 major characteristic of the pattern-II (WHO) infection in most of sub-Saharan Afri NUMBER OF AIDS CASES reported to the World Health Organization in each year from 1979 to 1988 is shown. The 1988 data, indicated by dashed lines, are ca is its prevalence among heterosexu projections. The Americas dominate the number of reported cases in part because of als. What accounts for the difference? high reporting efficiency, which perhaps approaches 90 percent. The total-cases Widespread IV drug use, which curve exhibits nearly exponential growth, with a doubling time of slightly over a year. would lead to increased heterosexual This striking rate of increase is due not only to an actual increase in the number transmission, is not a significant prob of AIDScases but also to improved surveillance. The cumulative total as of August lem in sub-Saharan Africa; although 1 was 108,176. Underreporting is still a problem in many parts of the world, how· homosexuality exists worldwide, it ever, and the WHO estimates that the true total was actually close to 250,000.

~~SCIENTIFIC AMERICAN October 1988 8S~~

© 1988 SCIENTIFIC AMERICAN, INC in these areas. Among sexual practic es, available studies strongly suggest that vaginal intercourse is the domi nant behavior in sub-Saharan Africa, reinforcing the supposition that fre quency of sexual contact is the pri mary factor governing the transmis sion of HIV there. Certain aggravating factors may help to explain possible differences in susceptibility to HIVinfection. For ex ample, individuals whose immune system has been activated by chronic infections might be more easily infect ed on exposure to HIV. There is also increasing evidencethat the presence of other sexually transmitted diseases increases the risk of HIVinfection. Studies in Africa indicate that such diseases (in particular those charar;: terized by genital ulceration, such as chancroid and syphilis) may increase susceptibility to infection on exposure to a partner carrying HIV or may in crease the infectivity of a person car rying HIV. Studies in the U.S. show that HIV infection is positively correlated with the presence of genital or anal lesions in homosexual men. More over, the higher prevalence of sexually <> transmitted diseases, including chan croid and syphilis, in tropical Africa compared with general populations in Europe is consistent with the hypothe sis that such diseases aggravate the spread of AIDSin Africa.

urning from Africa to Asia and the Pacific, one finds a less grim Tsituation. In Oceania, as of June 1, 1988, four countries have reported REPORTED AIDS CASES per 100,000 of population are mapped for 1987. Displaying a total of 892 cases of AIDS,all but two the case rate rather than absolute numbers has the advantage of showing approxi· of which were reported by Australia (813) and New Zealand (77). These two countries exhibit the pattern-I infec 1,000. Small pockets of relatively high ing a great potential for further spread tion characteristic of the U.S. Other infection rates, however, have been within the IV drug community, these countries in Asia and the Pacific have found among some prostitute groups people also providea relatively large generally low levels of HIV infection in the Philippines, where up to .5 per pool for sexual transmission of HIV and few AIDS patients. In these areas cent may be infected, and in India, within that community and outside it. HIVinfection and AIDShave been de where up to 6 percent may be infected. tected mainly in people who have vis In Asian and Pacific countries HIV n Europe the epidemiology of AIDS ited a pattern-lor pattern-II country or infections do not appear to be spread shows a sharp contrast from east have had sexual or needle-sharing con ing rapidly among the general hetero to west and from north to south. In tact with people from such countries. sexual population, but intensive sur WesternI Europe the pattern is strik In China and Japan the largest num veillance of prostitutes and patients ingly similar to that in the U.S., albeit ber of documented HIV infections are with sexually transmitted diseases is delayed by a couple of years. Homo among those people to whom import being undertaken to monitor this situ· sexual males and IV drug users ac ed blood or blood products were ad· ation closely. Of great public concern count for more than 90 percent of ministered before 1986. Still, in abso in Thailand was the documentation in AIDScases, as they do in the U.S. lute and relative terms the number is early 1988 of a marked increase of Regional differences in the share of very small. Among blood donors in HIV-infected IV drug users in Bangkok. AIDScases accounted for by homosex Hong Kong and Singapore, only about The infection rate in this group went uals and IV drug users are seen in one person in from 50,000 to 80,000 from zero in 1986 to 1 percent in 1987 Western Europe, as they are in the U.S. have been found HIV seropositive, that and 16 percent in early 1988. It is For example, in California homosexual is, to have antibodies against HIV. In estimated that there are 60,000 IV males account for 90 percent of AIDS female prostitute populations, the HIV drug users in Bangkok, and so there cases and drug users less than 10 infection rate has been found to be may now be close to 10,000 HIV-in percent; in New York each group ac either zero or at most about one per fected people in that city. Besides pos- counts for about 50 percent. In such

~~86 SCIENTIFIC AMERICAN October 1988~~

~~D [J D~~

D ----+----1--+1 mately what proportion of the population has AIDS. Such data with good AIDSsurveillance; the incidence tends to be under do, however, tend to overstate the incidence in small countries stated for countries that do not report most cases to the WHO.

northern countries of Western Europe world, is concentrated primarily in enable one to make some broad state as Denmark, Sweden and the UK, ho large urban areas. By June of this year ments about the present and future. mosexual cases account for from 70 approximately 8,000 cases had been The number of countries reporting to to 90 percent of the total, whereas reported from Latin America and the the WHO now stands at 175; 138 have in two southern countries, Italy and Caribbean; the number of unreported listed at least one AIDS case. As of Spain, N drug users account for more or unrecognized cases is probably sev August 1 these countries had reported than half of all AIDScases. eral times this figure. During the first 108,176 cases to the WHO Global Pro Eastern Europe presents a some few years of AIDSreporting Latin gram on AIDS.Of these cases about what differentpicture. The few AIDS America followed pattern I: virtually 10,000 were reported in the first half cases that have been reported there all the reported cases were homosex of 1988. Because of inherent delays in collectively represent only about .5 ual men or N drug users. This was reporting as well as the underreport percent of all reported European AIDS particularly the case in Brazil, where ing and underrecognition that persist cases. Of this small fraction the major about 3,000 cases have been reported in many parts of the world, however, a ity of cases are among homosexual to date, the highest figure from a Lat more reasonable estimate of the num men and N drug users who have gen in American country. During the past ber of AIDS cases that have already erally acquired their infection from year or two, however, the trend toward occurred would exceed 250,000. outside Eastern Europe. The delayed heterosexual acquisition of HN has appearance of AIDSin Eastern Europe been increasing. This is now true in stimating the number of HN-in and its low prevalence there compared the Caribbean countries of Haiti and fected people in 1988 is more with Western Europe are likely to be the Dominican Republic, where heter difficult, because the available se related to different social patterns of osexual cases now outnumber homo roprevalenceE data are limited. As more homosexuality and to drug use. sexual and N drug cases. AIDStesting is carried out and newer The AIDSepidemic in Latin America The data that contribute to the pre studies are made available, estimates and the Caribbean, as in the rest of the ceding epidemiological picture of AIDS will be revised, but the following

~~SCIENTIFIC AMERICANOctober 1988 87~~

© 1988 SCIENTIFIC AMERICAN, INC figures are reasonably conservative. known. Estimates have ranged from a In contrast, short-term projections The U.S. Public Health Service has low of about 10 percent within five (up to five years) of the number of estimated that between one and 1.5 years of initial infection to a high of AIDScases can be made because they million people are infected in the U.S. 30 percent or more. Whether the pro are virtually independent of any fu In Europe, epidemiologists responsi· portion will reach 50, 75 or 100 per ture trends in HIV infection. The rea ble for national AIDSsurveillance have cent within 10 or 20 years after infec son is that the vast majority of the estimated that by the end of 1987 at tion can only be answered with time. AIDScases and deaths over the next least half a million people were infect The pathogenicity and distribution of five years will involve people who ed by HN. Many serological surveys HN-2 co mpared with HIV-l are also are already infected; the cases would are still under way in Zaire and Uganda not known and need to be determined. develop and the deaths would oc but available data suggest that from The problem of prediction is com cur even if all HIV transmission were two to three million people in Africa plicated by the role of aggravating to cease in 1988. The average period may already have been infected by cofactors of the type already dis from infection to the development of HN. Adding Canada and Latin America cussed. It has been postulated, for AIDSis now estimated by most mod leads one to conclude that a consis instance, that the presence of other elers to be between eight and nine tent estimate for the minimum num sexually transmitted diseases may fa years. If five million people are infect ber of HIV-infected people worldwide cilitate the transmission of HN. Other ed worldwide, as estimated above, one would be five million. cofactors may speed the progression can conservatively expect one million To project the course of AIDS is as from infection by HIV to the actual new AIDScases over the next five difficult as it is important. Many fac development of AIDS,but their roles years. Beyond fiveyears the death toll tors complicate accurate prediction of have not yet been determined. Nor is from those infected as of 1987 could the pandemic's ultimate dimensions: the degree of infectiousness of HIV potentially double or triple. We em First, it has only been possible to infected people known with any accu phasize that this figuredoes not take study the scope of the pandemic for racy. Although there is some evidence into account the number of new infec about seven years, and there is virtu that infectiousness increases marked tions that will inevitably occur. ally no other viral infection in hu ly during the later stages of HIV infec The social and economic impact of man beings whose behavior is simi tion, more studies need to be done. such an AIDS explosion will be sub lar enough to provide an analogy for Finally, one hopes that current efforts stantial. Mortality rates among the predictions. Furthermore, the propor to prevent AIDSwill eventually invali economically and socially most pro tion of HN·infected individuals who date any long-term prediction based ductive age·groups, in particular peo will eventually develop AIDS is still not on current data. ple from 20 to 49 years old, will rise severalfold in severely affected pattern-I and pattern-II areas as a re sult of AIDS.This selective impact on young and middle-aged adults, includ ing business and government workers, as well as members of the social, eco nomic and political elites, will have grave economic consequences. The Harvard Institute of International De velopment estimates that by 1995 the ' annual loss to Zaire from AIDS deaths will be $350 million, or 8 percent of the country's 1984 G.N.P.; this was more than Zaire received in that year from all sources of development as sistance combined. The same study estimates that economic losses in cen tral Africa by 1995 will be $980 mil lion. It is not inconceivable that such social and economic impacts could lead to political destabilization of the countries involved.

he urgency of the situation has resulted in the creation of a global program against AIDSco ordinatedT by the WHO. The program has three objectives: to prevent new HIV infections, to provide support and care to those already infected and to link national and international efforts against AIDS. EDUCATIONAL BROCHURES warning Ugandans to "love carefully" and practice "zero grazing" are distributed in 10 languages. The pamphlets held by two girls from the The first objective is achievable in Sese Islands on Lake Victoria follow Ugandan slang in calling AIDS "slim"; this refers principle because it is now known to the final stages of the disease, when patients suffer radical weight loss. Since an that HIV is almost always transmit effective AIDSvaccine is unlikely in the near future, educational measures, now being ted through certain readily identifiable adopted by dozens of countries, are the only practical way to slow the epidemic. and mostly voluntary behaviors. It is

~~88 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC vital to emphasize this point; because and Latin America, unfortunately, the tion and abortion calls for varied ap they are recognizable, the behaviors cost of screening and the general in proaches adapted to the cultural back that transmit HIValso make it possi frastructure requirements for blood ground of the population. ble to prevent its spread. Consequent banking have limited the implementa The second objective of the WHO 'S ly information and education pro tion of such safety measures. Partic global AIDSstrategy is to reduce the grams are needed in all countries. For ularly in Africa, voluntary abstention personal and public impact of HIV these education programs to be effec of infected individuals from donating infection. This means giving AIDSpa tive, however, they must be supple blood or the screening of donors is tients humane care of a quality at least mented by health and social services. not likely to protect the blood supply equal to that provided in each society Advocating the use of condoms is and could drastically reduce the avail for other diseases. Counseling, social pointless if condoms are not available, able donor pooL A simple and inex support and services must be avail costly and of poor quality. Advocat pensive screening assay for HIV infec able to all infected individuals. HIV ing a change of behavior among drug tion appropriate for use in the devel infected persons must not be discrim users is fruitless if treatment centers oping world is urgently needed. inated against; the rights and dignity are not available. The prevention of perinatal trans of these people must be protected to Prevention of new HIVinfections mission depends primarily on protect ensure that AIDSprograms can be ef through blood transfusion is also fea ing women of childbearing age from fective and that the AIDSproblem is sible. Screening of donated blood for HIV infection. In women already in not simply driven underground. HIVantibodies is now routine in the fected with the virus it may be pos The third objective, to unify national U.S. and in many parts of the industri sible to prevent pregnancy. Dealing and international effortsagainst AIDS, alized world. In most areas of Africa with issues of childbearing, contracep- has speedily become a reality. More than 150 countries have now estab lished national AIDScommittees. As of June 10, 151 countries had requested COUNTRY 1987 (Cases) 1987 (Rate) 1988 (Cases) support from the WHO'S Global Pro gram on AIDS.Technical evaluation and assessment visitshave already Argentina 51 0.1 43 Australia 342 2.1 143 taken place in 137 of these countries. AIDS Austria 85 1.1 37 Short-term national plans to cov Bahamas 78 33.9 25 er an initial six-to-18-month period Belgium 85 0.8 25 have been established in 106 coun Brazil 1,361 0.9 206 tries; urgent technical and financial Burundi 652 13.0 235 support has been delivered to help Canada 513 1.9 232 start this work without delay. More Chile 34 0.2 13 than 40 countries have been given Denmark 97 1.8 25 support to develop medium-term Dominican Republic 256 3.9 152 (three-to-five-year) comprehensive na Ethiopia 19 0.0 18 tional AIDSplans. Through more than 1,852 France 3.3 555 40 scientificmeetings, the WHO has 45 56.2 10 French Guiana established the basis for national poli 53 0.5 18 Greece cy formulation; scientificconsensus is 332 5.0 231 Haiti leading to plans to coordinate interna Honduras 58 1.2 38 tional trials of therapeutic agents and Israel 13 0.3 11 AIDSvaccines as these become avail Italy 888 1.5 387 able for field testing. Jamaica 37 1.4 13 Japan 34 0.0 7 There is no precedent in the history Mexico 499 0.6 14 of pUblic-health efforts for the speed, Netherlands 215 1.4 75 intensity or scope of this global mobi New Zealand 30 0.9 21 lization against AIDS.This in itself is Norway 35 0.8 11 cause for optimism. Yet the control Portugal 44 0.4 35 and ultimate prevention of AIDSwill South Africa 46 0.1 19 require sustained, long-term, national Sweden 73 0.8 34 and international commitment. There Switzerland 163 2.4 84 will be no easy answer. United Kingdom 653 1.1 239 United States 21,846 8.9 6,442 West Germany 873 1.4 222 FURTHERREADING Yugoslavia 18 0.0' 12 CONFRONTING AIDS: DIRECTIONS FOR PuBLIC HEALTH, HEALTH CARE, AND RE Zambia 286 4.0 218 SEARCH. Edited by Roy Widdus.Nation al Academy Press, 1986. AIDS-A GLOBAL PERSPECTIVE. In The ALL COUNTRIES that have reported more than five AIDScases to the WHO in 1988 are Western Journal of Medicine, Vol. 147, listed here. The left column gives the total number of cases reported by each country No.6; December, 1987. 1987, 1987 (AIDS 100,000 for the middle column gives the rate cases per population) CONFRONTING AIDS: UPDATE 1988. Edit 1988. 1988 and the last column shows the number of cases reported in early Most ed by Robin Weiss. National Academy reports were for only the first quarter or third of the year, and so comparison with Press, 1988. 1987 should be avoided. Owing to reporting delays of six months or more, cases THE AIDS ISSUE. In SCience, Vol. 239, No. reported in 1988 actually were diagnosed in 1987. Moreover, some countries with 4840; February 5, 1988. high AIDSrates have not reported any cases in 1988 and so are not shown here.

~~The human immunodeficiency virus causes a spectrum of disease that culminates in AIDS. Early detection of HIV infection, often years before symptoms emerge, is key to prolonging health and life~~

by Robert R Redfield and Donald S. Burke � PhYSiCians we are often asked AZT), which has been shown to pro ease, in 1984 we developed a classifi to describe the typical course of long life in patients with late-stage cation system that provides a frame AIDS:the severe immune defi disease, holds promise as a therapy work for managing patients and un ciency that enables normally benign for patients in earlier stages of infec derstanding the progression of the organisms to flourish destructively in tion. Early diagnosis also eliminates disease. The system groups patients patients. Our answer is that people are the unwitting transmission of HIVand according to their stage of infection, asking the wrong question. Now that gives people the opportunity to con judged by several indicators of the AIDS is known to be caused by a vi sider changing their behavior before immune impairment that underlies rus-the human immunodeficiency they pass the virus to others. HIV disease. virus, or HIV-the focus should be on Although the continuing emphasis As the disease progresses, the pa the full course of the viral infection, on AIDS alone is seriously misguided, tient moves through six stages, the not solely on AIDS. HIV causes a pre it is somewhat understandable. When last of which is AIDS. In our system dictable, progressive derangement of AIDS was first identified in 1981, it was the presence of opportunistic infec immune function, and AIDS is just one, a mysterious syndrome: a cluster of tions is a criterion for the diagnosis late manifestation of that process. rare diseases that had suddenly be of AIDS, but the presence of Kaposi's An emphasis on HIVis important come alarmingly common in homo sarcoma is omitted because the can because it facilitates both treatment sexual men. In order to identify simi cer is not caused by immune suppres and prevention. Prompt diagnosis of lar cases of AIDS, and thereby help to sion and can appear early in the HIV infection enables the patient to uncover the cause and means of trans course of HIV infection. (Inclusion of receive optimal medical care from the mission, the U.S. Centers for Disease Kaposi's sarcoma in the CDC definition earliest moments of the disease. Such Control (CDC) adopted a strict ep hindered the understanding of the care can often prevent complications idemiological-surveillance definition. natural progression of HIV infection from developing or getting unneces People were said to have AIDSif they and confounded studies of longev sarily out of hand. For instance, the contracted Kaposi's sarcoma (a rare ity because patients with Kaposi's lethal opportunistic infection Pneu cancer) or if they developed any of sarcoma alone usually lived longer mocystis carinii pneumonia (PCP), a few rare opportunistic infections, than people who had severe immune which has been a hallmark of AIDS, can most notably PCP. impairment.) now actually be prevented with medi The extremely restricted definition cation given early in the course of HIV worked brilliantly: by 1984 HIV had he immune dysfunction on disease. (Opportunistic infections are been identified as the cause of AIDS. Twhich the Walter Reed scheme is ones that occur because the immune Moreover, workers had gained great based has long been known to system has broken down.) In addition, insight into the methods of transmis result mainly from depletion of a spe the medicine Retrovir (also known as sion, which are now known to be pri cific set of white blood cells called T4 marily intimate sexual contact, direct lymphocytes. The various parts of the contamination of the blood (as when immune system are highly interde ROBERT R.REDFIELD and DONAlD S. virus-contaminated drug parapherna pendent, but if anyone part can be BURKE are colleagues at the Walter Reed lia is shared) or the passage of virus called its quarterback, it is the T4 cell, Army Institute of Research in Washing from a mother to a fetus or to a also known as the helper Tcell. Among ton, D.C. Redfield is chief of the section of retrovirology, immunoregulation and suckling baby. Unfortunately the early other functions, it recognizes foreign immunotherapy and medical director of CDC definition also focused attention antigens, or markers, on infected cells the clinical virology laboratory. He was so narrowly on AIDS that many doctors and helps to activate another set of recently given the first annual Thomas and lay people failed to broaden their white cells called B lymphocytes. The Parran Award for his work on HN in view once HIVwas identified. B cells then multiply and produce fection. Burke is a colonel in the Med Because we and our colleagues at specific antibodies that bind to infect ical Corps of the U.S. Army. He has the Walter Reed Army Medical Center ed cells and to free organisms bear been chief of the Department of Virus Diseases at the Institute of Research believe HIV-infected patients must be ing the identified antigen, inactivat since 1984. treated on the basis of the fullest ing those cells and organisms or lead possible understanding of their dis- ing to their destruction. The T4 cell

~~90 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC BURK FAMILY, shown in 1985, looked like a typical U.S. fami· is not infected. This story underscores two important facts. ly. Yet the father, Patrick, a hemophiliac, had contracted HIV Anyone, regardless of age, sex or sexual orientation, can con· from a transfusion and, before he was aware of the infection, tract HIV if exposed to it through a known transmission route. had passed the virus to his wife, Lauren, who then transmitted And there usually are no symptoms of early infection; many it to their son, Dwight, while she was pregnant or breast·feed· people transmit HIV to others before they know they are ill. For ing. When the photograph was made, Patrick and Dwight al these reasons the authors recommend that anyone who thinks ready had AIDS; they have since died. The daughter, Nicole, he or she has been exposed to HIV seek an early diagnosis.

SCIENTIFIC AMERICAN October 1988 91 © 1988 SCIENTIFIC AMERICAN, INC also orchestrates cell-mediated im bile scavengers known as monocytes including T and B cells. T4 cells also munity: the killing of infected cells by and macrophages, which engulf in secrete cytokines of their own, notably cytotoxic cells such as T81ymphocytes fected cells and foreign particles. Ac ones that stimulate the proliferation and white cells known as natural kill tivated monocytes and macrophages of T and B cells. er cells. secrete a variety of cytokines: small The loss of T4 cells seriously im T4 cells influence the activity of an but highly potent proteins that modu pairs the body's ability to fight most other group of cells as well-the mo- late the activity of many cell types, invaders, but it has a particularly se-

~~CYTOTOXIC CELL (NATURAL KILLER CELL)~~

DESTRUCTION OF T4 CELLS, which are critical to immune de end result, called a syncytium, cannot survive, and all the once fense, is the major cause of the progressive immune dys healthy cells it contains are destroyed along with the infect function that is the hallmark of HIV infection. The virus is ed cell. HIV can also elicit normal cellular immune defenses known to killcells by replicating, budding from them and against infected cells (c). With or without the help of antibod damaging the cell membrane (a). HIV might also kill T4 cells ies, cytotoxic defensive cells can destroy an infected cell that indirectly, by means of a viral protein, gp 120, that is displayed displays viral proteins on its surface. Finally, free gp 120 may on an infected cell's surface. A molecule on T4 cells-the CD4 circulate in the blood of people with HIV(d). The free pro receptor-has a strong affinity for gp 120, and healthy T4 cells tein may bind to the CD4 receptor of uninfected cells, making can bind to the gp 120 and merge with the infected cell (b). The them appear to be infected and evoking an immune response.

~~92 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC vere impact on the defenses against HIV CHRONIC DELAYED viruses, fungi, parasites and certain ANTIBODY T-HELPER OPPORTUNISTIC STAGE LYMPHAD- HYPER- AND/OR CELLS/MMJ THRUSH INFECTIONS bacteria, including mycobacteria (the ENOPATHY SENSITIVITY VIRUS group that includes the bacterium that causes tuberculosis). Eradication of these organisms requires a strong, WRO - - >400 NORMAL - - highly orchestrated cell-mediated im mune response. Other organisms, in WRl + - >400 NORMAL - - cluding many types of bacteria, tend to be destroyed by the "humoral," or - WR2 + + >400 NORMAL - antibody-dependent, arm of the im mune system. In a humoral response WR3 + /- <400 NORMAL - - newly made antibodies or antibodies + that were stored after an earlier infec - - tion attack the invader without T- cell WR4 + +/- <400 P participation. Hence bacterial infec - - tions present a smaller threat to peo WRS + +/ <400 C AND/OR THRUSH ple with a limited number of T4 cells. - - WR6 + +/ <400 PIC +/ + ow exactly does HlV infect and Hkill T4 cells? Infection begins as a protein, gp 120, on the viral WALTER REEDCLASSIFICATION SYSTEM charts the course of patients from exposure envelope binds tightly to a protein to HIV(WRO) and the onset of infection (WRl)through stages of progressive immune known as the CD4 receptor on the dysfunction. The essential criteria by which patients are assigned to each stage are cell surface. The virus then merges shown in red and always include laboratory evidence of HIVinfection. Stage 2 is with the T4 cell and transcribes its characterized by chronic lymphadenopathy, or swollen lymph nodes. Stage 3 is reached when the T4-cell count drops below 400 cells per cubic millimeter of blood RNA genome into double-strand DNA and stays down. (A normal count is 800.) A patient moves into stage 4 after sub The viral DNA becomes incorporated clinical (asymptomatic) defects are found in delayed hypersensitivity: the ability to into the genetic material in the cell's react to skin tests that are a barometer of immune functioning. (UP" indicates a nucleus and directs the production partial defect.) The line is crossed into stage 5 when the patient completely ("C ") fails of new viral RNA and viral proteins, to respond to the skin tests or when thrush (a fungal disease of the mouth) develops. which combine to form new virus (Lymphadenopathy and abnormalities of T4-cell and skin tests must persist for at particles. These particles bud from least three months to serve as criteria.) Patients enter stage 6 and are said to have the cell membrane and infect oth AIDSwhen opportunistic infections (ones that occur because the immune system er cells. has broken down), such as cryptococcal meningitis, develop elsewhere in the body. Early investigations of T4-cell killing demonstrated that under certain cir cumstances HlV could multiply prodi many merged cells. Syncytia develop in monocytes, macrophages and sim giously in the helper T cells and kill after a single cell becomes infected ilar cells called tissue-dendritic cells them, suggesting that viral replication with HlVand produces viral proteins, found in the skin, mucous mem was the main cause of cell destruction. including gp120, which is displayed branes, lymph nodes, liver, spleen and In particular, it was discovered that on the surface of the infected cell. brain. Such cells are not killed by the HlV replication and cell death increase Because gp120 and the T4 cell's CD4 virus, but their functioning may none when infected helper T cells become receptor have a high affinity for each theless be deranged in some ways. In activated, as they do when they take other, uninfected T4 cells can bind to particular, HlV infection may some part in an immune response to HlV or the infected cell and merge with it. The how alter the amount or structure of to other viruses in other cells. Thus resulting syncytium cannot function the cytokines normally produced by the very process that should defeat and dies. The original infected cell is activated macrophages or activated HlV-an immune response-has the killed, but so are dozens or hundreds lymphocytes in a way that is toxic to diabolical effect of increasing the pro -of uninfected T4 cells. helper T cells. liferation of the virus. Infected T4 cells can also be killed Regardless of how helper T cells are Yet further investigation revealed by the standard antiviral activities of killed by HlV, their progressive decline an apparent paradox: HlV replication cytotoxic antibodies and cells. Even leads to a more general decline in could be demonstrated in only a small HlV-infected cells that do not pro immune functioning and hence is the fraction of T4 cells collected from HlV duce new virus are vulnerable to im primary factor determining the clini infected patients. The cells killed by mune destruction if they display vi cal course of the patient. In recogni replication alone might hamper the ral proteins. Similarly, in a process tion of those cells' importance, the immune system somewhat but would that is unique to HlV, free viral Walter Reed classification system re not cause the severe immune deficien gp 120 may circulate in the blood and lies on the T4-cell count and function cy seen in AlDS. The paradox could be the lymph and bind to the CD4 re as an indicator of a patient's stage of resolved only if the cells were also ceptor of uninfected helper T cells, disease. Other indicators include the killed by other means. To date several making them susceptible to attack by onset of chronic lymphadenopathy, or other mechanisms of killing have been the immune system: swollen lymph nodes, the response documented in the laboratory. Wheth A final process, which is more spec to a set of skin tests that reflect the er they also occur in the body is not ulative, has to do with HIVs effects overall functioning of cell-mediated yet known. on cytokine production in various immunity and the presence of infec One mechanism is the formation of cell types. The virus infects and rep tions that have been unequivocally as syncytia: massive bodies consisting of licates not only in T4 cells but also sociated with a specific degree of im-

~~SCIENTIFIC AMERICAN October 1988 93~~

© 1988 SCIENTIFIC AMERICAN, INC mune suppression. Lymphadenopathy The same is true for the various tant factor leading to HIV infection. and abnormal test results must per "constitutional" symptoms that some Once the presence of HIVhas been sist for at least three months before physicians have dubbed the AIDS-re documented by any reliable test, pa they are taken to be evidence of the lated complex, or ARC:unexplained tients are said to be in Walter Reed stage of infection. fevers, persistent night sweats, chron stage 1, provided they do not meet the The specific stages chart the course ic diarrhea and wasting. We hope the criteria for a higher stage. In addition of the immune system's decline. When data we are collecting about all these to identifying antibodies to HIVin HIVinfection is first detectable by disorders and their relation to the blood samples, some laboratories are standard tests, the T4 -cell concentra stage of disease will lead to new in now able to detect infection by cultur tion is often close to the normal level sights into their causes and to new ing whole virus or identifying viral of about 800 cells per cubic millimeter treatments. nucleic acid or protein in blood or of blood, and the patient feels well. tissue samples. Usually within six months to a year, he Walter Reed classification Although most people have no chronic lymphadenopathy develops. Tsystem begins with stage zero: symptoms when HIV infection is first Within a few years laboratory and oth exposure to the virus through diagnosed, some patients develop a er tests reveal more severe, subclinical any of the known transmission routes. disorder resembling mononucleosis. (silent) immune defects: first the slow Noting exposure facilitates early diag Its symptoms include fatigue, fever ly declining T4 -cell count falls below nosis: people who are known to have and swollen glands, which may or may 400 and then patients exhibit abnor been exposed to HIVcan be evaluated not be accompanied by a rash. In addi malities on the skin tests. Later, as the for evidence of infection, such as the tion self-limited disorders of the cen T4 -cell number drops further, overt presence of antibodies to HIVin the tral nervous system have been noted. disease sets in, first as chronic infec blood. Even before infection is detect These range from headaches to en tions of the skin and mucous mem ed they can be told that they may be cephalitis (inflammation of brain tis branes and then as disseminated, sys infected with HIVand so should take sue). The cause of these symptoms temic infections. steps to avoid spreading the possible is not entirely clear. In any event, Throughout the course of HIV infec infection to others; HIV usually caus they disappear, usually within a few tion people may also develop cancers es no symptoms at first and can take weeks. Unfortunately HIV does not and disorders of the central nervous root from six weeks to a year before do the same; it continues to replicate system. These are noted along with it is detected by the standard (anti and slowly but persistently destroys the Walter Reed stage of disease but body) HIV test. Stage zero has also T4 cells. are not included in the criteria for been included to emphasize the fact For the majority of patients the first

each stage because in most instan that, in 1988, exposure to HIV, rath sign that something is amiss in the ces their causes and their relation to er than membership in some "risk" immune system is the development the immune deficiency are not known. group, is the single most impor- of chronically swollen lymph nodes.

WRO WRl WR2 WR3 WR4 WRS WR6 <2 UJ UJ ct: ACUTE CHRONIC LYMPHADENOPATHY SUBCLINICAL IMMUNE DYSFUNCTION SKIN AND SYSTEMIC f- UJ 900 � INFECTION MUCOUS IMMUNE ::< 0 MEMBRAN DEFICIENCY ::J "- x IMMUNE ::::! 800 UJ DEFECTS ::< u co ::J 700 U ct: UJ "- 600 Vl ...J ...J UJ � 500 z 0 i= 400

~~0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 TIME (MONTHS)~~

DECliNE in T4-cell count (rounded to the nearest 50) was months it was chronically below 400), exhibited chronic, subtle tracked in the blood of a young man whose disease followed a abnormalities of delayed hypersensitivity. He displayed per typical course. About three months after sexual exposure to sistent anergy (the complete absence of delayed hypersensi HIV the patient tested positive for the virus; his T4-cell count tivity) at 63 months but had no overt symptoms of infection dropped and then rebounded, presumably because his im until about 68 months, when he developed thrush and oral mune system temporarily controlled the infection. He devel hairy leukoplakia, a tongue infection. Less than a year later he oped chronic lymphadenopathy at nine months and, at 51 was besieged by opportunistic infections, including cytomega months, after a long, slow decline in his T4-cell count (by 36 lovirus infection, which made him blind. He died at 83 months.

~~94 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC With the appearance of this chron ic lymphadenopathy a patient moves into stage 2. The cause of the lymph adenopathy is relatively straightfor ward. Although HIV infection sup presses many immune functions, it also is marked by one kind of hyperac tivity. The ongoing presence of HIV overstimulates B cells, which are abun dant in the lymph nodes, and keeps them in a state of chronic activation. The flood of antibodies produced as a result of such activation includes some antibodies that combat current infections or recurrences of past in fections. In general, however, the hy VIRAL INFECTION known as molluscum contagiosum normally produces a few small peractivity is not beneficial. The acti lesions (left)that disappear on their own within several months. In a patient with vation of large numbers of B cells advanced HN infection the lesions persisted, grew and multiplied so profusely diminishes the number of resting cells (right) that they disfiguredthe face, demonstrating that when the immune system that can differentiate to produce anti is compromis�d, even common, ordinarily minor infections can be overwhelming. bodies in response to new pathogens or to inoculation with vaccines. Stage 2 typically lasts for from three of the skin and mucous membranes. lent probably because the agents that to five years, and patients still feel well One example is chronic infection with cause them are ubiquitous in human even when it ends. The beginning of the Herpes simplex virus, which often beings. Similarly, infections that ap stage 3 is defined by a persistent drop produces painful and persistent sores pear in some geographic areas but not in the T4 -cell count to less than 400, in the skin surrounding the anus, the in others are probably caused by or which is a harbinger of a decline in genital area or the mouth. In addi ganisms that are prevalent in distinct immune functioning. Patients remain tion, Candida albicans, the fungus that locales. We should also point out that in this stage, however, until direct evi causes thrush, may spread through any pathogen that can be eradicated dence of an impairment in cell-medi out the vagina, resulting in chronic only with the help of vigorous cell ated immunity is discovered-usually infection there. mediated immunity can cause serious about 18 months later-at which point Recently many stage-5 patients have disease. Hence, in addition to the exot they enter stage 4. That evidence is the developed oral hairy leukoplakia: a ic infections that receive most of the failure to respond to three out of four mucous-membrane infection marked publiCity, a host of more familiar dis skin tests that measure what is called by fuzzy white patches, usually on eases, such as tuberculosis, can also delayed hypersensitivity: the individu the tongue, that cannot be rubbed off. develop and be quite severe. al's ability to mount a cellular immune The cause is not clear. Although these In addition to PCP, other disorders response against specific proteins in infections now appear to be the com associated with AIDS include the para jected under the skin. monest ones in stage 5, it is becoming sitic infections toxoplasmosis (which Although the T4-cell count in stage apparent that any viral or fungal path often infects the brain and can lead to 4 can dip quite low (for example, to ogen in the skin or mucous mem seizures and coma) and chronic cryp 50), the Walter Reed system requires branes can cause equally severe in tosporidiosis (which typically attacks only that it be persistently less than fection at- this stage of the immune the intestinal tract, causing chronic 400 in this stage and also in stages 5 defiCiency. diarrhea). Stage-6 opportunistic dis and 6. This criterion is not narrower, eases also include the fungal infec because patients can vary quite a bit in any people develop chronic tions cryptococcosis (which frequent their immune function at any speCific Mor disseminated opportunistic ly causes meningitis but may also low T4 -cell count. infections at sites beyond the damage the liver, bone, skin and oth Progression to stage 5 is usually skin and mucous membranes within er tissues) and histoplasmosis (which determined on the basis of the devel a year or two after entering stage 5. can cause self-limited pneumonia in opment of anergy (a total absence of The emergence of these infections re individuals with an intact immune delayed hypersensitivity). Some time flects an extremely severe decline in system but causes a disseminated in later the first overt symptom of a immune function and constitutes pro fection of the liver, bone marrow and breakdown in cell-mediated immunity gression to stage 6, or what is also other tissues in HIV-infected patients arises: the development of thrush, a called opportunistic-infection-defined and is a frequent cause of chronic fungal infection of the mucous mem AIDS.(Again, Kaposi's sarcoma is not fevers). branes of the tongue or the oral cavity. sufficient evidence of stage-6 disease.) A common viral infection is cyto Thrush, which can occasionally devel Most patients enter stage 6 with a megalovirus, a cause of pneumonia, op before anergy, is identified by the T4 -cell count of 100 or less and most, encephalitiS, blindness and inflamma presence of white spots and ulcers unfortunately, die within two years. tion of tke gastrointestinal tract. As is covering the infected area. By the time We cannot discuss all of the many the case with histoplasmosis and tu most people reach stage 5, their T4 - opportunistic infections that can de berculosis, the cytomegalovirus infec cell count has generally fallen to less velop during stage 6, but we shall tion seen in HIV patients is usually a than 200. mention a few that are particularly reactivation of a childhood infection In addition to thrush, stage-5 pa common or virulent in the U.S. The that was well controlled until HIV seri tients often develop unusually severe diseases that appear most often in ously hobbled the patient's immune or persistent viral or fungal infections this stage-and in stage 5-are preva- system. Such bacteria as Legionella

~~SCIENTIFIC AMERICAN October 1988 95~~

© 1988 SCIENTIFIC AMERICAN, INC and Salmonella can also be a severe workers are making progress against of infection could be a consequence problem for someone in stage 6. other HIV-related diseases as well. A of immune defiCiency, whereas condi Standard or experimental therapies drug called acyclovir is under study tions arising earlier would probably exist for all these disorders. Among for the prevention of Herpes simplex have other causes. the most exciting developments in re infection, and new treatments have Early neurological findings can in cent years is the discovery of several been developed for cryptococcal men clude subtle alterations in cognitive medications that control or even pre ingitis, disseminated histoplasmosis function, such as in memory and judg vent PCP. Pentamidine, Septra!Bactri and mycobacterial diseases. ment. The brain damage could stem urn and dapsone are all effective in from diseases that are transmitted in clearing up the infection; the first ust as investigators continue to the same way as HIV, such as syphilis, two-and a drug called Fansidar seek better treatments for the op and that often coexist with it. On the serve as preventives as well. Jportunistic infections associated other hand, HIV may cause trouble on Also exciting are new treatments for with HIV, so too the search contin its own, for example by replicating in cytomegalovirus. Just two years ago ues for the causes of the neurological brain cells or inducing the secretion of investigators had little hope of discov disorders and cancers that have been neurotoxic cytokines. ering an effective therapy for the vi associated with HIVinfection. Thus In the terminal stages of HIV infec rus. Today there are two treatments, far the causes-and their relation to tion many patients suffer from the including a medicine (ganciclovir) that immune deficiency-are a matter of AIDS dementia complex: a syndrome can halt the progression of cytomega conjecture. One would expect that characterized by a gradual loss of pre lovirus-induced blindness. Research conditions arising late in the course cision in both thought and motion. In

~~a STAGE AT FOLLOW-UP (MEAN 14 MONTHS) b STAGE AT FOLLOW-UP (MEAN 36 MONTHS)~~

~~2 3 4 6 2 3 4 5 6~~

1 45% 36% 9% 5% 4% 1% 1 0 100% u.J (n=38 1) (n= 1) lJ « u.J r- 2 10% Vl 65% 21% 7% 6% 1% lJ 2 25% 10% 30% 25% 0 (n=34 1) « (n=20) u.J r- (50%) u.J Vl c:: 0 29% c:: 3 u.J 3 u.J 67% 11% 15% 7% u.J 0 14% 57% (n=96) c:: (n=7) (50%) � c:: « u.J � 4 r- 4 71% -' 43% 30% 27% -' 29% (n=30) « (n=7) 0 « � (80%) f= -' Z « 5 5 100% 31% 69% 0 E (n=23) (n=58) z (87%)

~~6 (n=4) (100%)~~

~~c d~~

.L-....- u.J u.J 1+2 I I I lJ - lJ « ;:: r- I I I Vl ---"l Vl o 3 0 3 I I I I u.J u.J u.J u.J c:: c:: I I I I I c:: c:: u.J 4 u.J 4 I I r- � -' I I « j I j I j I � � -' -' 5 11 « « f= f= I I I I Z ALL � ALL - -, I I I SUBJECTS SUBJECTS I I I I j I I I o 10 20 30 40 50 60 70 80 90 100 o 10 20 30 40 50 60 70 80 90 100

~~PERCENT WHO PROGESSED TO PERCENT WHO PROGRESSED ONE WALTER REED STAGE 6 OR DEATH OR MORE STAGES~~

DISEASE PROGRESSION was examined in 906 patients followed followed, the more likely it is they will have moved to a severer for a mean of 14 months (a) and in a subset of 62 patients stage of disease. For example, the shorter study (pink) found followed for a mean of 36 months (b). (Numbers in parentheses that about half of the subjects advanced one or more stages reflect the percentage of stage-6 patients who died.) Compari by the end of the follow-up period, but the longer study (blue) son of the percentage of patients who moved from their initial found that more than 90 percent of subjects had advanced. Walter Reed stage to stage 6 (c) or who progressed by one or Until better treatments are found, it appears that most (if more stages (d) revealed that the longer people with HIV are not all) people who contract HIV will eventually develop AIDS.

~~96 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC the end, some people are unable to WR1 WR2 WR3 WR4 WRS WR6 walk or communicate effectively. The cause remains a mystery. The cancers associated with HN are also perplexing. In addition to Kaposi's sarcoma, which produces tumors in the skin and in the linings of internal organs, they include various lympho mas (cancers of lymphoid tissue) and cancers of the rectum and tongue. Some workers have postulated that Kaposi's sarcoma is caused in part by HN-induced changes in the amounts or types of cytokines produced by VIABLE VIRUS IN BODY defensive cells or by other cell types. These changes could occur quite early and could explain why Kaposi's sarco ma often appears relatively early in the course of HN infection. Certain lymphomascan also devel 3 4 5 6 7 10 op quite early, lending credence to the TIME (YEARS) notion that B-cell hyperactivity plays a role in their development. Lympho BAlANCE OF POWER between JDV (black curve) and the immune system (red curve) mas that arise later might result from shifts during the course of the infection, according to a model proposed by the cancer-causing viruses that take hold authors. The amount of JDVin the body soars in the first days of infection, but once in the course of immune deficiency. If the immune system "kicks in," it initially operates normally and reduces the amount the immune system provides constant of virus. The immune system remains in good control of the virus for several years, but JDV gains ground slowly. At some point the T4 cells that orchestrate the immune surveillance against cancer, as dogma response become so depleted that the balance of power switches. HIV then replicates says it does, the lymphomas and other wildly, killing the remaining T4 cells and hence any vestiges of immune defense. cancers that appear late in HN disease could also stem from the failure of the compromised immune system to rec ognize and destroy cancer cells. primary aim has been to facilitate op 6 or had died. These findings under timal medical care and prevention, but score the grim reality that, in the ab e expect that looking at can proper diagnosis combined with accu sence of a scientific solution to HN, Wcers and neurological disor rate staging has also provided infor most (and perhaps all) people who ders within the framework of mation about the natural history of are infected with HN will eventual the Walter Reed classification system HN infection in young adults. In addi ly develop end-stage disease and will will help to distinguish those that tion to diagnosing more than 5,000 die prematurely. stem from immune dysfunction from individuals with HN, military phYSi those that arise by other means. On cians have tracked the course of some ne question relating to disease another front, the system has made 900 of those patients for more than a Oprogression remains: Why is it possible to show that most peo year, a subset of some 250 patients for it that the disease progresses ple infected with HN follow about more than 18 months and a smaller slowly? One theory holds that the an the same basic course and do indeed subset of about 60 patients for more swer lies with the virus alone. For move from stage to stage. The notion than three years. instance, HN might be a slow-replicat that genetic variation in the virus or Looking at progression by one or ing organism that initially poses little distinctive features of the patient are more stages and not just at the devel danger to cells but later changes into the crucial factors influencing the dis opment of AIDS,we have found that a more active and highly cytotoxic ease course has now fallen by the the longer we follow our patients, the agent. Another theory postulates that wayside. greater the percentage is of people HN is active in the body throughout Early studies of disease progression who progress to a higher stage. Where the infection but its cytotoxiceffects by other investigators were relatively as 54 percent of the patients in the are held in check for a time by the optimistic, suggesting that only about group followed for one year remained immune system. Although viral fac 30 to 40 percent of patients infected in their initial stage at the end of the tors likely play some role, the activity with HN progressed to AIDS.Without a study period, only about 8 percent of of the immune system is probably of staging system, however, such studies the smaller, three-year group stayed in paramount importance. could not say whether the remaining the same stage. In other words, more One reason we think so is that a subjects progressed to some interme than 90 percent of the patients pro range of defensive activities have been diate stage of disease. gressed within three years. shown to occur after infection with In contrast, early diagnosis of HN When we looked at the progression HN; demonstrating that the body ini infection and the use of the Walter to stage 6 (opportunistic-infection-de tially mounts a vigorous immune re Reed system has been standard prac fined AIDS),we found that after three sponse. These activities include the tice in the U.S. military services for years 10 percent of the patients ini production of different types of anti several years (thanks to enlightened tially in Walter Reed stage 2, 29 per bodies against the virus-some that military leadership and extraordinary cent of those in stage 3, 71 percent of neutralize it, others that prevent it commitment and cooperation among those in stage 4 and 100 percent of from binding to cells and still others an array of health professionals). The those in stage 5 had moved into stage that stimulate cytotoxic cells to attack

~~SCIENTIFIC AMERICANOctober 1988 97~~

© 1988 SCIENTIFIC AMERICAN, INC infected cells. The response also in physician, there was no effective ther cludes direct activation of the cellular apy for bacterial diseases. Young chil Want to arm of the immune system. dren Were almost certain to die when Such findings suggest that the im they developed rather common bac brush up mune system limits viral replication terial infections such as periorbital on a for quite some time but that the po cellulitis, which affects the skin and tent virus slowly gains ground. Even soft tissue around the eyes. He had foreign tually a threshold is reached (probably to have the courage to tell the parents language? between stages 3 and 5): the decline of those children that, although he in T4 cells is so significant that the would do his best, in the end their With Audio-Forum's �.� immune system can no longer func seemingly healthy child would almost intennediate and ad materials, tion efficiently enough to hold HN certainly die. This was so in the late it's easy to maintain and sharpen your in check. Viral proliferation increas 1930's; it was so in the early 1940's. fo reign language skil ls. es, as does the virus's toxicity, and Yet by the late 1940's his practice Besides intennediate and advanced audio-cassette courses-most devel the balance of power shifts in favor required a little less courage. With the oped for the U.S. State Dept.-we of the virus. With time the decline in advent of penicillin, he had a new and offer foreign-language mystery dramas, T4 cells is so severe that the immune important tool for treating bacterial dialogs recorded in Paris, games, music, system becomes essentially nonfunc infections. Today most young children and many other helpful materials. tional. Then the virus proliferates wild with periorbital cellulitis survive. And ifyou want tolearn a new language, ly, destroying the T4 cells that remain We do not pretend that HN will be we have beginning courses for adults in the body. defeated easily, but doctors and pa and for children. This model postulates a gradual rise tients should keep in sight the day We offer introductory and advanced in the amount of virus in the blood when medical science will reduce HN materials inmost of the world's lan with time, rather than a steady, low infection to a curable disease. We have guages: French, Genna n, Spanish, level followed by a sudden rise. In no doubt that day will come. In the Italian, Japanese, Mandarin, Greek, deed, with each successive stage of study of new diseases there must first Ru ssian, Portuguese, Korean, Nor wegian, Swedish, and many others. disease the amount of viral protein be a time when physicians can only that can be detected increases, as describe symptoms and treat patients < Ca ll 1-800-243- 1234 for does the ability to isolate virus from with whatever seems to work best. �\�" •• , FREE 32 -p. catalog, or write: the blood. Then comes an understanding of cau \ aUDIC'�CRUm ® Room 1329 The implications of these observa sation and of the disease's natural 96 Broad Street, Guilford, CT 06437 (203) 453-9794 tions go far beyond proving the valid course, which enables physicians to ity of a theoretical model. More virus provide patients with an early diagno in the body means greater infectivity. sis and accurate clinical assessment. Indeed, we in the military, and work Next comes the development of ef THE MINI AD WITH MAX\ SA"\NGS ers elsewhere, have demonstrated that fective treatments based on the new S.B.H. ENTERPRISES as the T4-cell depletion progresses, an knowledge, and then refinement of 1678 -53rd St, BKLYN, NY 11204 • MON-FRI 8-7, SUN 9-6 CALL 1-800-451 -5851 li N NYC (718) 438-1027 infected person's likelihood of trans treatments until a cure is found. mitting the disease to a spouse in Investigators are completing the WORD PROCESSORS DlaION EQUIPMENT creases. Hence the longer people are descriptive phase and are fully im & TYPEWRITERS ·'5'MUIE infected with HN and the more im mersed in understanding the hows 5907 ...... 44.95 S911 ...... 62.50 L200 ...... 174.75 mune-deficient they become, the more PWP-6 Bl WordPro

~~98 SCIENTIFIC AMERICAN October 1988~~

VACUUM TECHNOLOGY TAKES AIR OUT OF OTHER HEATER CLAIMS HE TECHNOLOGY: The story begins in the TArctic. A small Colorado company had an order from the U.S. Government to manufac ture a vacuum insulated stainless steel can teen that would stand up to hard use and keep liquids from freezing in the torturous Arctic cold. It took the company a great deal of time to perfect the process of "pulling a vacuum" in a sealed metal system so that it stood up to hard use, yet could be manufactured economi cally. Now, af ter seven years of additional research and over twenty worldwide patents they have used that original technology to pro duce a room heating unit that leaps a genera tion beyond every other heater on the market. At the heart of the Heatech '" heater is the vacuum technology developed to preserve warmth in the Arctic. Here the vacuum is used to cause water to boil almost instantly at approximately 1300 instead of the usual 2120. Water inside the sealed Heatech system turns to steam and rises in vertical tubes. There the heat is transferred to fins which in turn heat the cold room air that is then blown through a diffusion screen to bring you warmth where you need it. THE PERFORMANCE: The system is super fast and effective. Comparison tests show the Heatech doing in 15 minutes what other heaters take up to an hour to do. Inside, as the heat transfer cools the steam, it condenses back into water droplets and the cycle starts again. distribution. While warm air from most other can pride, it is backed with a manufacturer's The vacuum sealed system does not need re heaters simply rises wastefully to the ceiling, 5-year limited warranty and is UL listed. You plenishing and does not require service. The Heatech provides a multi-directional heat flow can see why the Heatech was named winner of Heatech's unusual patented cabinet design that warms your room more uniformly from the 1988 Innovator Aw ard at the National Home provides greater air flow andmore even heat the floor up. Center Show! Thanks to an exclusive arrange ment with Heatech, you can now obtain THE SAFETY FACTOR: The 1500 watt Heatech - - - - Thermostatic __ also sets a new standard in safety. It is one of this state of the art heater direct from The Control the few electric heaters on the market not Lifestyle Resource. See for yourself how the required to carry the UL fire hazard warning Heatech can chase your chills away with por ' table heat that sets a new generation of stan Safe ty Grill sticker on the heater. Recent independent lab· oratory tests show Heatech's hottest surface dards for performance and safety. Order now while our supply is assured. Av ailable in three temperature is up to 2050 lower than other $199.95 He at Diffusion types of heaters tested . making it excep colors for #2220 (White); #2230 Screen tionally safe for use around children or (Black); #2240 (Red). pets. To further protect against accidents, the He at Fins Heatech has three separate safety devices FOR THE FASTEST SERVICE ON CREDIT - a tipover switch, thermal sensing switch and pressure relief valve. 800-872-5200 Fan CARD ORDERS CALL TOLL-FREE THE BOTTOM LINE: In recen t independent laboratory tests against 4 top competing heat Ifyou prefer, mail check or credit card number ers, Heatech achieved higher, more uniform Va cuum·Sealed with expiration date and authorized signature. temperatures faster than any of the other Steam Chambers Include $12.95 with each ord�r for UPS and In heaters including the best selling ceramic disc surance, along with each item number. Mail to: He ating Element heater. No other portable room hea ter we know of combines the safety, quick heating THE LIFESTYLE RESOURCE ability and superior heat distribution of DEPT. SFAKI8j Heatech. That's what we mean by beating the 921 EASTWINDDR ., SUITE 114, others cold! At 12.5 lbs. and 21"xlO"x9", the WESTERVILLE, OH 43081 Heatech. is portable and compact, it requires White ...... #2220 $199.95 only one square foot of floor space and uses Black ...... #2230 $199.95 standard 110 volts AC. Its handsome high-tech Red ...... #224 0 $199.95 Mu lti·directional He ats room look comes in a choice of baked enamel fin heatfiow fro mfioor up ishes -Red, White or Black. Made with Ameri- NO RISK 30-DAY RETURN PRMLEGE

~~THE MEOlA DEVElOPMENT GROUP <>1988 C76 ADVERTISEMENT~~

© 1988 SCIENTIFIC AMERICAN, INC INFECTED T CELL (a cell of the immune system) produces al Institute for Biological Standards and Control in England_ particles (small spheres) of the human immunodeficiency vi The scanning electron micrograph shows part of the infected rus (lllV) in this image, made by David Hockley of the Nation- cell's convoluted surface, magnified about 20,000 diameters_

~~100 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC HIV Infection: The Cellular Picture A key finding of AIDS research is that infection begins when HIV binds to a molecule called CD4 on the target cell. Knowledge of that interaction may help in developing therapies or vaccines

~~by Jonathan N. Weber and Robin A. Weiss~~

'ke all viruses, the human im denying access to the cellular CD4 re Dalgleish and Paul R Clapham in our munodeficiency virus (HIV) is an ceptor, both by covering up the vi laboratory at the Institute of Cancer intracellular parasite: the virus ral gp120 protein and by blocking Research tackled the question of the particle itself is inert and cannot prop the receptor. tropism of HIV from another direction. agateU or do any damage until it enters We tested antibodies to various cell a host cell. How does the virus actually he chain of experiments that surface antigens to see which of them enter the cell? The answer will help eventually identified CD4 as the would block molecules crucial to .the investigators to understand the clini molecule to which HIV binds be binding of the virus. In these experi cal course of AIDS,the disease caused gan in June, 1984, when samples of ments we first exposed susceptible T by the virus. More than that, an under theT virus became generally available cells to the antibodies and then to standing of how HIV enters cells may for research. In one of the earliest virus particles. Next we applied vari eventually make it possible to devel experiments, Mika PopoviC of the Na ous assays to determine how the an op vaccines or protective medications tional Institutes of Health studied the tibodies had affected HIV's ability to that can block the action of HIV at the growth of HIV in fresh peripheral infect the cells. These experiments re earliest possible stage: before it in blood lymphocytes (white blood cells vealed that monoclonal antibodies fects its first host cells. freshly separated from the blood (antibodies that bind only to a single, The first step in any viral infection stream) and in lines of tumor cells that specific molecular target) to the CD4 is the binding of the virus particle to are able to grow perpetually in cul antigen, but not those to other cell a component of the host cell's mem ture. He found that HIV grew best in a surface antigens, could block the in brane. In the case of HIV, workers have line of leukemic T cells. (The T cells, fectivity of HIV. Klatzmann, using dif found that the virus binds to the mole a major class of cells in the immune ferent assays, got similar results. cule known as the CD4 antigen. (An system, include the helper T cells and Another kind of assay took advan- antigen is a molecule that can be rec cells called cytotoxic, or killer, T cells.) ognized by an antibody.) Hence the At about the same time, David Klatz distribution of CD4 in the body re mann of the Salpetriere Hospital in JONATHAN N. WEBER and ROBIN A flects the tropism of HIV: the kinds of Paris noted that in fresh peripheral WEISS have been working together since cells and tissues the virus infects and blood lymphocytes infected in culture 1985, when Weber joined Weiss's lab destroys. The CD4 antigen is found with HIV there was a decrease in the oratory to get training in virology. Web primarily on cells of the immune sys number of cells bearing the CD4 anti er is a senior lecturer in infectious dis ease at the Royal Postgraduate Medi tem called helper T cells (although gen; the decrease was paralleled by an cal School at Hammersmith Hospital in other kinds of cells also carry it); HIV increase in the HIV replication rate. London. He took his undergraduate de infection is characterized by the loss Klatzmann then divided the T cells gree in archaeology and anthropology of these cells, which causes a deterio from a sample of peripheral-blood at the University of Cambridge and his ration of the immune system. lymphocytes into T-helper and T-cyto M.D. at St. Bartholomew's Hospital Medi For some time it has been known toxic subsets. He found that only help cal College in London. He is coeditor of that the binding takes place when CD4 er T cells-the cells that bear the CD4 International AIDS Journal. Weiss is di rector of the Institute for Cancer Re interacts with an "envelope" protein antigen-supported the replication of search in London. He studied at the of the virus called gp 120 (because it is HIV. Klatzmann's findings dovetailed University of London, where he was a glycoprotein-a protein containing well with an observation made in 198 1 awarded a Ph.D. in zoology in 1969. He sugar complexes-with a molecular in the firstpublished clinical descrip has been interested in retroviruses weight of 120 kilodaltons) that is tion of AIDS patients. In that report since the beginning of his research ca distributed on the outside of the vi Michael S. Gottleib of the University reer; his early work concerned the trans ral membrane. Investigators are now of California at Los Angeles School of mission of retroviruses in chickens, in identifying the speCific portions of the Medicine had noted that lymphocytes cluding the Mendelian inheritance of viral genes. In recent years Weiss has CD4 and gp120 molecules that take bearing CD4 were reduced in number concentrated on the retroviruses that or absent entirely from the blood of part in the binding interaction. Such cause leukemia and AIDS,with particular knowledge makes it possible to en AIDS patients. attention to their cellular receptors. visage a two-pronged attack on HIV: Simultaneously in London, Angus G.

SCIENTIFIC AMERICANOctobe r 1988 10 1 © 1988 SCIENTIFIC AMERICAN, INC tage of a sign of HN infection we had vesicular stomatitis virus(VSV). VSV is the appearance of plaques in various noted in cell cultures: the formation of a plaque-forming virus: it causes the kinds of cells indicates the presence "multinucleated syncytia." These are formation of visible plaques made up on the surface of those cells of the giant cells consisting of several nuclei of dead cells. When HN-infected cells receptor for HN. contained within a single membrane; are "superinfected" with VSV, they Dalgleish and his colleagues not they form when HN-infected cells produce a number of virusparticles ed that VSV(HN) pseudotypes would fuse with healthy cells bearing the that have the envelope proteins of HN form plaques only among cells bear receptor molecules. We found that an but the genetic material and plaque ing the CD4 antigen. Furthermore, the tibodies to CD4 could indeed block forming properties of VSv. These antibodies to CD4 that blocked the the formation of syncytia. "transvestite" particles are called VSV formation of syncytia also prevented (HN) pseudotypes. Because the pseu the formation of plaques. till another assay for receptors, dotypes have the same envelope char Subsequently]. Steven McDougal of first developed for work on ani acteristics as HN, they recognize the the Centers for Disease Control in At mal retroviruses by Jan Zavada same receptors and enter the target lanta (CDC) devised a physical assay of the Institute of Virology in Bratisla cell in the same way; their ability to for determining whether HN particles va,S is known as a pseudotype assay. infect particular cells should there had attached to cells; he found that This method involves exposing cells fore parallel that of HN. After they HN would bind only to cells bearing that have already been infected with enter the cell, however, they repli the CD4 antigen and, once again, that HN to a second, unrelated virus called cate as VSV and form plaques. Hence binding could be inhibited by anti CD4 monoclonal antibodies. McDou gal also showed that gp120 molecules attached to antibodies could draw CD4 CD4 molecules from a preparation of cell-membrane material. All these \ experiments suggested that the CD4 antigen-the disappearance of which had been part of the clinical definition of AIDS from the disease's earliest days-is itself the receptor for HN. The strongest evidence that CD4 is VIRUS PARTICLE TARGET CELL the receptor for HN came in 1986 from Paul Maddon and Richard Axel of the Columbia University College of Physicians and Surgeons. They trans ferred the gene that encodes the CD4 molecule into HeLa cells, a line of cervical-cancer cells that do not make CD4 and cannot ordinarily be infected with HN. Maddon and Axel found that the altered, CD4-bearing HeLa cells could now be infected withHN; when they were infected, they rapidly fused into giant syncytia. Expression of the CD4 gene was enough to confer sus ceptibility to HN. This experiment led to one unex pected result, which has not yet been explained fully. Maddon, working in collaboration with Clapham and Dal gleish in London and McDougal at the CDC, transfected the human CD4 gene into mouse T cells; the cells then produced human CD4. HN particles bound to these altered cells, but there was no evidence that the cells actual ly became infected: no syncytia were formed and no infectious virus was produced. This was surprising, be cause mouse cells can indeed produce HN under certain conditions; for ex ample, Jay A Levy of the University of California at San Francisco School of BINDING of a virus particle to a target cell depends on an interaction between a Medicine and other investigators suc molecule on the surface of the virus and a molecule on the membrane of the target cessfully transfected the entire HN cell. As the virus approaches the cell (1), a viral protein designated gp120 binds to a genome into mouse cells, which then cell-surface molecule known as CD4 (2). That interaction uncovers another protein produced infectious virus. Apparently, called gp41. One end of the gp41 molecule embeds itself in the cell membrane (3), however, mouse cells cannot be infect leading to the eventual fusion of the viral membrane and the cell membrane (4). ed by free HN particles, even in the

~~102 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC presence of the HIV receptor. Even 2 3 VSV(HIV) pseudotypes were unable to infect them, although VSV, once it en ters mouse cells, can usually replicate perfectly well. These results suggest another component of the cell surface is required for the virus to achieve full entry after it has bound to the cell membrane. The nature of this second factor is not known.

he binding of viral gp 120 to cel 3 lular CD4 is only the first step of viral entry into the cell. The later steps have been less thoroughly eluci dated.T For example, how does the vi rus's genetic material enter the cell? The simplest and likeliest possibility is that the viral membrane simply fus es with the cell membrane, injecting the core of the virus (including its genetic material) into the cell. Another possibility is that the cell membrane forms a small pocket that later be comes an enclosed sac called an endo cytic vesicle. The vesicle completely surrounds the virus particle and car ries it into the cell. Then a reaction within the cell acidifies the membrane of which the vesicle (now called an endosome) is made. When the endo some is acidified,it undergoes a con ENTRY of the virus's core, including its genetic material, into the target cell proba formational change and fuses with the bly takes place by one of two mechanisms. The likeliest (top) is direct fusion. In viral membrane, releasing the viral this mechanism the virus particle binds to the cell (1) and the viral membrane fuses core into the cell's interior. with the cell membrane (2), ejecting the core material into the cell (3). The oth Recent evidence casts doubt on the er mechanism (bottom), called receptor-mediated endocytosis, also begins when relevance of this mechanism, which the virus particle binds to the cell membrane (1). In the next stage, however, the is known as receptor-mediated endo cell membrane buckles inward to form a pocket (2) known as a coated pit. The mem cytosis. Barry S. Stein of the Stan brane encloses the virus particle (3) and detaches from the cell surface to form a ford University School of Medicine body called an endosome (4). Eventually the viral membrane fuses with the mem brane of the endosome (5), releasing the viral core into the interior of the cell (6). and Myra O. McClure of our laboratory have shown independently that the entry of HIV into the cell is indepen dent of acidity: drugs that block the acidification of endosomes do not prevent HIV infection. In addition, Dan R. Littman of San Francisco and Mad don have shown that mutations in the "tail" of the CD4 antigen (the part within the cell) that prevent the anti gen's incorporation into endosomes do not inhibit HIV infection. It is likely, then, that HIV enters the cell by fusing directly with the cell membrane. The direct-fusion mechanism would also help to explain the cell-to-cell fusion that leads to the formation of syncytia. Syncytiaform because HIV infected cells manufacture gp120 and carry it on their cell membrane. When an infected cell meets a healthy cell MULTINUCLEATED SYNCYTIA, clusters of many nuclei withina single cell membrane, that bears the CD4 antigen, the gp120 are a sign of HIV infection in cell cultures. They form when infected cells, which make of the infected cell can bind to the CD4 gp120 and carry it on their surface, fuse with healthy cells bearing the CD4 molecule. of the healthy cell. Then the two cells The photograph at the left shows HeLa cells, a line of cervical-cancer cells that do jOin, probably by direct fusion. The not make the CD4 molecule and cannot be infected with HIV. They have been exposed resulting syncytium continues to car to HIV , but no syncytia have formed. The photograph at the right shows HeLa ry gp120 on its cell membrane, and so cells that have been genetically altered so that they make the CD4 molecule. These

~~it can continue to fuse with healthy cells, on being exposed to HIV , have become infected and have formed syncytia.~~

SCIENTIFIC AMERICANOctobe r 1988 103 © 1988 SCIENTIFIC AMERICAN, INC cells. One infected cell may eventually as gp41, that is normally hidden un membrane, together with molecules bring together as many as 50 cells. der the gp120 molecule. This region known as Class II Major Histocom In any case, whether direct fusion of gp41 is hydrophobic: it will embed patibility Complex (MHC) glycopro or receptor-mediated endocytosis is itself in a cell membrane rather than teins. When helper T cells recognize the correct model, the viral membrane remaining exposed to the aqueous so this combination of an antigen and a must fuse with a membrane of the cell. lution surrounding the cell. Once it is Class II MHC glycoprotein, they initiate How does that happen? According to a uncovered, the hydrophobic region of an immune response against other plausible model, the binding of gp 120 gp41 interacts with the adjacent cell cells bearing the antigen, such as for to CD4 causes a change in the shape membrane and induces the viral mem eign or infected cells. It is thought that of the gp120 protein, revealing a part brane and the cell membrane to fuse an interaction between CD4 antigens of another envelope protein, known together. It is not clear whether some on the T cells and Class II MHC gly receptor on the cell surface other than coproteins on the antigen-presenting the CD4 antigen binds to gp41 or cells is a crucial part of the encounter

IMMUNOGLOBULlN whether gp41 embeds itself directly in between the cells. LIKE DOMAINS the cell membrane. It is now known that T cells are not After HIV enters the cell, its genetic the only cells that have the CD4 anti material, which is encoded in RNA, is gen embedded in their membrane. As converted into DNA The DNA "provi many as 40 percent of the peripheral rus" is then integrated into the DNA blood monocytes (cells that mature to Leu 3a/OKT4a of the target cell. This means that the become the scavenger cells known as BINDING SITE infection is persistent for the cell's macrophages), as well as certain an lifetime and that of its progeny if it tigen-presenting cells in the lymph multiplies. The integrated virus may nodes, skin and other organs, also MT 151 remain completely "silent," or else it express CD4 and can be infected by BINDING SITE may manifest itself in any one of at HIV. About 5 percent of the body's B least three ways. cells (cells responsible for the produc First, the viral genome may cause a tion of antibodies) may also express persistent infection, in which some CD4 and be susceptible to infection by new virus particles are created but few HIV. In all these cells the presence of cells are killed. Second, infection may CD4 can be shown relatively easily. lead to the creation of syncytia, which On the other hand, in some other die soon after forming. Syncytia are a kinds of cells that can be infected by dominant effect of HIV infection in cell HIV in culture it is not possible to culture. In human beings they are detect CD4 directly. These include cer sometimes seen (particularly in the tain cells of the brain known as glial OKT4 brain) during later stages of infection, cells, a range of malignant brain-tu BINDING S I TE but it is not clear whether they play a mor cells and some cell lines derived role in the early pathogenesis of AIDS. from cancers of the bowel. Neverthe A third possible result of HIV infec less, although these cells do not pro tion is the rapid death of cells without duce detectable amounts of CD4, they the formation of syncytia. It is not yet do contain low levels of messenger known how HIV kills cells. Perhaps RNA encoding the CD4 protein, indi some product encoded by the HIV cating that they produce some CD4. genes is directly toxic. Alternatively, Apparently the expression of only a perhaps the gp120 that is made and very small amount of CD4 is sufficient CELL MEMBRANE embedded in cell membranes as a for infection by HIV. result of infection binds to CD4 that Cells of the gut also do not produce is already there; such binding could appreciable amounts of CD4, but Ce

COOH damage the cell's membrane systems. cilia Cheng-Mayer and Levy at San The host's immune response also Francisco have recently shown that CD4 MOLECULE cannot yet be depicted shapes the fate of infected cells, since the gut cells known as chromaffin cells in detail, but some features of its struc the immune system can recognize vi do sometimes appear to be infected ture are known. Most of the molecule ral proteins on the surface of infected with HIV in vivo. They suggest that lies outside the cell, but a segment of it cells and destroy them. such a gut infection may be what leads passes through the cell !11embrane and to the AIDs-associatedweight loss and ends in a short tail inside the cell. Four he distribution of HIV-infected emaciation known in Africa as Slim sections of the molecule, designated VI, cells in the body is determined Disease. The role of CD4 in infections V2, V3 and V4, resemble the so-called primarily by the distribution of of brain cells and gut cells in vivo variable domains of some immunoglob cells bearing CD4. The CD4 antigen cannot be determined without further ulin (antibody) molecules. The site to wasT firstidentified by its presence on research. It is possible that in these which the HIV gpI20 molecule binds certain T cells, and indeed much of its cases the HIVparticle binds to an (color) lies in the outermost section. normal function seems to involve as alternative receptor molecule. Shaded regions indicate areas in which binding sites of certain monoclonal an sisting the complex network of com tibodies (antibodies that recognize spe munication among immune cells. umber of workers have recently cific molecular configurations) lie. The T cells bearing CD4 interact with determined precisely which part so-called Leu3a/OKT4a group of mono cells known as antigen-presenting � of the CD4 molecule is the clonal antibodies binds at the same site cells, which locate foreign antigens binding site for HIV. Most of the mole as HIV and can block infection by HIV . and display them on their own cell cule lies outside the cell, but a small

~~104 SCIENTIFIC AMERICAN October 1988~~

Trends in Computing™, from SCIENTIFIC ORDER FORM AMERICAN, the most interesting and useful I Please send me __copies of Trends in recent articles on the growing impact of I ComputingTMat $3.95 US each computers/computing on American business (10 or more: $3.45 each). and science. I enclose my check/money order (payable to

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To order direct from the publisher, please Payment must accompany order. complete and return the form, with Name ______appropriate remittance to: . Publisher, SCIENTIFIC AMERICAN Trends m Address ______Computing™, 415 Madison Avenue, City/State/Zip ______New York, NY10017 TlO © 1988 SCIENTIFIC AMERICAN, INC segment passes through the cell mem Beverley of University College London ing fewer than 40 percent of their brane and ends in a short intracellu have used large panels of anti-CD4 amino acids (the basic building blocks lar "tail." The extracellular region con monoclonal antibodies to draw a of protein) in common. In another sists of four domains that are similar "map" of the HN binding site (that is, study, McClure and Sattentau have ex in some ways to the "variable do to determine which regions of the CD4 amined how well various epitopes of mains" of antibody molecules. molecule are most important in bind CD4 have been conserved during the One way to determine the precise ing HN). They have found that the course of evolution. They have dem location of the binding site is to ex Leu3a antibody blocks not only HN-l onstrated that the Leu3a monoclonal pose CD4 molecules to monoclonal and HN-2 but also many strains of the antibody reacts with all primate lym antibodies that recognize various epi simian immunodeficiency virus (SN ) phocytes, including those of human topes, or molecular shapes, on the [see "The Origins of the AIDS Virus," beings, the great apes and African, CD4 molecule and note which anti by Max Essex and Phyllis j. Kanki, Asian and New World monkeys, and bodies block the binding of HN to page 64]. One implication of this find prevents them from being infected CD4. One group of antibodies, repre ing is that the region of gp120 that in vitro with HN. (In vivo most mon sented by the antibodies designated is most important in binding to the keys are not susceptible to HN infec Leu3a and OKT4a, is particularly effi cell is highly conserved, even among tion.) The implication is that the rel cient at blocking the binding of HN. strains of virus whose envelope pro evant parts of CD4 have been pre Quentin j. Sattentau and Peter C. L. teins are otherwise very different, hav- served even as the ancestors of these species diverged in other ways. A further way to determine which BRAIN parts of the CD4 and gp120 molecules GLIAL are crucial for binding is to introduce CELLS deliberate mutations in the genes that encode the molecules. For example, an investigator might simply delete the genetic sequence that encodes a re gion of the CD4 molecule and test the resulting mutant's ability to bind HN. Early experiments, in which large sections of the CD4 molecule were deleted, indicated that the amino-ter minal domain of the molecule (the section farthest from the cell mem brane) is essential for the binding of gp120. Ned Landau and Littman at San Francisco have confirmedthese re sults in experiments in which seg ments of mouse CD4 were combined with segments of human CD4. Mouse CD4 is broadly similar to the human molecule, but it is not recognized by gp120 or by the monoclonal antibod ies that are specific to human CD4. The "chimeric" molecules do bind gp120 very well if the first100 amino acids at the amino-terminal end of the molecule are human, even if the rest of the molecule is derived from the mouse. (The CD4 molecule as a whole consists of 433 amino acids.) In experiments that were even more specific, Andrew Peterson and Brian Seed of the Harvard Medical School made hundreds of tiny "point muta tions" in the human CD4 gene. They found that about seven amino acids residing near the middle of the initial 100-amino-acid segment are crucial for recognition by gp120 and by such monoclonal antibodies as Leu3a and OKT4a, which can block the binding of gp120. The major site on CD4 that is recognized by gp120, then, is a small region in the outermost part of the DISTRIBUTION OF TISSUESin the body that can be infected with IllV is closely linked CD4 molecule. to the distribution of cells bearing the CD4 molecule. With the possible exceptions The parts of gp120 that are essential of glial cells in the brain and chromaffin cells in the colon, duodenum and rectum, for binding have also been analyzed every cell that can be infected with IllV carries the CD4 molecule on its surface. by mutagenesis. William A Haseltine's

~~106 SCIENTIFIC AMERICAN October 1988~~

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© 1988 SCIENTIFIC AMERICAN, INC group at the Dana-Farber Cancer Insti SlY, soluble CD4 can neutralize any medical Research in San Antonio, have tute and Larry Lasky's group at Genen strain of the virus, making it an at inoculated mice with monoclonal anti tech Inc. have shown that three dis tractive candidate for treatment. bodies that recognize the part of CD4 tinct regions of gp120 are essential for Soluble CD4 would have some dis that is the binding site for gp120. the recognition and binding of CD4. advantages as an AIDS therapy, how These monoclonal antibodies are, in a Probably these regions come together ever. First of all, it would have to be sense, "negative images" of the bind to form a pocket that fits the binding injected repeatedly in large doses. In ing site: they fit around the binding site on CD4 when the gp120 molecule addition, soluble CD4 might bind to site on CD4 as a mitten fits a hand. In folds into its normal three-dimension Class IIMH C glycoproteins, interfer response to such an inoculation, the al configuration. ing with their normal function. That mouse immune system generates an would exacerbate the immune defi tibodies that bind to the monoclonal nowledge of the interactions ciency of AIDSrather than curing it. . antibody. Some of these new antibod through which HIVbinds to tar The problem could be surmounted, ies, the so-called anti-idiotypes, fit get cells suggests several pos however, if gp120 and the C lass' II precisely into the monoclonal anti sible ways of blocking HIVinfection. MHC glycoproteins recognize differ body's CD4-binding site; they are new OneK method would be to inject sub ent sites on CD4. It might then be hands that fit inside the mitten. jects with so-called soluble CD4 mole possible to make smaller segments of In some cases the anti-idiotype has cules, which consist of segments of the CD4 molecule that correspond a shape very similar to that of the site the portion of CD4 that normally lies just to the site recognized by gp120. on CD4 that is recognized by gp120. In outside the cell membrane. Soluble Another way to exploit our knowl a sense, then, these anti-idiotypes re CD4 has been produced through re edge of the CD4 molecule involves semble CD4; like soluble CD4, they can combinant-DNA technology by a num molecules known as anti-idiotype an bind to viralgp120 and should there ber of laboratories and biotechnology tibodies [see "Anti-idiotypes and Im fore be able to neutralize the infectivi companies. The molecules bind tightly munity," by Ronald C. Kennedy, Joseph ty of HIV. to gp120; when th ey saturate all the L. Melnick and Gordon R Dreesman; Thus it may be possible to use anti gp120 on the virus's envelope, they SCIENTIFIC AMERICAN,July, 1986]. A CD4 monoclonal antibodies as a kind neutralize its infectivity. Because the number of investigators, led by Ronald of vaccine in human beings. In re CD4-binding site on gp120 is essen C. Kennedy and Gordon R Dreesman sponse to an injection of anti-CD4 tially the same in all strains of HIV and of the Southwest Foundation for Bio- monoclonal antibodies, the immune

~~� MONOCLONAL ANTl } 7°TYP BOOY TO C04 �)r~~

~~VIRUS PARTICLE TARGET CELL OR INFECTED CELL~~

" POTENTIAL AIDS THERAPIES might block the binding of the vi antibodies, which would bear some resemblance to the CD4 rus particle or an infected cell to a target cell. Among the sim molecule. The anti-idiotypes might bind to gp120 molecules, plest therapies are antibodies that bind to gp41 (a) or to gp120 blocking them off and preventing them from binding to CD4 on (b). In another approach (c) the subject would be inoculated target cells. Still another approach (d) would be to inject the with monoclonal antibodies that bind to the CD4 molecule. The subject with "soluble CD4" molecules (which consist of the presence of these antibodies might stimulate the patient's portion of CD4 that normally lies outside the cell membrane). immune system to produce "anti-idiotypes": a second set of Soluble CD4 would bind tightly to gp120, blocking infection.

~~108 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC system might produce anti-idiotypes ---- that bind to the virus and neutralize ' - • 13 Taft Court it. These anti-idiotypes would protect ��'�"-----" PAN-DATA SYSTEMS, INC. __Rockville, Md., 20850 against all strains of the virus, because all strains of HIVrecognize the same site on the CD4 molecule. The actual neutralizing effect of QUALITY PRODUCTS AND SERVICES such anti-idiotypes has been investi FOR RETROVIROLOGY AND HERPESVIROLOGY RESEARCH gated independently by Dalgleish and by Sattentau and Beverley. They find AP PO AP PO TESTING SERVICES that anti-idiotype antibodies do in • -HBLV (HHV-6), EBV, CMV, HSV-1/2, ' 60- deed neutralize HIV, but only very ' -HIV-1 HIV-2, HTLV-I, HTLV-II, CAEV, EIAV 120 - 1 • • weakly. There are several possible ex , by: IFA, ELISA, WESTERN BLOT, RIA, RIPA, PCR planations for such weak neutraliza fi6- 55- - IMPROVED DIAGNOSTIC KITS tion. First, it may be that the anti r -Weslern Bioi, IFA idiotype antibody does not fit the ::� i I : gp120 protein very well. Second, the ANTI-VIRAL DRUG TESTING '! i - part of the gp120 molecule that recog "-I GROWTH FACTORS

24- . nizes CD4 probably resides in a pocket 1 .. - -ECGF, human IL-2JTCGF or crevice within the molecule, so that MOLECULAR BIOLOGY ! the relatively large antibodies cannot 151��=1- -Plasmid Produclion, Subcloning, cDNA Library gain access to it easily. Third, the anti A B C D Conslruclion, DNA Sequencing. .. 00 ,;00 idiotypes may not actually neutralize INTERFERONS AND MONOCLONAL AP Alkaline Phosphalase HIV at all; instead they may stimulate PO . Immunoperoxldase ANTIBODIES (MaB) TO INTERFERONS the immune system to produce an SERUM-FREE, PROTEIN-FREE MEDIA HIV-1 DNA Sequence Gel other set of antibodies that have the Western Blot Strips' produced in PDS's COMPUTER SERVICES opposite affinity: anti-anti-idiotypes, Sequencing Laboratory which might block the CD4 receptor -DNAIProlein Sequence Analysis Sofiware/Services -Laboralory Dala Base ManagemenliReporting just as the original antibody does. *HTLV-I Strips are also available

eople who are infected with HIV TOLL FREE 1-800-543-6059 generate an impressive immune Phone (301) 294-2297 fax(301) 294-8095 response to the virus. They pro duce antibodies to all the viral pro teins,P and their immune systems acti vate the various types of killer and scavenger cells that are part of any normal immune response. Yet once infection has occurred, these respon ses do not appear to halt the progress of the disease. Perhaps our increasing THE LADY DAVIS knowledge of the viral envelope and the cellular protein to which it binds will provide new approaches to de FELLOWSHIPP.O. Box 1255, Jerusalem 91904, TRUST Israel feating the virus. FELLOWSHIP FOR 1989/90 AT THE HEBREW UNIVERSITY OF JERUSALEM OR THE TECHNION-ISRAEL INSTITUTE OF TECHNOLOGY, HAIFA FURTHER RFADING GRADUATE AN D POST-DOCTORAL FELLOWSHIPS THE CD4 (T4) ANTIGEN Is AN ESSENTIAL ELIGIBILITY: Lady Davis Fellows are selected on the basis of demon COMPONENT OF THE RECEPTOR FOR THE strated.excellence in their studies and promise of distinction in AIDS RETROVIRUS. Angus G. Dalgleish, their chosen fields of specialization. Peter C. L. Beverley, Paul R Clapham, APPLICATION INFORMATION: Graduate applicants may apply dur Dorothy H. Crawford, Melvyn F. Greaves ing their senior undergraduate year or after they have undertaken and Robin A Weiss in Nature, Vol. 312, study in a graduate school. Post-doctoral applicants to the Hebrew No. 5996, pages 763-767; December University may apply not later than 3 years after completion of 20-27, 1984. their doctoral dissertation. THE T4 GENE ENCODES THE AIDS VIRUS RECEPTOR AND Is ExPRESSED IN THE IM The Fellowships are tenable for one academic year and may be extended for another year. MUNE SYSTEM AND THE BRAIN.Paul Jay The grant covers travel, tuition fees (whenever applicable) and Maddon, Angus G. Dalgleish, J. Steven reasonable living expenses. McDougal, Paul R Clapham, Robin A Weiss and Richard Axel in Cell, Vol. 47, VISITING PROFESSORSHIPS are intended for candidates with the No. 3, pages 333-348; November 7, rank of Full or Associate Professor at their own institution. They 1986. are tenable from one semester to a full academic year. The grant GENETIC ANALYSISOF MONOCLONAL AN includes a professorial salary and travel. TIBODY AND HIV BINDING SITES ON THE DEADLINE: November 30,1988. Requests from applicants (includ HUMAN LYMPHOCYTE ANTIGEN CD4. An ing Israelis) indicating category of Fellowship should be sent to drew Peterson and Brian Seed in Cell, above address. Vol. 54, No. 1, pages 65 -72; July 1, 1988.

~~SCIENTIFIC AMERICAN October 1 988 109~~

~~One drug-AZT-is already in clinical use. New knowledge of HIV makes it possible to design drugs that interrupt specific phases of the viral life cycle. More effective therapies are on the way~~

~~by Robert Yarchoan, Hiroaki Mitsuya and Samuel Broder~~

ack in 1984, when AIDSwas con to complications that may be difficult the cells' genetic machinery in order clusively shown to be caused to eradicate in their own right. The to reproduce. When viruses are ac Bby the human immunodeficien complexity of HIV, combined with the tively replicating, it is often difficult cy virus (HIV),many investigators and devastating nature of the disease it to distinguish between viralproteins clinicians doubted that a drug capable self, led many to regard AIDS as a that interact with the cell and host-cell of attacking the virus directly would uniquely challenging and perhaps in proteins themselves. The host cells' ever be found. Their fears were under surmountable problem. intimate involvement in many stages standable: past efforts to find antiviral That grim prognosis, however, has of the life cycle of the virusmakes it drugs had turned up only a handful of improved in a remarkably short time. difficult to find agents that selectively effective agents. Moreover, retrovirus A survey of off-the-shelf antiviral sub inhibit viral replication while damag es such as HIV present a particularly stances, initiated in our laboratory at ing the host as little as possible. elusive target: they can integrate into the National Cancer Institute (NCI), Moreover, virtually no drug-not the genome of body cells, where they turned up one, azidothymidine (AZT), even penicillin-is completely devoid can lie dormant and go undetected for that has already been shown to pro of side effects and toxicity. One must long periods of time. long the lives of certain AIDSpatients. therefore always consider the balance In the case of HIV, the problem is In the past four years investigators between harm to the pathogen and exacerbated by the virus's ability to have come to understand the life cycle harm to the host. Anessential aspect infect a variety of tissues and cells in of the AIDSvirus better than that of of any potential drug is its "therapeu the body. In particular, the virus can perhaps any other virus, and with that tic index": the ratio of the toxic dose hide in cells of the central nervous understanding we have begun to be to the effective dose. Drugs to treat a system, where it is protected by the able to rationally design drug thera minor illness must have a high thera blood-brain barrier, which many drugs pies aimed at specific stages during peutic index. For a life-threatening ill cannot pierce. Even if certain drugs which the virus might be vulnerable. ness such as AIDS,one may have to could cross the barrier, brain cells al We expect such drugs to have a major accept drugs with a lower therapeutic ready damaged by the virus may never impact on this disease in the future. index, at least in the beginning. heal. Also, secondary diseases associ Against this background one can be ated with AIDS,such as Kaposi's sarco �y therapeutic agent against an gin to appreciate some of the consid ma, aggressive lymphomas and cer infection caused by a pathogen, erations surrounding the search for tain opportunistic infections, can lead whether it is a virus,bacteria, AIDStherapies. In the summer of 1984 fungus or protozoan, must either kill two of us (Mitsuya and Broder) ob the pathogen or stop it from multiply tained the AIDS virus from Robert C. ROBERT YARCHOAN, HIROAKI MITSU ing. This it must do without harming Gallo's group and began testing a YA and SAMUEL BRODER are in the Clini-' the infected host Significantly. Gener number of substances for activity cal Oncology Program of the National ally such drugs accomplish their task against HIV. Many of these had previ Cancer Institute (NCI). In 1984 they be gan searching for antiretroviral AIDS by attacking a biochemical pathway ously been shown to be active against therapies. Yarchoan , a senior investiga unique to the pathogen. In the case of mouse retroviruses by a number of tor , earned his M.D. from the University bacteria this is relatively easy to do, inyestigators, including Wolfram Os of Pennsylvania in 1975. He joined the because there are many differences tertag of the Max Planck Institute for NCI in 1978, where he specialized in viral between the structure and metabo Experimental Medicine in G6ttingen, AIDS. immunology and later focused on lism of bacterial cells and those of Philip Furmanski of the Michigan Can Mitsuya received an M.D. in 1975 and mammalian cells. Penicillin, for exam cer Foundation, Joel A Huberman of a Doctor of Medical Science degree in ple, interferes with the synthesis of the Roswell Park Memorial Institution 1982 from the Kumamoto University Medical School in Japan. He joined the bacterial cell walls; mammalian cells, and Eric De Clercq of the Rega Institute NCI in 1982, where he developed the because they lack these cell walls, are in Leuven, Belgium. Their work had assay system used to find the anti-HIV not affectedby the drug. languished in relative obscurity for activity of dideoxynuc!eosides. Broder , Viruses present a more formidable years because no pathogenic human who is head of the program , received problem. Viruses are simply packets retroviruses had yet been identified his M.D. in 1970 from the University of of genetic material (RNA in the case of and in any case many people assumed Michigan. He joined the NCI in 1972. He the AIDSvirus) cloaked in glycopro that retroviral infections were by their ' was among the first to identify antiviral drugs that could be moved quickly from teins and lipids. They cannot replicate very nature untreatable. The urgent the test tube into AIDSpatients. on their own. Instead they infect cells search for a drug against AIDSrevived of another organism and commandeer our interest in this earlier work. By the

~~110 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC TIlREE BRAIN SCANS reveal that lDV-induced dementia can be activity in several brain regions_ The scan at the bottom right relieved by treatment with azidothymidine (AlT)_ The scans is from the same patient after treatment with AlT_ Meta were made by the technique called positron-emission tomog bolic activity became closer to normal. The patient's intellec raphy_ Red and yellow regions correspond to areas of high tual function also improved_ The scans were made by Ste metabolic activity_ The scan at the top is that of a healthy ven M_ Larson, Gary Berg and Arturo Brunetti of the Clinical individual. The one at the bottom left is from a patient with Center of the National Institutes of Health_ The Wellcome Re dementia caused by lDV infection; it shows relatively reduced search Laboratories supplied the AlT used in all our studies_

~~SCIENTIFIC AMERICAN October 1988 III~~

© 1988 SCIENTIFIC AMERICAN, INC late spring of 1985, 15 of the 300 as a drug suitable for the therapy of was active in some HIV-infected pa drugs tested had been found to stop AIDS.We gave the drug to the first tients. By September, 1986, clinical HIVreplication in the test tube. patient on July 3, 1985. By the end of studies at 12 U.S. medical centers One of these was 3' -azido-2' ,3' -di that year our group, in collaboration demonstrated that AZT can improve deoxythymidine, or AZT (also called with workers at Duke University and both the survival period and the quali azidothymidine or zidovudine). We be the Wellcome Research Laboratories ty of life for patients with AIDS.For the gan an intensive effort to develop AZT in Durham, N.C., could infer that AZT first time, a drug was shown to exert a positive effect against a pathogenic retroviral infection. Anintensive glob al effortis now under way to find other agents for the treatment of AIDS. To understand how these agents · might work, one must consider the structure and replicative cycle of the WAYS TO INTERVENE AIDSvirus. In HIV and other retrovi ruses, genetic information flows in a :....r-_...... -- ��it-- 1. BLOCK BINDING backward, or "retro," direction: from RNA to DNA,whereas the usual direc tion for other organisms is from DNA to RNA Retroviruses achieve this feat by means of a special enzyme, reverse transcriptase, which can take RNA and ------+---- 2. INHIBIT UNCOATING exploit it as a template for assembling

REVERSE a corresponding strand of DNA TRANSCRIPTION Replication in HIVis a complicat �------+--- 3. INHIBIT REVERSE TRANSCRIPTION ed affairinvolving a large number of � steps. The virus's outer coat of glyco � protein binds and fuses to the mem o brane of a host cell, enabling the viral RNA, along with reverse transcriptase, to invade the cell's cytoplasm. There INTEGRATION the reverse transcriptase synthesizes DNA from the viral RNA; the DNA then inserts itself into the host's chromo· TRANSCRIPTION NUCLEUS somes. Later this "proviral" DNA may be transcribed back to RNA, which the cell's protein-production machinery VIRAL·PROTEIN 4. TRANSLATION translates into viral proteins. These SYNTHESIS ARREST proteins reassemble into complete vi rus particles, which emerge from the

~~- --r=,�------i--- 5. INHIBIT PROTEIN host cell and can infect new cells. It MODIFICATIONS is clear that HIVs complex life cycle helps the virus to infect-and evade~~

------, --- INHIBIT ASSEMBLY 1- 6. cells of the immune system. From the AND BUDDING therapist's standpoint this complexity may prove to be as much a boon as it is a curse: it provides many targets for antiviral agents to attack during the

~~life cycle of HIV.~~

he first stage at which an anti- , HIV agent might intervene is Tduring the binding of the virus to a cell. HIV has an envelope glyco protein called gp120, which forms a strong bond with a glycoprotein called CD4 (or T4), found on the surface of certain cells in the body. CD4 is partic ularly abundant on the surface of a HIV UFE CYCLE is subject to attack by drugs at several stages. Certain antibodies class of white blood cells called helper could block the binding of the viral envelope glycoprotein, gp120, to CD4 receptors T cells, which are therefore a prime on the surface of helper T cells (1). Other agents might keep viral RNA and reverse target for HIV infection. Indeed, a transcriptase from escaping their protein coat (2). Drugs such as AZT and other dideoxynucleosides prevent the reverse transcription of viralRNA into viral DNA gradual depletion of such cells is a (3). Later on, antisense oligonucleotides could block the translation of mRNA into hallmark of AIDS.Normally helper T viral proteins (4). Before they can be assembled, viral proteins must be modified; cells are crucial regulators of immune certain compounds could interfere with such processes as the cleavage of proteins defense systems. Without enough or the addition of sugar groups (5). Finally, such antiviral substances as interferons functioning helper T cells, infected in could keep the virus particle from assembling itself and budding out of the cell (6). dividuals become subject to oppor-

~~112 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC tunistic infections and malignancies. toxin; it could then bind to and de unique sites to which an antibody can HIV-infected helper T cells do not stroy infected cells, such as macro bind. A third reason may be that the work as well as they should, and they phages, that harbor the virus and pro CD4-binding site is in a deep cleft in can be killed outright by the virus. In duce HIV proteins. One might also the envelope glycoprotein, making it addition, studies in test tubes have develop antibodies to CD4, but such relatively inaccessible. Finally, it is shown that a few infected cells can an approach is potentially hazardous, possible that the crucial sites are ex kill large numbers of uninfected cells because the antibodies would attack posed only during binding and are through a process called syncytium the body's healthy immune cells. Most hidden from the immune system most formation: the fusion of an infected research, therefore, has focused on of the time. cell with healthy cells. JeffreyD. Ufson antibodies to gp 120. and Edgar G. Engleman of Stanford There are inherent difficulties in n order to overcome these difficul University, William A Haseltine of the creating an effective neutralizing anti ties, investigators have tried sever Dana-Farber Cancer Institute and their body to gp120. Not all antibodies to Ial approaches. One is to develop colleagues showed that syncytiaare gp120 will block the critical CD4-bind a monoclonal antibody by identifying initiated when the gp120 on virus par ing site. Moreover, patients who pro an antibody that does bind to a criti ticles at the surface of infected cells duce neutralizing antibodies (gener cal site, and then to clone it and grow binds to CD4 on the surface of healthy ally only in low concentrations) as a it in the test tube. With this meth cells. A drug that interferes with viral natural response to HIV infection may od, Shuzo Matsushita of Kumamoto binding therefore may not only inter still develop AIDS.Why is that? No one University and his colleagues recently rupt the viral life cycle but also block is certain, but one reason may be that produced a neutralizing antibody to the formation of syncytia. HIV has a high rate of mutation. Some gp120 that they call O.5-�. This an There are several approaches to in variants may have an altered envelope tibody neutralizes some, but not all, hibiting the initial binding of HIV to a glycoprotein that cannot be neutral strains of HIV. A similar approach may cell. One approach is to develop an ized by the antibodies. A second rea in the future produce antibodies to a antibody that binds to a critical part of son may be that sugar chains on the broader range of HIV strains. the viral envelope, thereby neutraliz envelope glycoprotein are similar to A second approach is to make an ing the gp120's ability to bind to CD4. those on the surface of human cells, "anti-idiotypic antibody": an antibody Such an antibody could be linked to a so that the envelope lacks enough to an antibody against CD4. The idea

~~a VIRUS c~~

~~GP41-----+~~

~~GP120~~

~~CD4 SOLUBLE CD 4~~

~~CELL~~

~~ANTIBODY TO CD 4~~

~~:> :>~~

~~ANTI-IDIOTYPE~~

VIRALBINDING depends on the interaction of viral envelope glycoprotein, gp120 (green), with CD4 receptors (yellow) on the surface of helper T cells (a). Anantibody directed against gp120 could block the site that binds to CD4 (b); so could a soluble form of the CD4 protein (c). An"anti-idiotypic antibody" (d) to gp120 is made by taking a monoclonal antibody against CD4 and forming an antibody to it. A "chimer ic" molecule (e) could be more stable than soluble CD4; it combines gp120-binding sites on the CD4 molecule with the constant region of an immunoglobulin molecule.

~~SCIENTIFIC AMERICAN October 1988 113~~

© 1988 SCIENTIFIC AMERICAN, INC 8,000 daltons inhibit HIV replication in vitro, as recently shown by Ryuji Ueno and Sachiko Kuno of Ueno Fine Chemicals Industry, Ltd., in Osaka, Ja pan, Masahiko Ito of Fukushima Medi cal College and two of us (Mitsuya and Broder) at the NCI. Our group found that one way this compound may have its effect is by inhibiting viral binding. Dextran sulfate has also been shown to inhibit syncytia formation in vitro, as one would expect from a molecule that blocks viral binding. Dextran sulfates have been admin istered for some time as plasma expanders, anticoagulants and cho lesterol-lowering drugs. This clinical history suggests (but by no means proves) that the anti-HIV form of dex tran sulfate may be relatively non toxic. It remains to be seen, however, SYNCYTIA are giant, multinucleated structures that form when HIV-infected cells whether doses sufficient to inhibit HIV fuse with uninfected cells, as is seen in this phase-contrast micrograph (left). They can be achieved by giving the drug occur because viral envelope glycoprotein on the surface of infected cells binds to orally, or indeed whether it will be CD4 molecules on other cells. Dextran sulfate, which may inhibit viral binding, pre effective at all against AIDS. Also, we vents syncytium formation in a mixed culture of infected and uninfected cells (right). do not yet know whether the drug will interact with other drugs in patients. Donald 1. Abrams is studying dextran is that a monoclonal antibody against plan to begin testing the substance sulfate in patients at the San Francisco CD4 might resemble the CD4-binding (called rCD4) in AIDS patients in the General Hospital. site on gp120, and therefore an anti very near future. body (the anti-idiotype) made against In the future it may be possible to �ter HIV has bound to a cell, it this anti-CD4 antibody (the idiotype) create "chimeric" molecules by taking fuses with the cell membrane, might in turn bind to gp120. The con the sites on CD4 that bind to HIV and releasing its contents into the cept is somewhat analogous to mak spliCing them onto the constant part cytoplasm. There the inner protein ing a negative from a photographic of a human immunoglobulin (anti coat is partially removed to expose the negative to produce a positive. To in body) molecule. There are several pos viral RNA Antibodies could neutralize vestigate this possibility, two groups, sible advantages to such "customized gp41, the envelope glycoprotein that one led by Ronald C. Kennedy of the antibodies." We think certain parts of mediates fusion, and so prevent fu Southwest Foundation for Biomedical the so-called heavy chain of the immu sion from occurring. Antiviral drugs Research and the other by Peter C. L. noglobulin molecule may be able to may be able to interfere with the un Beverley of University College London, activate other parts of the immune coating process. took several CD4 antibodies known to system into destroying the virus. The The target that has received perhaps inhibit HIVbinding and produced sev chimeric molecule would act like a more attention than any other, howev eral monoclonal antibodies to them. bloodhound-and-policeman team: the er, is the next stage of viral replication: Both groups found that some of these CD4 sniffs out the virus, and the im the synthesis of viral DNA by the en anti-idiotypic antibodies bound to and munoglobulin radios for the troops. zyme reverse transcriptase. This strat neutralized HIVin vitro. What is more, the chimeric molecule egy is attractive because it attacks a Another approach is to create a free may stay in circulation for a longer step that is unique to retroviruses. floating, or soluble, form of CD4 that time than soluble CD4 alone, because Early in our own efforts to find an can bind to HIV, monopolizing its certain immunoglobulins have a long antiretroviral agent, we made this our CD4-binding sites and thus keeping it half-life in the bloodstream. Such an prime target. In particular we focused from binding to the CD4 on a helper approach has never been tried in hu on compounds belonging to a fami T cell. Soluble CD4 was recently pro man beings, but structural similarities ly of reverse-transcriptase inhibitors duced with recombinant-DNA meth between CD4 and immunoglobulins called dideoxynucleosides. These are ods by fivegroups, including research (CD4 belongs to the immunoglobulin nucleoside analogues, molecules that ers at Genentech Inc., Biogen N.Y., Co "supergene" family) give us hope that closely resemble the nucleotides that lumbia University, the Smith Kline & such chimeras will retain functional serve as building blocks in DNA and French Laboratories, the Dana-Farber propertie� of both molecules. RNA: the pyrimidines (thymidine, uri Cancer Institute and the Basel Insti The approaches described above in dine and cytidine) and the purines tute for Immunology.These molecules volve complex biological molecules (adenosine and guanosine). did indeed adhere to the CD4-binding that bind to HIV envelope glycopro One such compound is 3' -azido- sites on the HIVenvelope and inhibit tein. Other molecules, however, may 2' ,3' -dideoxythymidine, the AZT we the virus from infecting T cells. It will also do the trick. Several large, sulfat mentioned above. AZT was originally probably be difficult for the virus to ed, negatively charged molecules have synthesized in 1964 by Jerome P. Hor mutate in such a way that it loses its been shown to inhibit HIV replication. witz of the Michigan Cancer Founda affinity for the CD4 molecule while One prototype is dextran sulfate. Mol tion as a potential anticancer drug . (It retaining its ability to infect Tcells. We ecules weighing between 7,000 and failed, but Burroughs Wellcome con-

~~114 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC tinued to make it). In February, 1985, ent species. Animal models, therefore, and so the host cell can continue to our laboratory found it to be a potent may not accurately predict whether a function. Reverse transcriptase might inhibitor of HIVin T-cell cultures at particular dideoxynucleoside will be be altered in such a way that it too will concentrations of between one and effective in human beings. not prefer AZT triphosphate. five micro molar (or between about .25 Another question is whether muta In an attempt to study this point, and 1.25 micrograms per milliliter). tion might alter the viral reverse tran Brendan A Larder, Graham K.Darby Moreover, the compound was not sig scriptase so that it is no longer inhibit and their colleagues at the Wellcome nificantly toxic to T cells below con ed by AZT. This is not idle speculation: Research Laboratories in the UK mu centrations of from 20 to 50 micromo it happens that AZT works because the tated HIV reverse transcriptase in lar. Soon after this work, AZT proved virus's reverse transcriptase actually specific ways. They found that some to be effective in AIDS patients at con prefers AZT triphosphate, and tends of the altered reverse transcriptases centrations of between one and five to bind and incorporate it rather than were more resistant to inhibition by micromolar, the amount initially pre thymidine triphosphate. The DNA po AZT triphosphate. These agents were, dicted by our T-cell assay system. lymerases in mammalian cells, how however, impaired in their normal ac ever, do not prefer AZT triphosphate, tivity. No one knows whether viruses oW does AZT protect T cells against HIV?The key lies in its Hresemblance to the nucleoside thymidine. In the cell, enzymes add T T phosphate groups (in a process called phosphorylation) to convert AZT into AZT triphosphate, the active form of the drug. (AZT triphosphate cannot be given directly because cells cannot absorb it.) AZT triphosphate is an " analogue of thymidine triphosphate, one of the building blocks of DNA, and it appears to inhibit the pro N, duction of viral DNA by at least two 2' -DEOXYTHYMIDINE 3' -AZIDO-2' ,3' mechanisms: competitive inhibition DIDEOXYTHYMIDINE (AZT) and chain termination. In competitive inhibition, AZT tri phosphate binds to reverse transcript ase at a site that ordinarily binds to physiological nucleoside triphos C C phates. In chain termination, reverse transcriptase is fooled into incorpo rating AZT triphosphate in a growing chain of viral DNA in place of the normal thymidine triphosphate. When �O �O it tries to add the next link, it is thwart ed because AZT triphosphate lacks the hydroxyl (OH) group that is needed to I I forge the chemical bond to the next OH H link. The virus cannot repair this 2' -DEOXYCYTIDINE 2' ,3' -DIDEOYXCYTIDINE (ddC) mistake, and the viral DNA synthesis comes grinding to a halt. Other dideoxynucleosides that are active against HIV also appear to work by these mechanisms. All these com pounds appear to be effective against a number of retroviruses (indeed, A A against every one tested so far), but only when they are in the triphosphate form. Their therapeutic effectiveness, then, depends in part on how easily they enter cells and undergo phos phorylation by cellular enzymes called kinases. This process is in fact more � efficient for some compounds than it OH H is for others. For example, 2' ,3' -dide 2' -DEOXYADENOSINE 2' ,3' ·DIDEOXYADENOSINE (ddA) oxythymidine-which is AZT with a hydrogen atom in place of the azido DIDEOXYNUCLEOSIDE ANALOGUES (right column) could prove to be potent drugs (N3) group-is poorly phosphorylated against HIV because of their resemblance to deoxynucleosides (lett column), the in human cells and so is less potent building blocks of DNA Both types of molecules consist of a base-here thymine (T), than AZT against HIV. In addition, the cytosine (C) or adenine (A)-joined to a sugar ring. A hydroxyl group (OH) on the way these compounds are phosphor sugar ring forms a bond that links one nucleotide to another in a DNA chain. In the ylated varies greatly among differ- analogues the hydroxyl group is replaced by a group that is unable to form the link.

~~SCIENTIFIC AMERICAN October 1988 115~~

~~RNase H~~

~~DIRECTION OF MOVEMENT < 5'~~

~~POLYMERASE CATALYTIC CENTER~~

AZT TRIPHOSPHATE (red) can halt the synthesis of viral DNA, nucleosides such as thymidine, as well as to analogues such as shown in this drawing. Reverse transcriptase (yellow) binds as AZT. Normally, the reverse transcriptase then cleaves off to viral RNA and to a lysine tRNA-3, which provides the start· two of the phosphates, and the remaining phosphate forms ing point for the DNA. The growing strand sits in the primer a phosphodiester linkage to the hydroxyl group at the end of binding groove. (After the DNA strand is completed, RNase H the chain. But if AZT t�iphosphate is added instead, no fur removes the RNA so that a second DNA strand can form in its ther nucleotides can be added because the azido (N3) group of place. Cellular enzymes add three phosphates (black dots) to AZT cannot form the linkage, and so viral DNA synthesis stops.

~~"ANTISENSE" PHOPHOROTHIOATE OLiGODEOXYNUCLEOTIDE~~

ANTISENSE OUGONUCLEOTIDES are segments of DNA that make them resistant to the enzymes, one can substitute a are complementary to a portion of HIVmRNA. They are sulfur atom (yellow) for an oxygen on the phosphate links thought to bind to the viral mRNA and so prevent ribosomes between the nucleotides. The resulting compound, which from translating the mRNA into viral proteins. Oligonucleo is called a phosphorothioate, is resistant to degradation and tides, however, are rapidly degraded by cellular enzymes. To has been shown to inhibit the expression of HIV in vitro.

~~116 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC with such mutations would be infec structs can bind to viral mRNA se teams, one led by Joseph G. Sodroski tious or cause disease; specifically, no quences in a process called hybridi and Haseltine and the other led by one is sure whether AZT-resistant mu zation, possibly obstructing the cell's Robert Gruter of the Netherlands Red tants can arise in patients. ribosomes from moving along the Cross Transfusion Service, recently Another point to consider with dide RNA and thereby halting the transla showed that when HIV is produced oxynucleosides is that because they tion of RNA into viral protein. This is in the presence of castanospermine, resemble important cellular chemi called translation arrest or ribosomal a plant alkaloid that inhibits a trim cals, they may interact with a variety hybridization arrest. ming glycosidase, it is less able to of enzymes in the body. For example, One disadvantage with oligonucleo form syncytia or to infect cells. Casta 2' ,3' -dideoxyadenosine (ddA) in tri tides is that many of them can be nospermine analogues, designed to be phosphate form is a potent HIV inhib degraded by enzymes in the host cells. more potent and yet less toxic than itor in vitro, but in the body ddA is They can, however, be made resistant castanospermine itself, might provide more likely to be converted by the by modifying certain phosphate links a treatment for HIV infection. ubiquitous enzyme adenosine deami between the nucleotides. For example, Finally, the viral proteins and RNA nase into 2' ,3' -dideoxyinosine (ddI), one can substitute a sulfur atom for are transported to the cell membrane which in its phosphorylated form is one of the oxygen atoms to form a and there assembled into virus par only weakly active against HIV. Yet ddI phosphorothioate. Makoto Matsukura ticles, which escape by budding out is effective against HIV in culture be in our group, working with Gerald Zon of the cell surface. The budding may cause it is itself metabolized to ddA of Applied Biosystems, Inc., and Jack be stopped by interferons, antiviral triphosphate in cells. In fact this may c. Cohen and Cy A Stein of the NC!, substances that are produced natural be the dominant pathway by which recently found that such antisense ly in cells. Interferons are thought to ddA is phosphorylated in the body. We phosphorothioates can indeed inhibit act at other steps in the HIV life cycle may not be as lucky with other com HIVproduction in cells chronically in as well. Certain substances that can pounds, however, which might simply fected by HIV. induce a cell to produce interferon be converted into useless metabolites It may also be possible to stop vi have also been found to inhibit HIV before they can reach target cells. ral production by blocking viral genes replication in vitro. Indeed, interfer or proteins that regulate this process. ons have a wide range of effects and �ter a strand of DNA has been The translation of viral RNA into pro therefore may benefitAIDS patients in copied from the viral RNA, the tein is tightly controlled by the virus. several ways. For example, alpha-inter reverse transcription proceeds Regulatory sequences, called long ter feron helps to suppress Kaposi's sar to a second stage: the synthesis of a minal repeats, at each end of the viral coma, and so it might benefitcertain second DNA copy of the first DNA genome may directly control viral pro AIDS patients by acting as both an strand. This stage is also subject to tein synthesis. Several viral proteins antiretroviral and an antitumor agent. attack One could, for example, try to regulate this process as well. These interfere with the viral enzyme RNase regions might provide targets for se f all the substances that show H, which chops up viral RNA in an lectively inhibiting HIV replication. activity against HIV, AZT has orderly fashion after the firstDNA In addition, HIV replication can be Oundergone the most extensive copy of it has been made, thus making influenced by proteins made by the clinical study. Five months after our room for the second DNA strand. It host cell or even by other viruses that laboratory showed in February of may also be possible to block anoth happen to also infect the cell. Gary ]. 1985 that AZT inhibits HIV replication, er enzyme, viralintegrase, which is Nabel and David Baltimore of the we administered the drug to the first thought to serve as a chemical sewing Whitehead Institute for Biomedical Re patient in the Clinical Center at the kit that cuts the DNA of the host cell search have recently shown that the National Institutes of Health (NIH). before stitching viral DNA into the site cellular protein NF-KB, which acts as This patient had AIDS and had recently of the cut. an intracellular activation signal in recovered from Pneumocystis carinii The next target for therapy presents certain lymphocytes, may turn on HIV pneumonia. His immune functions itself some time later in the cycle of replication. Certain herpes viruses were severely suppressed and his

HIV, when the host cell is activated. produce a protein called ICPO that can helper T cells were markedly depleted. The cell may begin to produce new also trigger HIV replication. In patients When we exposed his skin to common proteins or receptors, and it may di infected with both a herpes virus and antigens (in a test analogous to a tu vide. The same process that activates HIV, it may therefore be possible to berculosis test), he failed to produce the cell may also trigger the transcrip delay the progress of AIDS by control the reddish swelling that signals a tion and translation of viral DNA into ling the herpes infection, for example normal immune reaction. After tak viral proteins. We and others are in with the drug acyclovir. ing AZT for several weeks, he gained vestigating whether this process can After the viral proteins are pro weight and had an increased number be interrupted by the use of "anti duced, they undergo a series of modi of helper Tcells. He also reacted to the sense oligonucleotides," an approach fications that result in a complete, skin test, indicating that the overall first suggested more than 15 years functional virus. In one of these steps function of his T-cell immune system ago by Paul C. Zamecnik of the Worces a viral enzyme cleaves the viral pro had improved. ter Foundation for Experimental Biolo teins. Because this enzyme is unique Other patients at the NIH and at the gy. The idea is to create short nucleo to HIV, several laboratories are now Duke University Medical Center who tide sequences, or oligonucleotides, searching for agents that specifically received AZT in this first trial also had that are complementary to a part of inhibit it. In another step viral proteins improved clinical symptoms and im the viral mRNA (The mRNA is in the gain carbohydrates in a process called munological function, which we at "sense" mode, that is, irdirectly codes glycosylation, in which enzymes add tributed to the drug's antiviral effect. for proteins; these oligonucleotides sugars and then other enzymes called We also found that AZT could reduce are "antisense," that is, complementa trimming glycosidases trim offsome the amount of HIV present in patients. ry to the mRNA)These antisense con- of the terminal sugar groups. Two In many cases, however, these im-

~~SCIENTIFIC AMERICAN October 1988 117~~

© 1988 SCIENTIFIC AMERICAN, INC provements were only temporary, and, of California at San Diego and their Six months into the trial, 19 patients given the side effects that occurred colleagues studied some 280 patients. in the placebo group had died, where in some patients, some investigators These patients had either recovered as only one patient in the group re questioned whether the benefits were from Pneumocystis carinii pneumonia ceiving AZT had died. Also, patients sufficient to have a substantial impact or had severe AIDs-related complex. receiving AZT had fewer complica on the course of the disease. They were randomly chosen to receive tions of the disease. At this point the To find out, the Wellcome group either AZT or a placebo. Neither doctor trial was halted and all the patients organized a randomized, placebo-con nor patient knew whether the patient were offered AZT. It now appears that trolled trial of AZT in 12 major medi was receiving AZT or the placebo. Pa AZT can increase the median survival cal centers around the U.S. Margaret tients were not given any prophylaxis time of patients with advanced AIDS A Fischl of the University of Miami, for the pneumonia, nor were they giv by about a year. (The median survival Douglas D. Richman of the University en any other AIDS therapy. time is the time at which 50 percent of the patients have died.) This evidence prompted the Food and Drug Admin MECHANISM istration, in March of 1987, to approve DRUG COMMENTS OF ACTION AZT as a prescription drug for severe HIV infection. DEXTRAN SULFATE Probably inhibits viral Used orally outside the U.S. to reo binding duce cholesterol levels; proto· AZT may have an even greater effect type for polyanionic polysaccha· if it is given earlier in the course of HIV rides that have anti·HIV activity; Phase II clinical trials begun at infection. In fact, it is possible that it San Francisco General Hospital. may actually prevent the progress of AIDS in at least some individuals, per SOLUBLE CD4 Inhibits viral binding Genetically engineered form of (ALSO CALLED rCD4) CD4; Phase I trials under way. haps both by its direct antiviral effect and by partially restoring immune

AZT (AZIDOTHYMIDINE Reverse·transcriptase Prescription drug; increases sur· function. Gene M. Shearer of the NCI OR ZIDOVUDINE) inhibitor, chain vival time and reduces opportu· and Robert T. Schooley and Martin S. terminator nistic infections; can ameliorate HIV·induced dementia; toxic to Hirsch of the Massachusetts General bone marrow. Hospital have shown that T cells from I patients given AZT may be better able ddC Reverse·transcriptase Antiviral effect even at very low inhibitor, chain dose; toxic effects on peripheral to kill HIV-infected cells. Clinical trials terminator nerves can be reduced by taking are now under way to test this idea. We alternately with AZT; Phase II trio wish to stress that until these trials als under way both alone and in combination with AZT. are concluded, it will not be possible to draw valid inferences about the role ddA and ddl Reverse·transcriptase Relatively little bone·marrow tox· of AZT in the early stages of HIV infec inhibitor, chain icity in vitro; Phase I trials under terminator way. tion. Moreover, the long-term toxicity of AZT is not yet known. PHOSPHONOFORMATE Reverse·transcriptase Also active against cytomegalovi· inhibitor rus; Phase II trials show evidence of some activity against HIV. ur early work with AZT showed it could penetrate into the flu RIFABUTIN Possible reverse· Also active in vitro against cer· id surrounding the brain, and transcriptase inhibitor O tain mycobacteria that can infect AIDS patients; Phase I trial being so we wondered if it could treat the completed. devastating dementia that sometimes develops in patients infected with HIV. RIBAVIRAN Mechanism unknown Only partial anti·HIV effect;an· tagonizes activity of AZT in labo· When we gave AZT to afflicted pa ratory; clinical trials have so far tients, in most cases in which care not shown that it reduces HIV an· ful tests of intellectual function were tigen. in serum of patients. done we found at least temporary im PHOSPHOROTHIOATE Probably several May have sequence·specific and provement. This was apparent within OLiGODEOXYNUCLEOTIDES mechanisms, including nonspecific activity; still in very the first few weeks of therapy. In addi arrest of viral protein early development. synthesis tion, Philip A Pizzo of the Pediatric Branch of the NCI has given continu CASTANOSPERMINE Inhibits enzymes that Reduces syncytium formation and trim sugar groups from infectivity of virus; still in very ous infusions of AZT to a number of viral proteins early development. children with AIDS, whose intelligence quotient (IQ) had fallen as a result of ALPHA INTERFERON May reduce viral Also has direct antitumor activity the disease. In some cases he found I budding; probably has against Kaposi's sarcoma; Phase other mechanisms as well II trials under way, both alone that the IQ returned to normal levels and in combination with AZT. during treatment. We do not understand all the mech AMPLIGEN Interferon inducer; Little toxicity observed in pa· may work by other tients; large·scale Phase II and anisms that lead to AIDS dementia, mechanisms as well Phase III trials under way. and so the beneficial mechanisms of AZT are also unclear. It is of course possible that the improvements di AIDS lHERAPIES at various stages of testing are shown in this chart. All of the substances on the list have shown some activity against HIVin the test tube. Many of rectly result from controlling HIV in them are now in various stages of clinical trials. Phase I trials usually involve a small fection in the brain. Carlo-Federico number of patients and are designed to establish toxicity, maximum tolerated dose Perno in our group has shown that and the drug's mechanism of action in the body. Phase II and Phase m trials involve cells of the monocyte-macrophage larger numbers of people and are designed to assess the effectiveness of the drug. lineage, prime targets for HIV infec-

~~118 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC tion in the nervous system, can be ripheral sensory and motor nerves), that are capable of seeking out and protected against HN replication even primarily in the feet. This neurop suppressing hidden pockets of in by low concentrations of AZT and oth athy gradually subsided after patients fection. Finally, the patient might be er dideoxynucleosides. Whether this stopped taking the drug. maintained on a low-dose regimen to accounts for the clinical improvement Because the toxicity of ddC is differ suppress any recurrences. The drugs, in these patients, or whether another ent from that of AZT, we wondered the dosage and the dispensing sched mechanism is involved, is a matter for whether we could obtain a better re ule may differ from one phase to an further research. sult if the two drugs were alternated. other. For example, a potent drug that Because of the rapid development Such a regimen might allow vulnerable might playa crucial role in the initial of AZT, there remain many unan tissues to recover from the toxic ef phase could be too toxic for long-term swered questions regarding its effects fects of each drug; similar strategies maintenance. It seldom makes sense and the best method of administra have been successful in treating and to draw conclusions about the safety tion. We do not know if it is better to even curing certain cancers. Some pa and efficacy of any given drug without keep AZT circulating at as constant a tients are now on an alternating regi considering in detail both the dosage level as possible or to allow it to fluc men of ddC and AZT. Preliminary re and the schedule of administration. tuate. AZT levels decline by about 50 sults show that some patients can tol percent over the course of one hour, erate such a treatment for more than �this time investigators must not and the present schedule of one dose a year without developing either neu pin their hopes on any single every four hours is designed to keep ropathy or suppressed bone marrow. drug or approach but instead circulating levels fairly constant. In The dideoxynucleoside ddA and its should strive to develop a variety of the case of dideoxynucleosides, one metabolite ddI also strongly inhibit agents to attack HN at different must also consider the metabolism of HN in culture. These drugs appear to points. In bringing these drugs to a the phosphorylated products. For ex be less toxic in cultures of helper T stage where they can benefit patients, ample, David G. Johns of the NCI has cells than either AZT or ddC. In addi there is a lesson to be drawn from the found that the intracellular half-life tion they are less toxic to bone mar experience with AZT. Little more than of ddA triphosphate, a metabolite of row in culture. We are now carrying two years elapsed from the time we both ddA and its alter ego ddI, may be out trials to determine the toxicity and first observed the drug's anti-HIV ef as high as 24 hours. It may therefore effective dose of ddA and ddI in pa fect in our laboratory until the time be possible to give ddA to patients tients. The preliminary results are AZT was approved as a prescription just once or twice a day. encouraging. drug. We attribute this rapid develop The question posed at the beginning ment to the careful, scientifically con n spite of its beneficial effects, AZT of this article has been answered in trolled process by which the clinical is not a finalanswer. The drug can the affirmative. An antiretroviral drug, trials were conducted. We cannot em Ibe toxic, particularly to bone mar AZT, has been found that can reduce phasize enough the importance of the row, so that patients on AZT often the severity of illness and prolong the controlled-trial method to the success develop anemia (a decrease in red survival of AIDS patients. AZT repre of future therapies-and to much of blood cells) and in some instances low sents only a beginning, however, and it what must be learned if AIDS is to be numbers of white blood cells and is certainly not a cure. Indeed, over conquered. platelets as well. Indeed, this often time the true value of AZT may prove limits the amount of AZT that can be to be its validation of the key assump administered, particularly in patients tions that underlie antiviral strategies FURTHER READING AIDS: MODERN CONCEPTS AND THERA with established AIDS, and bone-mar for intervening in this illness. PEUTIC CHALLENGES. Edited by Samuel row suppression is a major reason for In the future, as we learn more about Broder. Marcel Dekker, Inc., 1987. failure of the drug. The mechanism of how to attack HN at differentpoints DEVELOPMENT OF ANTIRETROVIRAL THER toxicity remains unclear at present, in its life cycle, it may be possible to APY FOR THE ACQUIRED IMMUNODEFI but there is some evidence that it may model AIDS therapies on successful CIENCY SYNDROME AND RELATED DISOR not necessarily occur with other dide therapies for cancers such as certain DERS: A PROGRESS REpORT.Robert Yar oxynucleosides. childhood leukemias. For example, as choan and Samuel Broder in The New England Journal of Medicine, Vol. 316, Ultimately, the only way to tell researchers develop agents that have No. 9, pages 557-564; February 26, whether other dideoxynucleosides different modes of activity against 1987. that display anti-HN activity in tissue HN, it may be possible to design mul STRATEGIES FOR ANTIVIRAL THERAPY IN culture will be more beneficial than tiple-drug therapies that will achieve AIDS.Hiroaki Mitsuya and Samuel Bro AZT is to test them in patients. To this better results than any one drug alone. der in Na ture, Vol. 325, No. 6107, pages end; our group at the NCI and a multi In fact, investigators have already 773-778; February 26, 1987. center group headed by Thomas C. found that each of several drugs, in THE EFFICACY OF AzIDOTHYMIDINE (AlT) IN THE TREATMENT OF PATIENTS WITH Merigan, Jr., of the Stanford University cluding acyclovir (an antiherpes drug), AIDS AND AIDS-RELATED COMPLEX: A School of Medicine recently conduct ampligen, alpha-interferon and dex DOUBLE-BLIND, PLACEBO-CONTROLLED ed clinical trials of 2' ,3' -dideoxycyti tran sulfate, appears to have more TRIAL. Margaret A Fischl et al. in The dine (ddC) in patients suffering from than an additive effect when it is test New England Journal of Medicine, Vol. severe HN infection. These studies ed in vitro with AZT. 317, No. 4, pages 185- 191; July 23, showed that ddC can markedly reduce As with the treatment of childhood 1987. the amount of HIV replication and can leukemia, it may be necessary to em BLOCKING OF HlV- l INFECTIVITY BY A SOL UBLE, SECRETED FORM OF THE ANTI also induce some improvements in ploy several phases of therapy. For CD4 GEN. Douglas H. Smith, Randal A Byrn, immune function. Unfortunately pa example, one might first have to ad Scot A Marsters, Timothy Gregory, Je tients who took continuous high dos minister relatively toxic drugs that rome E. Groopman and Daniel J. Capon es of ddC for more than from eight to would halt viral replication and per in Science, Vol. 238, No. 4834, pages 12 weeks developed a painful periph haps also destroy infected cells. One 1704- 1707; December 18, 1987. eral neuropathy (a disorder of pe- might then follow up with treatments

~~SCIENTIFIC AMERICAN October 1988 119~~

~~Several candidates are being tested and more are on the way, but success is far from assured. The life cycle of the virus and the logistics of AIDS vaccine testing make HIVa foe without precedent~~

~~by Thomas J. Matthews and Dani P. Bolognesi~~

he best way to combat any dis· slows investigations of vaccine strate duces the antigen in a harmless form Tease is to prevent it. Vaccination gies to combat these ploys, and the called an immunogen, so that the body is the simplest, safest and most difficulties expected with clinical tri becomes primed to fightoff the infec effective form of prevention, and vac als, which face scientific uncertainty, tious agent without risk of contracting cines have achieved legendary suc ethical concerns and possibly a short the disease itself [see illustration on cess against viruses. Because of vac age of volunteers. page 123]. cines the campaigns against smallpox Several vaccines are currently being If the immune system is to defeat a and polio are resounding triumphs; tested in humans. It is much too early pathogen, it must be able to attack the the decline of yellow fever, measles, to pronounce on their performance, invader free in the blood as well as in mumps and rubella is also due largely but most investigators are not opti association with cells. The immune to vaccination. Against this backdrop mistic. Yet no one is entertaining the response has two interrelated arms of successes the human immunodefi idea of failure. A vaccine offers the that combat infection on both fronts: ciency virus (HIV) looms large. A vac best hope of stemming the AIDS crisis. a "humoral" response and a "cell-me cine against AIDS is perhaps the most A great deal has been learned about diated" response. In the humoral re formidable and urgent challenge fac the virus since the firstAIDS vaccines sponse blood cells called B lympho ing virologists today. were designed, and we hope that to cytes generate exquisitely speCific an Vaccine development has been a top morrow's vaccine candidates will have tibody molecules that circulate in the priority of AIDS research since HlV was a better chance of defeating HlV if the blood and bind to antigens, thus nul conclusively shown to be the cause of current ones fail. Otherwise this dec lifying the pathogen. The cell-mediat the disease in 1984. Yet in spite of the ade in the shadow of AIDS will have ed response involves "killer" T8 cells millions of dollars and hundreds of been just a foretaste of the virus's (also known as cytotoxic lymphocytes) scientists devoted to vaccine research, ultimate impact on public health, be that attack and destroy infected cells. Surgeon General C. Everett Koop has havior and economy across the globe. Central to both responses is anoth warned the public not to expect a � er group of T cells, the T4 or "help vaccine before the end of the century. iCh tradition of vaccine research er" cells. Helper cells send out chemi Why not? guides the effortto develop cal signals called lymphokines, which Researchers are daunted by three an AIDS vaccine. Hundreds of help to activate T-and B-cell popula particulars: the devious nature of the years ago controlled inoculations of tions and cause them to proliferate. virus itself, which can "hide" in cells, the pus from smallpox victims was The lymphokines from T4 cells also change the composition of its coat used to immunize healthy individuals prompt the generation of antigen-spe and install its own genes within the in the Far East and Middle East. Then in cific "memory" cells for the T- and genes of its host; the lack of a good 1796 Edward Jenner found that cow B-cell populations; it is these cells that animal model for the disease, which pox virus could serve as a smallpox are responsible for hastening and am vaccine. His discovery led to the real plifying the immune response in sub ization that the pathogenic organism THOMAS J. MATIHEWS and DANI P. sequent encounters with the antigen. BOLOGNESI work together in the surgi itself need not be present to rally B cells and T cells interact with an cal virology laboratory at the Duke Uni the immune system's defenses; only antigen differently. B cells have recep versity Medical Center, where they have certain characteristic parts of an or tors akin to antibodies that can rec been researching AIDSvaccines for the ganism trigger an immune response. ognize free antigen particles, but in past four years. Matthews got his Ph.D. These parts (oft�n proteins or protein order for a T cell to "see" an antigen from the University of Missouri in 1967 fragments) are known as antigens. the antigen mtist be presented on the and held a postdoctoral appointment at Vaccines exploit the body's ability to surface of another cell. When a patho the University of Wisconsin at Madison before going to Duke in 1977. Matthews "remember" an antigen. The first time gen first invades the body, blood cells is a member of the National Cancer the immune system encounters a giv known as macrophages endocytose, or Institute's AIDSVaccine Task Force. Bo en antigen in the course of infection it "swallow," the invader, process it and lognesi got his Ph.D. from Duke in 1967 is caught unawares, but as a result of display its antigenic portions on their and has been on the faculty there since the encounter cells are generated that surface. T-cell receptors can bind to 1971. He is a consultant for the National retain an immunological memory of the processed antigens, and T cells Institutes of Health AIDSExecutive Com the antigen for the lifetime of an indi thereby learn to identify infected cells, mittee and a member of the scientific advisory committee of the American vidual. Consequently subsequent re which bear the same processed anti Foundation for AIDSResearch. sponses to the same invader are swift gens on their surface. Owing to these er and more potent. A vaccine intro- different modes of interaction, B cells

~~120 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC ENVELOPE PROTEIN is found on the surface of HIV and the cells would induce a potent immune response. The immune system it infects. The protein is thought to be a trimer of three of people infected withHlV attacks the envelope protein, but virtually identical molecules, shown here in red, orange and the assault does not prevent disease. It may be that the sugar purple. Much of the protein backbone is buried in a cloud cloud protects vulnerable areas of the backbone, such as the of sugar molecules (gray-green). There is reason to believe pit (left)where the virus binds to its receptor, while less critical a vaccine that mimics certain antigenic parts of the protein parts such as the loop (right) are exposed, perhaps as decoys.

SCIENTIFIC AMERICAN October 1988 12 1 © 1988 SCIENTIFIC AMERICAN, INC usually recognize external antigens using antigenic subunits rather than ble, although a vaccine might still be of a pathogen, whereas T cells can re the pathogen itself would be prefera able to stimulate the immune system spond to both external antigens and ble because they eliminate the threat enough to keep the virus from caus internal components that become ex of inadvertent infection. The technolo ing disease. For example, in studies of posed during cellular processing. If a gyfor producing such vaccines has mouse leukemia, a retroviral disease, vaccine is to elicit humoral and cell evolved only recently, and a subunit Werner Schafer and his colleagues at mediated immunity, it must contain vaccine against hepatitis B, made by the Max Planck Institute for Virus Re immunogens that both arms of the Merck Sharp & Dohme, has already search in Tl1bingen found that an ex immune system would see in the been approved in the U.S. perimental vaccine could protect the course of an ordinary infection. Subunit vaccines have several draw animals from disease, but the virus backs of their own. Subunits by them reappeared late in life, when the ani accine development is a greater selves can be invisible to the immune mals' immune systems began to falter. Vchallenge with HN because the system and must often be combined The virus did not cause leukemia virus infects some of the same with some kind of vehicle to improve when it reemerged, and so it seems cells the vaccine needs to activate. their immunogenicity. For example, that a total blockade of infection may While there is evidence that HN can the subunit may be complexed with a not be necessary for long-term protec invade the central nervous system, the so-called adjuvant, which attracts the tion against a retroviral disease. In primary targets of infection are mac immune system's attention by causing deed, most successful vaccines pro rophages and T4 cells. Indeed, the inflammation or by acting as an anti tect against disease rather than in macrophages, which can survive HN gen in its own right. In addition the fection. There is one way, however, infection, may serve as shuttles that subunit used in a vaccine must be in which a retroviral infection differs carry HN to T4 cells during the routine carefully chosen, because not all com from most other viral infections for interactions of the two cell types. The ponents of a pathogen represent ben which vaccines exist: retroviral genes T4 cells usually do not survive HIV eficial immunological targets. Some contain regulatory elements that can infection. Because these cells play a may even induce inappropriate re disrupt a cell's normal growth pat critical role in the immune defense, sponses that preempt protective ones. terns. In other words, the genes can on which any vaccine would rely, an In the case of AIDS there is no prece- cause cancer. AIDS vaccine would have to prevent 'dent lending support to any one of Thus the mere presence of retroviral the virus from becoming entrenched these approaches. Hence workers are genes in the body is a real cause for in T-cell and macrophage populations pursuing a number of strategies in concern. This raises the daunting pos in the first place. designing their AIDS vaccines. sibility that an AIDS vaccine may have The vaccine would also have to halt to achieve a complete blockade of in the virus before it invades the central ndeed, lack of a precedent plagues fection. It is not practical to expect nervous system, where pathogens be Iquite a few aspects of AIDS vaccine such a blockade from any vaccine, and come invulnerable to immune attack. research. HIV belongs to a class so vaccine developers hope that some Furthermore, a vaccine must ensure of viruses, called retroviruses, with degree of infection can be tolerated. In that the immune system will recog which the research community has any case, the option of an attenuated nize any and all of the innumerable had limited experience. Human retro whole-virus vaccine has been all but HIV variants, and that protection will viruses were discovered less than a eliminated, since disabled retroviral extend to all vaccine recipients regard decade ago and animal retroviruses genetic material could induce malig less of age, gender and extent of expo have never been deemed significant nancy even if it could not orchestrate sure. And the vaccine must carry no enough to provide a practical incen the production of virus particles. risk of itself causing AIDS. Unless an tive for vaccine development. The only immunogen has been shown to meet real field trials of a retroviral vaccine nfortunately the problems sur all these criteria, it cannot be called an were done in cats, with a vaccine Urounding vaccination against AIDS vaccine per se; it is more correct against feline leukemia. In these trials HIV are not limited to those to refer to it as a vaccine candidate. a subunit vaccine provided partial associated with its being a retrovirus. In devising vaccine candidates, it is protection; experimental vaccines us HN has several features of its own important to recognize that the way ing attenuated virus or better-defined that make it a singular opponent. an immunogen is presented can have subunits with improved adjuvants Perhaps the most infamous charac some bearing on its efficacy. Today have shown greater promise. But now teristic of the virus is its propensity to vaccine researchers have a variety of that the search for an AIDS vaccine has mutate. This tendency is particularly options for presentation. Traditional taken center stage, it has become pain pronounced in the gene that codes for vaccines are made of the virus itself, fully clear how difficultthe develop its envelope protein, gp 120. Vaccine either killed or attenuated to render it ment of vaccines against retroviruses developers have focused a great deal harmless. These have been quite suc can be. of attention on gp 120 because it is cessful, presumably because whole vi Retroviruses, like a few other types displayed on the surface of both the rus is a potent immunogen. Vaccines of virus, can insert their own genes virus and infected cells, which makes against measles, mumps and rubel into the genes of the cells they infect, it a likely target for an immune re la all contain live, attenuated virus, thereby establishing a permanent in sponse. The virus probably confounds whereas rabies vaccines are made fection. Even if a cell is not actively the immune system by continually from killed virus. There are both atten producing virus particles, it may still varying the sequence of amino acids uated- and killed-virus polio vaccines. harbor "dormant" retroviral genes. that make up this outermost protein. Exposing people to whole virus is Such a cell might remain invisible to If a vaccine is to exploit the immuno not entirely without risk: in the U.S., the immune system because no viral genicity of the gp 120 molecule, more for example, a handful of children antigens would be displayed on its will have to be learned about the diver every year get polio from attenuated surface. Hence eradicating a retroviral sity of gp 120 variants. polio vaccines. In most cases vaccines infection could prove to be impossi- Another troublesome aspect of HIV

~~122 SCIENTIFIC AMERICANOctober 1988~~

~~MACROPHAGE~~

~~LYMPHOKINES •~~

~~• . . • • • • • • • • •~~

~~• • • • • • • • HELPER T 4 CELLS •~~

~~• • • e• • • . • • • ( . .. • :>~~

~~KILLER T8 CELLS HELPER T4 CELLS 8 CELLS~~

~~ANTIBODIES~~

~~INFECTED CELLS MEMORY CELLS~~

IMMUNE ATIACKon a pathogen involves both humoral (B cell) destroying infected cells. Meanwhile external antigens on the and the cell-mediated (T cell) responses. Scavenging cells pathogen interact with receptors on B cells. If the B cells re called macrophages engulf the invader and display its inter ceive lymphokine signals, they proliferate and secrete antibod nal (square) and external (triangular) antigenic components ies that bind to the antigens and neutralize them. Antigen-. to receptors on T cells. The "helper" T4 cells multiply and specific "memory" cells are also generated; these enable the produce lymphokines (red), chemical signals that regulate B immune system to combat the same invader more effective " cells and T cells. Interaction with macrophages and T4 cells ly in future encounters. Vaccines work by prompting the gen causes "killer" T8 cells to mature and roam the bloodstream, eration of memory cells without posing any threat of disease.

SCIENTIFIC AMERICAN October 1988 123 © 1988 SCIENTIFIC AMERICAN, INC infection has been brought to light by a phenomenon, which is known as wise, HIV is probably not invulnerable. recent evidence that virus particles an autoimmune reaction, could occur Components of the immune system can be trapped in vesicles-enclosed with any vaccine, but in existing vac have proved able to neutralize the pockets in the cell cytoplasm-with cines the combining site of the virus virus in the test tube, and people who out betraying their presence through need not be the primary antigenic con are infected with HIVinitially launch viral proteins on the cell surface. With stituent. Furthermore, there is reason strong humoral and cellular assaults. out surface antigens the cell-mediated to believe that vaccines representing They make antibodies against compo arm of the immune system cannot other sites on the HIV envelope pro nents of the viralenvelope, and their detect the infection and will not attack tein might also trigger an autoimmune killer T cells recognize internal com the cell. Ashley T. Haase of the Uni response, because some parts of the ponents of the virus as well as parts versity of Minnesota Medical School envelope are known to mimic normal of the envelope. These defenses may applied the term "Trojan horse" to cell-surface markers. hold the virus in check for several describe such evasive behavior in ani The fact that HIV attacks the cells. years [see "HIV Infection: The Clinical mal retroviruses; if a virus adopts this that are responsible for defeating in Picture," by Robert R Redfield and strategy, the immune system never fection adds its own twist to vaccine Donald S. Burke, page 90]. Yet these gets a glimpse of it. Thus the virus development. In particular, some in people eventually develop AIDS any might be passed between cells in an vestigators are concerned that a vac way. The immune system fights back; individual or even transmitted from cine could actually enhance the infec it j ust does not fight hard enough. one person to another while remain tivity of the virus. Certain cells of the The trick is to discover which part of ing hidden. immune system have receptors that HIV elicits the most powerful natural In addition the virus has a remark bind to antibodies opposite the anti immune response and amplify that able affinity for the cell-surface pro gen-binding region. Macrophages are response enough to overcome the vi tein, known as CD4, to which it binds among these cells, and macrophages rus. It might even be possible to teach [see "HIV Infection: The Cellular Pic are a target of HIV infection. Antibod the immune system to recognize anti ture," by Jonathan N. Weber and Robin ies attached to free virus could there genic sites that are ordinarily hidden A Weiss,page 100].Antibodiesinduced fore be attracted to macrophages, in by the virus. At present there is no by a vaccine will have to overcome this creasing the chances that a macro reason to narrow the scope of investi powerful affinity if they are to impede phage will become infected. Hence gation to any particular piece of the binding. Antibodies to the part of the raising antibodies to HIV by means of virus, but most studies focus on the virus that binds to the CD4 receptor a vaccine could conceivably facilitate gp 120 envelope protein. could mechanically obstruct the bind rather than deter the spread of the The gp stands for "glycoprotein"; ing process, but that approach has its virus. It is still not clear that this effect in its natural state the protein is own hazards. In particular, antibodies actually potentiates infection during wrapped on itself like string and cov to the virus's combining site actually natural exposure to the virus. ered with a cloud of sugar (glyco�) resemble the CD4 receptor, and if, as molecules. It is anchored to the sur often happens, a second round of anti oes such a recalcitrant virus face of the virus or an infected cell bodies is produced against the first, Dhave an Achilles' heel? Even by a protein called gp4 1, which pen they would in turn mimic the binding though examples of success etrates the surface membrane. The site on the virus. Consequently the ful vaccines against retroviruses are glycoproteins are derived from a pre second round of antibodies could at lacking, vaccine developers have chal cursor called gp 160. tack CD4, incapacitating or destroying lenged other formidable viruses and Most of gp 120 is obscured from the very cells that are already under won. The virus that causes hepatitis immunological sight by the cloud of siege from the virus. B, for instance, also has sophisticat sugar ; the sugar molecules are poorly Recent evidence that people infect ed strategies for escaping immune de antigenic at best, because they are ed with HIV make antibodies to CD4 struction and can establish persistent made by the host cell. The topography lends credibility to this scenario. Such latent and chronic infections. Like- of the molecule, as far as it is known, is

STEPS IN HIV INFECTION include binding, anchorage and fu becomes anchored in the cell membrane (2), holding the mem sion, which are mediated by envelope components of the virus. branes in proximity so that they can fuse (3). Infected cells Initially the virus associates with a receptor called CD4 on an fuse with uninfected cells in much the same way. The loop uninfected cell. The pit of gp120 binds to CD4 (1); then gp41 probably has a role in the process, but it has not been identified.

~~124 SCIENTIFIC AMERlCAN October 1988~~

~~NOT VARIABLE AMONG VIRUS STRAINS~~

~~FUNCTION KNOWN (-.l----, o}-- ANTIBODIES BLOCK FUSION AND INFECTION~~

~~VARIABLE AMONC VIRUS STRAINS~~

~~NO KNOWN FUNCTION~~

ANTIBODIES BLOCK STEPS IN INFECTION if they bind to the pit block fusion (middle box). The two sites have distinctly differ or the loop of the gp120 protein. Antibodies against the pit ent characteristics that affect their suitability as immunogens, block binding (box at left), and antibodies against the loop or substances that provoke an immune response (box at right). distinguished by two features: a pit or block binding do not block infection from the clinical trials to guide cur cleft where the protein binds to CD4, as well as one would expect. rent research or hint at the superi and a loop that protrudes from the On the other hand, antibodies that ority of one approach over the other. sugar cloud. What is known about interfere with postbinding steps are Most workers, however, are employ these two features has largely been very good at blocking infection. Scott ing the subunit approach, and most inferred from observations of their D. Putney, James R. Rusche and Kashi are using whole envelope proteins as immunogenic properties. For exam Javaherian at the Repligen Corpora the subunit. ple, it is difficult to raise antibodies tion, Flossie Wong-Staal and Robert C. At least two modes of presentation against the CD4 binding site in the Gallo at the National Cancer Institute are being considered to ensure that laboratory, and so it has been as and our group at the Duke University the immune system does not overlook sumed that the site is recessed within Medical Center with our colleagues the envelope antigen. The subunit can the molecule and probably shrouded Thomas J. Palker and Barton F. Haynes be complexed with an adjuvant, or the with sugar. The loop, on the other have demonstrated that such antibod gene for the subunit can be inserted hand, is highly immunogenic and is ies bind to the loop portion of the into an attenuated virus that will ex therefore thought to be exposed. envelope protein. Indeed, the loop press the HIV protein in its own en Antibodies against both regions seems to be easily and rapidly recog velope. The firstAIDS vaccine candi have been successful in blocking early nized by the immune system and is date to enter clinical trials in the U.S. steps in viral infection. A common se therefore called the immunodominant is a gp160 subunit combined with quence of events characterizes the ini site on gp120. People infected with the simple household chemical alum tial encounter. First gp120 binds to the HIV produce antibodies against the as an adjuvant. The vaccine, which CD4 receptor on an uninfected cell; loop in the earlier stages of the infec is made by MicroGeneSys, Inc., in then gp41 becomes anchored in the ad tion; these antibodies might be re West Haven, Conn., entered trials in joining membrane; next the two mem sponsible for controlling the spread October, 1987, at the National Insti branes begin to fuse, and the virus of the virus during the disease's la tute of Allergy and Infectious Diseases spills its contents into the cell. An im tent period. (NWD). Results gathered so far are mune reaction that interferes with any Interestingly, the loop is also one of ambiguous, but investigators think in of these steps-binding, anchorage the most variable regions of the pro creasing dose levels may improve the or fusion-could prevent infection. tein, and no one has been able to candidate vaccine's performance. In In some ways the CD4 binding site ascertain its function. Might the loop Switzerland a gp120-adjuvant vaccine of gp120 would seem to be the ideal be a decoy? Its prominence could di made by the Chiron Corporation of immunogen. Although, as mentioned vert the immune system's attention Emeryville, Calif., and the Swiss phar above, it could provoke an autoim from less accessible and more essen maceutical company Ciba-Geigy AG mune response, it is integral to the tial sites, while its hypervariability has been approved for human trials. virus's function and is highly con would enable it to dodge the immune The trials will include about two doz served; that is, it does not vary much response it draws (a single change in en volunteers. from strain to strain. The process by the loop's amino acid sequence cre For subunit-adjuvant vaccines the which the immune system gets at the ates a different antibody specifiCity). type of adjuvant employed is often CD4 site is probably complex, requir It might be possible to overcome the critical to the vaccine's performance. ing prolonged exposure to the virus, variability with a vaccine that would Immune recognition might well be since people who are infected with anticipate all mutated forms-the improved by complexing the subunit HIV do not start making antibodies equivalent of a "universal loop." with more sophisticated adjuvants, that interfere with CD4 binding until such as artificial membranes called about a year after they become infect ven as investigators puzzle out liposomes or so-called immune-stim ed. A vaccine making the CD4 site Estrategies for new vaccine candi ulating complexes. Work by Bror Mor conspicuous might expedite the im dates, the first crop of AIDS vac ein of the University of Uppsala has mune reaction. There is a problem, cines is being tested in human sub demonstrated the efficacy of this ap however, in that the antibodies that jects. So far too little has been learned proach withother immunogens, and

~~SCIENTIFIC AMERICAN October 1988 125~~

~~Salk Institute for Biological Studies Whole or disrupted Whole inactivated HIV University of California at Davis inactivated HIV with in infected people e KILLED VIRUS genetic material removed~~

Genentech Inc. HIV envelope, pieces of gp160, gp120 and MicroGeneSys, Inc. envelope proteins or other synthetic frag ment of p1 7 Immuno AG structural antigens made National Cancer Institute by genetically engineered Repligen Corporation/Merck Sharp & Dohme cells or synthesized Duke University Medical Center in the laboratory Ciba-Geigy AG/Chiron Corporation HIV SUBUNIT Smith Kline & French Laboratories WITH ADJUVANT Merieux Institute/ Cambridge Bioscience Corporation [fJ Viral Technologies, Inc. University of Uppsala Wistar Institute of Anatomy and Biology University of Paris Southwest Foundation for Biomed ical Research

University of Paris Gene for HIV envelope Vaccinia/HIV recombinant Bristol-Myers, Co. protein inserted in and cells infected with HIV SUBUNIT Merieux Institute!Transgene S. A. vaccinia virus or recombinant IN VIRUS VECTOR Wyeth Laboratories adenovirus, or cells National Institute of Allergy and infected with HIV/ Infectious Diseases vaccinia recombinant e National Cancer Institute Clinical Research Center/Southwest Antibody against CD4 Antibody against CD4 Foundation for Biomedical Research/ = ANTI-IDIOTYPE Becton Dickinson Monoclonal Center, Inc'; Imperial Cancer Research Fund/ University College London

VACCINE RESEARCH encompasses several different strategies, like CD4 and compete with it for binding to HlV . Killed HlV in various phases of testing. Subunit vaccines are by far the vaccines, which immunize with whole or disrupted virus, have most popular; they are made by combining a piece of HlV with been deemed too risky for inoculating people who have not an adjuvant or by inserting a gene for an HlV protein among already been exposed to HlV . This partial list is by no means the genes of a harmless virus "vector." Anti-idiotype vaccines exhaustive; the field is growing rapidly, and many of the consist of antibodies carrying an internal image of the CD4 groups are exploring more than one approach and collaborat receptor, meant to evoke another set of antibodies that look ing with one another as well as with groups that are not listed. its extension to experimental AIDS long duration. It is too complicated to duce antibodies against p17, and their vaccines has already shown promise. be feasible as a vaccine strategy, but infected cells often display the protein The most impressive results to date, it demonstrates that immunity to HIV on their surface. however, have been obtained from can be achieved in human beings. Za � trials of a .subunit vaccine candidate gury is looking for a simpler way to omewhat more esoteric ap using an attenuated vaccinia (cow elicit the same response. Meanwhile proach is under investigation in pox) virus vector. These trials were results are just beginning to come in England by Angus G. Dalgleish conducted in Zaire, where the virus from U.S. trials of another gp160-vac of the Clinical Research Centre in Har is endemic. They were the first test cinia vaccine made by Oncogen, a Seat row and Ronald C. Kennedy of the of an AIDS vaccine in humans; it took tle, Wash., subsidiary of the Bristol Southwest Foundation for Biomedical many by surprise when the head of Myers Co. Research in San Antonio, Tex. The two the research group, Daniel Zagury Allan L. Goldstein and his colleagues are part of an international consorti of the University of Paris, announced at the George Washington University um including the Imperial Cancer Re that he had inoculated himself along School of Medicine and Health Scien search Fund, University College Lon with the first volunteers in Novem ces were among the firstinvestigators don and the Becton Dickinson Mon ber, 1986. to design a subunit vaccine based on oclonal Center, Inc. Their approach Zagury and his colleagues utilize a an internal component of the virus assumes that antibodies that mimic vaccinia technology pioneered by Ber rather than an envelope antigen. Their the receptor for the pathogen-in this nard Moss of the NIAID to create the vaccine candidate, called HGP-30, is case CD4-will compete very well with vector for the initial inoculation. They made by Viral Technologies, Inc., in the receptor in binding the pathogen. follow the inoculation with boost Washington, D.C. It is undergoing clini Such antibodies can be generated with ers consisting of purified gp 160 and cal trials in London and awaiting ap an immunogen that represents the a special preparation of T cells: cells proval for trials in the U.S. HGP-30 "internal image" of the receptor the that were taken previously from the mimics a part of the protein p17, way a key represents the internal im same individual, infected with the HIV which lines the inside of HIV's enve age of a lock. Hence inoculations of vaccinia vector and then killed before lope. The protein is probably exposed antibodies against CD4 should raise a reinjection. to immune attack during processing population of antibodies, known as This protocol produces potent hu by macrophages and infected cells: anti-idiotype antibodies, that resem moral and cellular anti-HIV activity of people who are infected with HIV pro- ble CD4. These could tie up free virus

~~126 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC in the blood. Indeed, CD4 made by There is also evidence that rabbits in social and logistical considerations. genetic engineering is known to inhib fected with HIV display some signs Should a limit be placed on the num it HIV infection in vitro, and the sub of disease. ber of vaccines that can win approval stance itself has been slated for clini Other retroviruses may serve as HIV for human testing? cal trials. In London two individuals analogues. Simian immunodeficiency Finally, the liability issues surround have already received anti-idiotype in virus (SIV), for example, causes a dis ing the testing of an AIDS vaccine re oculations; preliminary results have ease much like AIDS in monkeys. Un main unresolved. Leaders of corporate not been reported. fortunately the first test of an SIV research, such as Maurice R. Hilleman An experimental vaccine made from vaccine, at the New England Regional of the Merck Institute for Therapeutic killed HIV has been prepared by jonas Primate Center in Southboro, Mass., Research, have warned that the uncer Salk and his colleagues at the Salk failed. Retroviruses that cause immu tainty surrounding the risks of vac Institute for Biological Studies. Be nodeficiency syndromes in cows and cine-related injuries and compensa cause of the risks of inoculation with cats are also being investigated. tion for them could ultimately hinder whole HIV, the vaccine would be ap In the meantime there is no way to development. Some framework must propriate only for boosting the im establish criteria for the efficacy of be drawn up that will allow companies mune reaction of people who are al AIDS vaccines before injecting them in to proceed with vaccine development ready infected with the virus. Such humans. When other vaccines were and testing without courting litigious so-called postexposure vaccines have about to enter clinical trials, investiga disaster. been somewhat effectivein rabies-vi tors had a good idea of what kind of In surveying all the difficulties bear rus infections, but their efficacy has immune response was necessary to ing on the development of an AIDS not been demonstrated for retroviral fend offthe disease. But no one knows vaccine, it would be easy enough to infections. Salk has administered his what constitutes protective immunity lose heart. But at one time the situa vaccine to roughly a dozen individuals against AIDS. Is it a certain titer of tion must have appeared just as hope with early symptoms of AIDS. SO far he antibodies, a particular level of killer less to jenner. A vaccine against HIV is reports no pronounced benefits. T-cell activity, or some synergistic in the highest aspiration of AIDS research � teraction between the two? and would represent a triumph for thOUgh encouraging results are And when can a given immunizati9n virology as well. in short supply, it is remarkable be judged a success? Ethical obliga Small wonder that scientists from in itself that so many candi tions require that clinicians counsel all over the world have become en date HIV vaccines have reached the their volunteers to avoid behavior that gaged in this effort. Many of them human testing phase just four years could lead to HIV infection, and so a participate in Gallo's international after the cause of AIDS was discovered. low incidence of AIDS in these people HIVAC (HIV vaccine) group, which This progress attests to the arduous could reflect "safe sex" practices rath brings together workers from lO dif efforts of vaccine researchers here er than the action of an experimental ferent countries. Major vaccine re and in other countries, faced with one vaccine. How can anyone be sure a search programs have also been es of the most intractable viral diseases vaccine has warded offdisease short tablished in Great Britain, France, Swe in medical history. Yet AIDS vaccine of injecting the vaccine recipient with den, Germany and japan. In the U.S. researchers are still working in the HIV and observing the consequences? the Public Health Service has drawn dark compared with their predeces Given that the disease's latency period up a plan for vaccine development sors in at least one respect: they have can last for five years, how long should and evaluation that includes Nation no good animal model for the disease. doctors wait before concluding that al Cooperative Vaccine Development Other human viral diseases have protection has been achieved? Groups, which will coordinate collabo ' analogues in laboratory animals, but Clinicians also expect to be con ration between government, industry most animals do not get AIDS from fronted with a shortage of trial vol and academic efforts. Many other in HIV. No one knows why. Considerable unteers, first because healthy people vestigators are independently pooling effort is being spent to find out, be may be understandably reluctant to their expertise in a multitude of virus cause the answer would probably re try a vaccine that has no demon types, in the mechanisms of gene reg veal how human beings could defend strated efficacy, and second because ulation and in the workingsof the themselves against the virus. Chim there simply may not be enough peo immune system. We believe HIV can panzees can be infected with the vi ple in high-risk categories to provide not outwit such.a combination. rus, but chimps infected years ago still statistically significantresults. (Peo show no signs of illness. ple in low-risk groups have such a Several advances announced earli slim chance of encountering the vi FURTHER READING er this year offer hope of an alterna rus that it would be virtually impos PlAGUES ANDPEOPLES. William H. Mc tive. Macaque monkeys infected with sible to demonstrate efficacy in a rea Neill. Doubleday & Co., 1976. WHITHER IMMUNIZATION AGAINST HIV-2-a variant of HIV found pre sonable period of time.) VIRAL INFECTIONS? Maurice R Hilleman in dominantly in West Africa-contract The recruitment problem will get An nals of Internal Medicine, Vol. 101, No. ed AIDS and thus became the first worse, not better, as more vaccines are 6, pages 852-858; December, 1984. subhuman animal ever to get a disease developed. Each vaccine candidate re PROSPECTS FOR A VACCINE TO PROTECT from a human retrovirus. The finding quires from 50 to 100 high-risk volun AGAINST AIDS. Maurice R Hilleman in has excited the research community teers for the first phase of trials, and Viral Hepatitis and AIDS, edited by Vic because it demonstrates that animals the final phase of testing could involve tor M. Villarejos. Editorial Trejos Her can get AIDS, and macaques are much thousands of people. Each volunteer manos (San Jose, Costa Rica), 1987. NATURAL IMMUNIlYTO ANDITS POS easier to work with than chimps. It can take part in only one trial. Mas HIV SIBLE RELATIONSHIP TO VACCINE STRAT is not clear, however, to what extent sive testing is theoretically feasible in EGIES. Dani P. Bolognesi in Microbio the lessons learned from HIV-2 can areas of the Third World where the logical SCiences, Vol. 5, No. 8, pages be applied to its commoner and pos virus is endemic, but such a program 236-241; August, 1988. sibly more pathogenic relative, HIV-l. would be complicated by political,

~~SCIENTIFIC AMERICAN October 1988 127~~

~~AIDS exposes the hidden weaknesses in human society; how the epidemic is dealt with will have a profound effect on society's future. A crucial issue is protection from discrimination~~

~~by Harvey V. Fineberg~~

he AIDS epidemic exposes hid lency inevitably feels like a trespass; trialized and less developed countries. den vulnerabilities in the human worse, like the violation of a taboo. " HIV is insidious. It corrupts vital Tcondition that are both biologi Although she was reflecting on can body fluids, turning blood and semen cal and social. AIDS prompts coura cer, Sontag's words are even more ap from sources of life into instruments geous and generous acts, and it pro propriate for AIUS, a condition that is of death. The virus insinuates itself vokes mean-spirited and irrational literally as well as morally contagious. into the genetic material of selected responses. AIDS throws new light on The contagion is compounded by the cells, where it may remain quiescent traditional questions of value, com stigma attached to the behaviors most for prolonged periods of time. When pels a fresh look at the performance prominently associated with HIV in it is active, the virus gradually un of the institutions we depend on and fection in the U.S.: homosexual in dermines the body's immune system, brings society to a crossroads for col tercourse and intravenous drug use. eventually rendering it vulnerable to lective action that may, with the pas Kriowledge of HIV and its mode of opportunistic infections. During the sage of years, mark a key measure of spread, convincing as it is to scientists latency period, which may average our time. and epidemiologists, is not powerful eight years or longer, the patient feels In the seven years since AIDS was enough to fully dissolve the public perfectly well yet is capable of trans recognized, the epidemic has touched sense of mystery and old-fashioned mitting the virus to others. HIV infec on almost all aspects of society. Its dread. The protective garb needlessly tion remains at the present time incur reach extends to every social institu donned by workers transporting a per able, a pointed reminder of humani tion, from families, schools and com son with AIDS is reminiscent of the ty's thrall to the tyranny of nature. munities to businesses, courts of law, costume worn by physicians treating the military and Federal, state and plague victims in 18th-century France. ecause of its association with local governments. It has also had a People known to be infected with HIV sex and its long latency period, profound impact on the way science, have lost jobs, homes and friends. BAIDS has altered our thinking medicine and public health are prac Children with AIDS have been denied and prompted much discussion about ticed in the world. access to public schools and in 1987 a human relations, love and sexuality. Through its association with sex, . major air carrier temporarily refused The AIDS epidemic has heightened blood, drugs and death, AIDS evokes to transport patients with AIDS.Peo awareness of homosexuality in our basic human fears and inhibitions. In ple with AIDS have even been denied society, promoting understanding and her book Ill ness as Metaphor Susan transportation to the grave, as some tolerance in some and reinforcing Sontag writes: "Although the way in funeral directors have refused to han aversion in others. The ease and readi which disease mystifies is set against dle their corpses. ness with which many now speak in a backdrop of new expectations, the AIDS is a modern affliction. The AIDS public about homosexuality, sexual disease itself ...arouses thoroughly epidemic was fomented by changes in practices, the use of condoms and old-fashioned kinds of dread. Any dis social mores and lifestyle that are similar matters could hardly have ease that is treated as a mystery and unique to the latter part of the 20th been foreseen 10 years ago_ The will acutely enough feared will be felt mor century: urbanization in Africa, gay ingness of so many to see formerly ally, if not literally, contagious ....Con consciousness and liberation in the taboo subjects presented in the media tact with someone afflicted with a dis U.S., development of technologies for testifies to the extent to which AIDS ease regarded as a mysterious malevo- the preservation and shipment of has affected the standards of public blood-clotting factors for hemophil discourse. The National AIDSAware iacs, and modern air travel. Unlike ness Test presented on U.S. television HARVEY V. FINEBERG is dean of the some other infectious diseases, the in September, 1987, was introduced Harvard School of Public Health. He is interested in medical and governmental AIDS virus is carried and transmitted with the warning that some viewers decision making and has helped to set by the human host; there is no appar might be offended; viewers were as Government policy with respect to the ent insect or other animal vector and sured that nearly all those surveyed AIDSepidemic. He was a member of the the virus has no special climatic re during the program's preparation be National Academy of Sciences/Institute quirements. Because AIDS spreads di lieved the subject should be aired. of Medicine committee that published rectly from one person to another, Soon such reassurances about the the 1986 report fine Confronting AIDS. the disease at least potentially-a need to discuss AIDS candidly will berg is a three-time Harvard University is seem superfluous, because it will be alumnus, having received his BA, M.D. universal problem. It is the one con and Ph.D. degrees there. temporary disease that is keenly felt obvious that we can no longer afford an as urgent problem in both indus- to live according to old inhibitions in

~~128 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC discussing sexual practices and other Middle East and Asia, very few cases be lopsided for some time, but the rest risk factors that relate to this disease. have been reported. Officials in these of the country is tending to catch up The HIV epidemic is marked by countries tend to ascribe most of their with the epicenters of the epidemic in sharp variation in geographic, racial cases to travel, or to contacts with New York City and San Francisco. In and gender composition. Globally travelers from endemic areas, much 1984 these cities had half of all the three disparate patterns in the distri as cases of heterosexual transmission AIDS cases in the U.S.; in 1987 they had bution of AIDS have been discerned. In in the U.S. are mainly attributed to only 25 percent of new cases. the U.S. and other industrialized coun contact with individuals who are bi In San Francisco 85 percent of all tries with large numbers of cases, the sexual or intravenous drug users. In reported cases of AIDS are among ho predominant modes of spread have neither setting should the current pat mosexual men who deny use of intra been through homosexual activities tern offer much reassurance about venous drugs; in contrast, 36 percent and intravenous drug use, and the the future. of cases in New York City are related ratio of male to female cases is ap to intravenous drug use. The majority proximately 10 to one. In central, east ithin the U.S. the geographic of infected women in the U.S., who ern and southern Africa and in parts distribution of AIDS is highly constituted more than 10 percent of of the Caribbean, heterosexual spread Wuneven, minorities are dispro the new cases of AIDS in the firsthalf predominates, with a male to female portionately represented and intrave of 1988, are exposed by intravenous ratio of about one telone. In these nous drug use plays an increasing role drug use, and an estimated 70 percent economically disadvantaged parts of in transmission. By mid -1988 the U.S. of HIV infection in newborns is related the world perinatal transmission is had counted 65,000 cases. More than to intravenous drugs. The epidemic high and blood-borne spread contin half the states have reported fewer has hit minority communities particu ues to be a significant problem be than 400 cases each, with a range of larly hard. Blacks and Hispanics con cause of inadequate or absent screen from fewer than 10 in each of the stitute about 20 percent of the U.S. ing procedures. In some parts of the Dakotas to more than 16,000 in New population yet make up 40 percent of world, such as eastern Europe, the York. The distribution is expected to AIDS cases.

NEW YORK MEMORIAL QUILT is a reminder of lives lost to AIDS. died of the disease. The quilt, shown here in Central Park, Each panel represents a resident of the New York area who will be incorporated in the national Names Project AIDSquilt.

~~SCIENTIFIC AMERICAN October 1988 129~~

© 1988 SCIENTIFIC AMERICAN, INC The principal means by which the condoms and women should tell their munodeficiency Virus Epidemic to call spread of HIV infection can be sexual partner to use a condom. Yet for 2,500 new treatment sites and an stemmed-education and altered be the reported numbers and frequency additional annual investment of $1 .5 havior patterns-are at once clear and of sexual contacts in the preceding billion in drug-control programs. At elusive. Behavior related to sex and month had not changed and more the community level, street workers in drugs is biologically based, socially than 60 percent of those surveyed a number of cities are attempting to conditioned and resistant to change. said they had failed to use a condom protect drug users from HIV by show In some of the homosexual communi more than just some of the time. If the ing them how to clean their needles ties most severely affected by AIDS, effectiveness of education is to be and syringes with dilute bleach solu particularly those in San Francisco, measured by behavioral change, suc tion. Following the lead of European sustained and intensive educational cess will not come easily. cities, Portland, Ore., recently under efforts have been rewarded by strik took a trial program of providing drug ing changes in behavior and arrested ealth officials are particularly users with sterile needles in exchange transmission of the HIV. concerned about the increase for dirty ones. Similar proposals have Yet the gap between knowledge and Hin HIV infection among intrave been made in Boston and New York, personal action remains wide. In a nous drug users. In 1987 they repre where they have met with consider national poll conducted in August, sented 16 percent of new AIDS cases; able controversy. Critics oppose any 1987, more than 90 percent of Ameri in the first half of 1988 that number appearance of state-sanctioned drug cans knew they could contract AIDS had grown to 21 percent. Serum sur use and doubt the efficacy of exchange from having sex or sharing needles veys reveal that 50 percent or more of programs; advocates hold the preser with an infected person. Yet when the intravenous drug users in New vation of life as a higher value and they were asked about the possibility York City have antibodies to HIV . Of argue in favor of trial programs. of contracting AIDS themselves, 90 the more than 1.2 million intravenous Another controversial proposal to percent of all respondents said they drug users in the U.S., fewer than stem the spread of AIDS, considered viewed their own risk as low or nonex 250,000 are estimated to be in treat by legislatures in more than 30 states, istent. Surveys taken after a 1987 New ment at any one time. In some cities is mandatory premarital screening for

York City advertising campaign for the waiting period for those who seek antibodies to HIV. Public-health offi AIDS prevention showed that 80 per treatment is longer than six months. cials and others have argued strenu cent of the respondents agreed that Such bleak statistics led the Presi ously against such measures, saying sexually active people should carry dent's Commission on the Human Im- that universal premarital screening

FEAR OF CONTAGION was a legitimate concern during the fleas (left). Such fear is unjustified in the case of AIDS, but it plague outbreak of 1720, when French physicians wore special remains widespread. Two ambulance workers in Hong Kong garments to avoid infection from respiratory droplets and (right) donned protective suits to transport an AIDS patient.

~~130 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC would be counterproductive at this time. They point out that such tests would yield few truly positive results in a low-risk population, yet would overwhelm test sites, produce need less anxiety among those tested and waste resources. For the most part the arguments against screening have been convincing, although several states, including illinois, adopted such legislation last year. Early experience in illinois, however, bears out the pre dictions of pUblic-health officials, sug gesting that there are many problems and few benefits associated with uni versal premarital screening. As with many other pUblic-health measures, decisions about HIV screen ing tests should be reexamined in light of the changing dynamics of the AIDS epidemic. As the prevalence of the disease increases, the ratio of false-positive results to true positives SPECIAL-PRECAlITION SIGNS identify hospital rooms of HIV-positive patients (here will decrease. (The reasons for the children) and remind staffto follow special procedures for handling blood or other decrease are technical and somewhat fluids. Recently the Centers for Disease Control have recommended that hospitals beyond the scope of this article, but adopt universal precautions and treat all patients' secretions as if they contained HIV. basically they stem from the increase of the fraction of the population that is infected.) Technical advances in tion program that includes AIDS edu HIV epidemic over the next 25 years. testing and improvements in the qual cation for minority communities in 15 The advent of AIDS has indelibly ity assurance of laboratories where eastern states. marked the practice of medicine in the the tests are conducted will also Intravenous drug use flourishes in U.S. The adoption of universal precau enhance performance. If there are areas that are burdened by unemploy tions by many hospitals means that advances in therapy, such as develop ment, homelessness, welfare depen the blood and certain body fluids of all ment of an effective and safe treat dency, prostitution, crime, school patients are to be regarded as poten ment for the asymptomatic HIV car dropout and teen-age pregnancy. tially infectious to health-care work rier, then increased emphasis on These conditions are so intertwined ers. Some hospitals in cities with large screening would be more desirable. that no one of them can be solved numbers of AIDSpatients have estab Containing the spread of HIV infec in the long term without providing lished dedicated clinical units to care tion in the U.S. today requires special the fundamental infrastructure-jobs, for hospitalized AIDS patients. At the attention to minority communities. schools and housing-needed by any other extreme, a private pediatric hos Some black leaders have been under community. Such an infrastructure pital recently announced that it was standably reluctant to add the stigma would go a long way toward creating not going to admit HIV-infected chil of AIDS to the burden of racism. An the individual self-respect, dignity and dren. If an admitted child is found to increasing number of them, however, hope for the future that can forestall harbor the AIDS virus, then the child are now prepared to take up the chal the turning to drugs in the first place. will be transferred to another hospital. lenge of stopping the spread of HIV . The same hospital also began a sys The singer Dionne Warwick, for exam erhaps the specter of AIDS will tematic testIng program for its em ple, who was appointed Ambassador arouse the nation's determina ployees to ensure that the entire in of Health by the U.S. Department of Ption to face up to those realities. stitution would remain free of HIV in Health and Human Services in 1987, The darker possibility is that racial fection. Many hospitals frankly do has made AIDSone of her highest discrimination will become camou not want AIDS to drive away their priorities. She has focused her efforts flaged under the delusion that AIDS is "real" patients: those who can most on the minority community, enlisting a problem for poor blacks and Hispan easily pay. the support of other celebrities to ics and need not concern white, mid The stress of AIDS on health-care raise money for education, research dle-class America. It is as dangerous workers can be tremendous. Doctors and patient services. In fiscal 1988 the and shortsighted for whites to view and nurses face young and desperate U.S. Centers for Disease Control spent AIDS as a minority disease as it has ly ill patients suffering from a disease $10 million on state programs to com been for blacks and Hispanics to view for which there is at present no cure. bat HIV in minority communities, with AIDS as a white homosexual disease. The medical and insurance systems $3 million earmarked for community Anyone who engages in risky activi around them resist the kind of coun organizations. Some private founda ties, including heterosexual sex out seling, home treatment and hospice tions are also giving special attention side of a monogamous relationship, care that the patient may need most. to community-based programs. With stands a chance of becoming infected. The doctor may be caught in conflicts the support of the Kaiser Family Foun The risk in some geographic areas and between patients, lovers, family and dation in Menlo Park, Calif., the School some population groups is now ex friends; other AIDS patients may have of Medicine at Morehouse College in ceedingly low, but no one can fore no evident social support at all. Atlanta is managing a health-promo- see with confidence the course of the What is more, health-care workers

~~SCIENTIFIC AMERICAN October 1988 131~~

© 1988 SCIENTIFIC AMERICAN, INC have legitimate concerns about occu to more than $900 million in fiscal commitment to building these organi pational exposure to HIV , although 1988. The budget request for 1989 zations has come from the homosex that risk is low. (Available data suggest exceeds $1.2 billion, including $400 ual community. Groups such as the that the risk of transmission from a million for the Centers for Disease Shanti Project in San Francisco, the single needle stick is less than half of Control and $600 million for the Na Gay Men's Health Crisis, Inc., in New 1 percent.) Some may harbor prejudice tional Institl\tes of Health. These sums York City and the AIDS Action Com or moral judgments about the behav cover scientific research, disease sur mittee in Boston were begun in an ior of their patients. Fewer physicians veillance, prevention and control ef effort to reach out and relieve the suf today are choosing to pursue careers forts. Total Federal expenditures for fering of patients the world seemed in internal medicine, and it may be AIDS in fiscal 1989 are projected to to have turned against. As nonprofit, that AIDS is part of the reason. No exceed $2 billion, including $600 mil community-based organizations, they other disease in modern times has lion for the Federal share of patient have provided a way for thousands of engendered such frustration, resent care through Medicaid. volunteers to give countless hours of ment and anxiety or demanded more At the state level, expenditures on assistance and comfort to patients, compassion, intelligence, selflessness AIDS have also risen dramatically, their loved ones and families. These and integrity on the part of health from less than $10 million in 1984 to organizations developed AIDS tele professionals. more than $150 million in 1988. Much phone hotlines and created specific of that is spent by California and New educational materials for various cul �isease such as AIDS drains an York; in fiscal 1988 the two states tural groups at high risk of HIV in economy illmany ways. AIDS. Im accounted for 46 percent. of all AIDS fection. They have also been outspo poses an economic toll on ev cases and more than 60 percent of ken and effective advocates for all ery business, school, public agency, state expenditures. On the level of the those touched by the epidemic. In a church congregation and community cities, expenditures are also great larger social sense, these groups have group responsive to the epidemic. In New York City spent more than $130 served as bridges between the gay direct costs (those covering medical, million on AIDS in 1988 and has bud and lesbian and the straight commu scientific and other social expendi geted $170 million for the fiscal year nities, bringing together individuals tures) AIDS will cost the American pub 1989, mainly because most of the who share a commitment to humani lic tens of billions of dollars over the city's AIDS patients are cared for in tarian goals and a refusal to give in to next decade; indirect costs (such as public hospitals. a lethal enemy. lost wages from premature death and One of the most remarkable and AIDS has attracted the support of disability) will add several hundred heartening by-products of the HIV epi celebrities, business leaders and pri billion more. demic in the U.S. has been the devel vate foundations. Following the death U.S. Public Health Service expendi opment of grass-roots organizations of her friend Rock Hudson, Elizabeth tures on' AIDS have grown from ap dedicated to serving the needs of peo Taylor became the National Chair of . proximately $60 million in fiscal 1984 ple with AIDS.An early and sustained the American Foundation for AIDS Research (AmFAR), the only national foundation dedicated solely to com bating AIDS.AmFAR has raised and devoted millions of dollars to scientif ic research and has recently broad ened its agenda to include innovative educational and community-based service programs. In 1986 the Robert Wood Johnson Foundation of Princeton, N.j., commit ted more than $20 million to projects for developing comprehensive and co ordinated care for patients with AIDS. More recently the Johnson Foundation has invited applications for support of community-based prevention and service programs. In 1987 the Ford Foundation announced a collabora tive, $4.5-million AIDS prevention and service program. By mid-1987 more than 150 foundations were providing support to AIDs-related projects. Several major insurance companies have spent millions of dollars spon soring AIDS education programs. Met ropolitan Ufe underwrote the 1987 broadcast of the National AIDS Aware ness Test on U.S. television. The New York Ufe Insurance Co. provided sup port for the New York City Department GAY COMMUNITY has fought for increased awareness of AIDS and for greater fund of Health's initial advertising cam paign to prevent AIDS, a campaign that ing of AIDs-related projects. About 100,000 people marched in New York's Gay lib eration Day parade earlier this year, including the People With AIDS Coalition. was developed pro bono by the adver-

~~132 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC tising firm Saatchi & Saatchi Compton, Inc. Scores of prominent individuals in the arts, sports and business commu nities have lent their time, names and dollars to the struggle against AIDS.

edical care for those suffering from AIDS is expensive. Esti Mmates of the average lifetime medical costs per patient in the u.S. have ranged from less than $30,000 to more than $140,000, with more recent figures in the vicinity of from $50,000 to $60,000 per patient. These costs do not, of course, include the many thou sands of hours that volunteers, family members and friends have contribut ed to the care of AIDS patients in cities across the u.s. It should be noted that although the cost of treating a patient with AIDS is high, it is well within the range of costs for severely ill patients with other conditions. Patients who require liver transplants, for example, have lifetime medical costs that are three to four times higher on the aver age than those of an AIDS patient. Advances in medical care have be gun to lower the cost of high-quality services to AIDSpatients. The Kaiser Permanente Medical Group of north ern California, for example, estab CAMPAIGN by the New York City Department of Health with the help of Saatchi lished an outpatient center in 1986 & Saatchi Compton, Inc., is aimed at preventing the spread of AIDSamong hetero to administer various AIDS therapies, sexuals. This poster was distributed in New York subways in English and Spanish. including the life-prolonging drug AlT. During its first 18 months of op eration the outpatient treatment cen adopts universal precautions requir people in the community develop ac ter saved an estimated 3,500 hospital ing frequent use of disposable gloves, tive tuberculosis the risk of spread days. Although pharmacy costs nearly gowns, masks and protective eyewear, to those not infected with HIV will doubled between 1986 and the first hires additional infectious-disease increase. As if to taunt progress in half of 1987, average costs for the care specialists and infection-control per the life sciences in the 20th century, of an AIDS patient declined 20 percent sonnel, follows special blood-screen HIV not only has caused the disease because of a 36 percent drop in overall ing and laboratory procedures and un most feared in America near the end hospital expenses during that peri dertakes education and counseling of the century but also has fueled a od. New treatments in the future may programs for its staff, such costs are resurgence of tuberculosis, the dis further reduce and possibly elimi spread over all patients and are not ease most feared at the beginning of nate some costs. On the other hand, found on the bills of those having a the century. new and expensive treatment could in diagnosis of AIDS. crease the average cost of care. The The HIV epidemic also results in etween 10,000 and 20,000 chil uncertain cost of future therapy is medical expenditures for patients dren in the u.S. are expected to another hazy segment in the crystal who are not infected with the virus. Bhave symptomatic HIV infection ball foretelling the future of AIDS. The "worried well" who experience in 1991, most of them infected at birth Total personal medical costs for general symptoms of fatigue, anxiety by their mothers. This will represent a AIDS will depend both on the average or poor appetite may seek medical 10-to-20-fold increase over the num cost per patient and the number of care and testing because they are con ber of newborns afflicted by the end patients. Uncertainty about the future cerned about HIV infection. Family of 1988. In New York City at present size of the epidemic increases with members and friends of patients with between 1 and 2 percent of all women the distance of the projection. The U.S. HIV infection may appropriately seek giving birth are infected with HIV, and Public Health Service recently predict psychological counseling. HIV infec the proportion rises to more than 5 ed that 450,000 cases will have been tion can also indirectly contribute to percent in some areas. The circum diagnosed by the end of 1993, extend the rise of other infections in the com stances of life for many of these moth ing its earlier estimate of 270,000 munity. After declining for many dec ers-poor, ill, unwed and dependent by the end of 1991. Personal medical ades, tuberculosis has begun to in on drugs-prevent them from caring costs for AIDS patients during 1991 crease in the u.S. Between 1984 and for their infants. Half of the babies have been projected to reach levels of 1986 reported cases jumped 36 per may escape infection, yet they have between $4.5 and $8.5 billion. cent in New York City. Today these no place to go; many remain in the Other costs associated with AIDS pa new cases are found mainly in pa hospital, where the cost for their care tients are subtler. When a hospital tients with HIV infection, but as more can exceed $250,000 per year. Both

~~SCIENTIFIC AMERICAN October 1988 133~~

© 1988 SCIENTIFIC AMERICAN, INC the newborns and those who pay their In parts of Africa and the Caribbean, lations at high risk of infection. The bills would benefitfrom expanded where HIV infection is more prevalent third requires building new human nursery care outside the hospital, than in the U.S., weakened economies and institutional capacities, balancing and if the projected number of infect are much less able to sustain the on basic and applied objectives and de ed newborns is even remotely correct, slaught of the disease. In the city of signing coherent research plans. the need for many more nonhospital Kinshasa in Zaire between 4 and 8 A strategy to accomplish these ob nursery facilities is acute. percent of the total population and jectives stands on four cornerstones. The HIV epidemic exposes and exac more than a fourth of the hospitalized The first is leadership that will inspire, erbates shortcomings in the system of patients are thought to be infected direct and organize the fight against paying for health care in the U.S. One with HIV. Many of those infected are in AIDS at local, state, national and in in fiveAIDS patients has no insurance; the educated middle class and are ternational levels. The second is ad 40 percent of AIDS patients are cov business people and professionals. In equate financial resources to do the ered by Medicaid (more than four a dramatic press conference held in job, drawn mostly from public sources times the proportion in the general October, 1987, the president of Zam but also from some private ones. The population). Medicaid, a program de bia announced that his son had died third is legal protection against dis signed to cover the medical costs of of AIDS.Demographic projections sug crimination, on which so much else the indigent, is a partnership between gest that the long-term impact of AIDS depends. And the fourth is an accurate the Federal and state governments. on these populations may be similar and timely surveillance system that Because of the variability in state rules to a prolonged war. In countries where can track and project the status of the for eligibility, Medicaid covers only 40 the per capita national product is epidemic. The future course of the HIV percent of those with incomes below measured in hundreds of dollars and epidemic is uncertain and a strategy the poverty line and frequently pays annual per capita expenditures on that takes account of such uncertainty less than the cost of care. Even private health care are $5 or less, a drug such is imperative. insurers often do not cover the kinds as AZT that costs $8,000 per year Our world has been made a different of services-outpatient, home and might as well be nonexistent. place by the human immunodeficien hospice care-most needed by people cy virus. More profoundly, our society

infected with HIV. Private health insur he World Health Organization's is being shaped by our response to the ance, for example, generally covers Global Program on AIDS con epidemic. Will AIDS enhance under only 15 percent of the cost of drugs Tvened an extraordinary World standing and tolerance of different prescribed outside the hospital. Summit of Ministers of Health in Lon sexual orientations, or will it harden These problems can be solved by don in January, 1988. Their conference traditional norms of acceptable and adopting a number of different strate concluded with a declaration on AIDS deviant sexual behavior? Will AIDS be gies: state-based insurance risk pools prevention that emphasized broad perceived as a universal threat to all or subsidies for uninsured patients; ening the scope of education, promot humanity, or will it be regarded as a reliance on case managers to deter ing worldwide exchange of informa problem of the underclass, the poor mine whether insurers should pay for tion and reinforcing the importance of and uneducated, and the minorities? services normally not covered; adjust nondiscriminatory poliCies. The 41st Will AIDS heighten the tension be ments in the national standards of World Health Assembly in Geneva in tween moralistic and pragmatic ap Medicaid eligibilitY and payment; sim May adopted a formal resolution en proaches to behavior and health, or plification of procedures for states to dorsing confidentiality of HIV testing can solutions be found that are both request flexibility in Medicaid cover and urging member states to avoid effective and morally acceptable? Will age; further extension of insurance discrimination against AIDS patients AIDS evoke the selfless dedication of coverage for employees who lose their in the provision of services, in employ physicians, nurses and other health jobs; mandated employer health in ment and in travel. A similar call for professionals, or will caregivers shun surance, and broadened Federal and antidiscrimination laws was the first AIDS patients and seek other ways to state support of health insurance. In recommendation of the June 1988 re practice their craft? How we choose to the case of AIDS,medicine and econo port of the U.S. Presidential Commis answer such questions, and the socie my go hand in hand:'failure to bring sion on the HIV Epidemic. ty we thus shape, is up to us. the means of payment into line with Public-health officials should have patient needs is dime wise and dollar three primary objectives in coping FURTIIER READING foolish. with the epidemic. They are, first, AIDS CONFRONTING AIDS: DIRECTIONS FOR Although the costs associated with to provide compaSSionate, effective PuBLIC HEALTH, H EALTH CARE, AND RE AIDS are undeniably great, those costs and cost-sensitive care to the people SEARCH. Edited by Roy Widdus. Nation must be put into perspective. The U.S. who have the disease; second, to pre al Academy Press, 1986. spends more than half a trillion dol vent further transmission of the dis AIDS PREvENTION AND CONTROL. World lars per year on medical care. Even ease, and third, to aggressively pur Summit of Ministers of Health on Pro grammes for AIDS Prevention. Perga allowing for a relatively pessimistic sue scientific research that may lead mon Press, 1988. projection of the AIDS epidemic, the to more effective prevention, diagno CONFRONTING AIDS: UPDATE 1988. Edit billions spent on AIDS over the next sis and treatment. The first objective ed by Robin Weiss. National Academy five years will amount to a small frac requires committed and well-trained Press, 1988. tion of the country's total health-care health professionals, increased serv REpORT OF THE PRESIDENTIAL COMMIS expenditures. In the cities and states ices and a responsive health-care fi SION ON THE HUMAN IMMUNODEFICIEN hardest hit by the epidemic, however, nancing system. The second requires a CY VIRUS EPIDEMIC. U.S. Government 1988. the financial toll will be much heavier. sustained and unprecedented educa Printing Office, EDUCATION TO PREVENTAIDS: PROSPECTS Medical care for the additional cases tional effort, judicious use of available AND OBSTACLES. Harvey V. Fineberg in expected in New York City by 1991 are pUblic-health measures and special at Vol. 239, 4840, Science, No. pages estimated to cost $100 per resident, in tention to minority communities, in 592-596; February 5, 1988. San Francisco $35 0 per resident. travenous drug users and other popu-

~~134 SCIENTIFIC AMERICANOctober 1988~~

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Long March to Approval gist at the Mayo Clinic, has spent much time testing ways of cleaning ob Companies and clinicians unite structing calcific deposits from the to create medical devices aortic valves. One of his latest plans: find the resonant frequency of the ithin the next year at the Mayo depOSits, focus sonic energy on them Clinic in Rochester, Minn., 20 and hope that they will fracture. A Wpatients undergoing spinal Medical devices, California manufacturer responded surgery will help to test a new device enthusiastically. Now Holmes is send that monitors their motor abilities by European microchips, ing specimens of the deposits to the stimulating the brain so that it trig television blues, company's engineers, who are in turn gers muscles in the legs or arms. In designing a device. Baltimore eight diabetic patients at clever fruit Some workers even turn to a consor the Johns Hopkins Diabetes Center tium of companies. In the develop have stopped injecting themselves ment of the programmable, implant with daily doses of insulin, relying the safety of complex medical equip able insulin pump at Johns Hopkins, instead on an experimental implanted ment, Congress empowered the Food for example, investigators chose Pace pump to supply the hormone. and Drug Adminstration to regulate setter Systems in Sylmar, Calif., to Although these inventions may be devices-from Band-Aids to X-ray ma manufacture and market the pump, the spiritual descendants of earlier chines-in the same way as the agen but they worked with two other com medical devices, including pacemak cy monitored pharmaceutical prod panies to develop the pump's fluid ers, the birth process has certainly ucts. Under the regulations, develop handling systems and refine the varie changed. In the late 1950's Wilson ers of devices that could pose signifi ty of insulin it infuses. Greatbatch labored in a barn over de cant risks to patients must prove Investigators begin preclinical tri signs for the first successful implant through a series of clinical trials that als-usually with animals-when they able pacemaker, using $2,000 of his they are safe and effective.Medical think the technology is ready and con savings to support the work. Today instruments on the market before the tinue until they judge there is enough investigators often ally themselves 1976 act and later ones judged "sub experience to warrant human trials. with companies and spend several stantially equivalent" are exempted Christopher D. Saudek, director of the years and millions of dollars before an until the FDA can assess the available Johns Hopkins Diabetes Center, super instrument reaches the market. The data on them. vised five years of animal trials for the shift largely reflects the increasingly Nowadays investigators sometimes implantable insulin pump. Some com complex regulatory process the devic begin collaborating with a company panies bypass animal studies in the es must weather. when they have only an idea for a U.S. by substituting clinical experience In 1976, spurred by concerns about device. David R. Holmes, Jr., a cardiolo- from abroad. This was the route taken by the medical division of Dornier, a West German company, when it intro duced the lithotripter to the U.S. Litho tripters smash kidney stones by aim ing sonic energy at the stones. By the time Dornier applied to begin clinical trials in the U.S., the equipment had been approved for sale in Germany. Before starting trials with human patients, cliniCians must gain approval first from their institutional review board and then from the FDA-a proc ess that can be lengthy. For the past year Jasper R. Daube, a neurophysi ologist at the Mayo Clinic, has had sitting in his laboratory a magnetic stimulator for testing muscles and nerves. Actuated near a patient's arm, the device stimulates the muscles and causes a Jerk. But it is most valuable, Daube says, for testing a patient's mo tor pathways by stimulating the brain. In this way he hopes the stimulator will help to check for damage to mo tor coordination-and the likelihood The Iithotripter, built by West Germany's Dornier company, crushes kidney stones of paralysis-in an anesthetized pa by aiming sonic waves at them. The first Iithotripter was approved by the Food and tient undergoing spinal surgery. Even Drug Administration for u.s. distribution in 1986. though doctors in Europe have already

~~136 SCIENTIFIC AMERICAN October 1988~~

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© 1988 SCIENTIFIC AMERICAN, INC employed the device to stimulate ers and clinicians. Eric B. Rosenbaum, done. That's what the governments the brains of thousands of patients, a consultant at ArthurD. Little, es also feel." the Mayo Clinic's institutional review timates that hospitals spent almost As a first step, Siemens and Philips board moved cautiously. Daube had to $ 7 billion last year on diagnostic and agreed to focus on dynamic and static revise his test protocols several times therapeutic equipment such as mag random-access memory chips, called in order to gain the board's approval. netic-resonance imagers, pacemakers DRAM'S and SRAM'S. (SRAM'S are faster The FDA required still more revisions. and balloon catheters. Nonprofit med and more expensive than DRAM'S.) Al Daube's experience is not unusual. ical centers including the Mayo Clin though Siemens and Philips engineers The FDA returns for revisions roughly ic and johns Hopkins are setting up designed the chips and manufacturing 60 percent of the applications for per for-profit divisions, in part to exploit processes jointly, each company plans mission to begin human trials. De the commercial potential of their in to manufacture a different device. Sie pending on the device, clinical trials vestigators' ideas. Running experi mens will make four-megabit DRAM'S, can last for anywhere from a few mental technology through human while Philips will concentrate on one months to several years. Saudek im trials in addition puts state-of-the-art megabit SRAM'S. Earlier this year Sie planted the first programmable insu equipment into clinics at relatively mens started mass production of lin pump in a patient in November, low cost. -Elizabeth Corcoran a smaller DRAM: a one-megabit chip 1986; clinical trials are now being ex based on technology developed by panded to include several sites. The Toshiba. When production of the larg project has so far cost more th�n $15 Mega Projects er DRAM'S as well as Philips' SRAM'S million; Pacesetter Systems represen begins in 1989, Meyer says, the MEGA tatives will not say how much higher European partnerships aim Project will have done its job. they estimate the costs will run. to make powerfUl microchips What will follow? Siemens and Phil When investigators have finished ips are now planning an even more the clinical trials, all data are submit n the race to build an integrated ambitious scheme, the joint European ted to the FDA for "premarket approv Icircuit industry Europe has tended Semiconductor Silicon Initiative, or al," or permission to sell the product. to be a bench warmer. Indeed, as JESSI. Rather than producing a few spe According to Charles H. Kyper, direc of last year European companies held cific chips, JESSI will aim to turn out a tor of the premarket approval staff, only 10 percent of the world market family of 16- and 64-megabit memory only a very few, simple applications for semiconductors, according to Da chips. Meyer estimates that some 100 make it through the FDA'S evaluation taquest, a market-research firm in San European companies have taken part on the firstattempt. Kyper says it jose, Calif. That may be changing. in planning JESSI, including compa takes approximately 15 months for a In 1984 Siemens in West Germany nies that make equipment for manu device to win approval once clinical and Philips in the Netherlands em facturing chips. Siemens, Philips and data have been submitted. Much of barked on a five-year program called France's SGS-Thomson are likely to that time passes as the company gath the MEGA Project to develop and build lead the project, according to R Ham ers additional data, he says; the FDA is advanced memory devices. Next year, ersma, a managing director of Phil supposed to finish its evaluation of a right on schedule, the two companies ips' components division. Government complete application within 180 days. will be producing large quantities of funding is also expected. In the firsthalf of fiscal 1988 the FDA chips developed by the project. Such programs are not cheap. Over had received some 11 0 applications; Memory chips, essential to electron the course of the MEGA Project, Sie Kyper says the agency will probably ic devicesranging from the avionics mens will have spent about 2.5 billion approve a total of 50 by year-end. on board civilian and military aircraft West German marks and Philips more Within the FDA, specific sections of to personal computers, have long than two billion marks. The German an application are likely to be eval been a mainstay of the semiconductor and Dutch governments together con uated by different experts. Coordi industry. Since typical memory chips tributed another 480 million marks. nating assessments becomes even have a highly regular deSign, efficient According to Hamersma, preliminary more complicated if the application manufacturing techniques can help to plans for JESSI call for an outlay of as describes a device and a drug used lower costs significantly.Two years much as 6.5 billion marks between jointly, as in the case of lithotripsy ago, at the height of the chip-trade 1989 and 1996. applied to gallstones. disputes between japan and the U.S., With a fully integrated European In conventional lithotripsy, patients fierce price competition from japa market looming ahead, "there are can pass kidney-stone fragments rel nese memory-chip producers drove all many people who believe that JESSI atively safely. But gallstone gravel but two of their U.S. counterparts out might be the first step in trying out lodged in the bile duct could cause of the field. As a result U.S. compa some common industry," Meyer says. serious problems, including jaundice. nies, withGovernment support, estab "But that's not the main focus." In Consequently workers are adding a lished the SEMATECH project to devel stead he looks for a strong European chemical agent to the therapy to dis op better chip-manufacturing tech microelectronics industry. -E.C solve the fragments. Even though the niques. Robert N. Noyce, coinventor drug has already received the FDA'S of the integrated circuit, has recently full market approval for independent agreed to lead the project. Signing Off? use, regulators from both the devices In Europe both industry and gov and drugs divisions must work to ernment "see the necessity of hav Tune in for the next episode gether to determine whether the drug ing a microelectronics industry," says in the television saga can be safely used in conjunction with Hans Meyer, a deputy director at Sie lithotripsy. mens and a MEGA Project manager. n the 1950's there were about 190 In spite of the difficulty of bringing "When we compare ourselves with the Itelevision manufacturers in the medical devices to market, they can japanese, or now withSEMATECH in U.S. Next April, on the 50th anni pay off handsomely for manufactur- the U.S., we see something has to be versary of RCA's invention of televi-

~~138 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC sion, there may not be a single U.S. clearer picture, the American Electron tent, shipping. Although the Agricul owned company making its own sets. ics Association is already promoting ture Department has spent many As of August, Zenith Electronics, in advanced televisionas an important years trying to find ways to reduce Glenview, Ill., was still selling the sets potential market for U.S. semicon the damage, miniaturized electronics it made; most of the more than 20 ductor makers. "The technology cuts have now made it possible to build a other television plants in the U.S. are across every product line you can im sensing device that can follow fruit. owned by Japanese companies. But agine," says Richard Elkus, cochair of Since, as Brown points out, "an apple is last year was a bad one for Zenith: the an AEA task force on advanced televi a very sensitive fruit," it seemed a company lost money on television sion. He predicts that the strong play promising candidate for a study of sales and reported its third year-end ers in advanced television will also where fruit gets battered. loss in a row. As a result Zenith has dominate other industries, including The device for impact measurement been hounded by rumors that it will semiconductors. fits inside a 3.5-inch-diameter sphere sell its consumer-products division. Advanced television is still more an made of foam and beeswax. It incor In mid-August, Zenith would say idea than a product. Possible technical porates a piezoelectric transducer to only that it was "continuing to exam standards for the service in the U.S. are measure impacts, a microprocessor to ine all options to restore overall cor hotly debated. Most of the "high def log and time those forces, a memory porate profitability." But ''you don't inition" television systems proposed chip to store the data and a nine-volt, make any money in televisions," con by Japanese and European manufac rechargeable battery. The beeswax cedes Joseph Reilly, president of turers would be incompatible with ex transmits the vibrations clearly and Wells-Gardner Electronics in Chicago. isting television sets and would force can be easily molded, Zapp says. Al The company closed its television as consumers in the U.S. to buy new though he first shaped the instrument sembly line in May. equipment. A handful of investigators, in the likeness of an apple, he found it Even though manufacturers sold notably those at the Sarnoffcenter, are recorded forces irregularly. A sphere, more than 19 million color television experimenting with ways of deliver he discovered, registers the average sets to retailers last year, the produc ing compatible albeit somewhat less forces on apples better. ers say that prices are too low to yield vivid Signals that could in time be up Since not every bump will bruise, a profit. Price wars among manufac graded to the status of high-definition puncture or cut an apple, the investi turers date back to the 1950's but have television. gators practiced dropping the com intensified as first Japanese and then Even if advanced television takes puter and apples from many heights South Korean manufacturers purs).led hold, points out Robert B. Hansen, to findout what measurements were the U.s. market. president of Zenith's consumer-prod worth taking. Even though a Rome "All studies show that the industry ucts group, selling prices will remain apple is tougher than a Macintosh, is operating at a loss," notes David a crucial issue. "The same pressures an impact equivalent to 50 times the Lachenbruch, editor of Television Di will exist that have pushed consumer force of gravityis enough to inflict a gest, an industry newsletter. "Japanese electronics out of this country," he half-inch bruise on both varieties. "At manufacturers aren't doing any better wrote recently to the Federal Commu 130 g the apple's only good for Cider," than the American ones," he adds. nications Commission; "there is little Brown says. According to Zenith's year-end re about A1V [advanced television] that To test the bumpiness of a packing ports, if 1985 prices had been the would change the trend regardless of line, the investigators randomly toss same as those of 1984, the company whose system was adopted." -E.C four bright blue "apples" into a har would have reaped a before-tax profit vest of some 300 real ones. After the of $98 million from its television and apples bounce down the packing lines, videocassette-recorder sales. Instead Smart Apples the investigators stop the line, pick Zenith made just over a fourth of that. out the computers and examine the A In contrast, operating profitsfor Ze chip a day bruises and cuts on the real apples for nith's computer systems and compo may up the fruit's pay later comparison with the computer nents division jumped by $ 73 million data, which are downloaded to a per last year. hese days a handful of apple sonal computer. Even if Zenith grows weary of tele Tpicking operations in Michigan After more than a year of experi vision manufacturing, interest in the are throwing computers into the mental runs down 15 different pack next generation of television-high packaging line along with the fruit. ing lines, the investigators have found definition or advanced television serv The microprocessors are unlikely to that the bagging operation is the most ice-is percolating among U.S. elec make it as far as the local grocer's damaging. They are currently working tronics companies. The technology de bins, however. The computers are part with a company that manufactures pends on packing broadcasts with of an experimental project to analyze bagging machines to try to make the much more information than is cur precisely where the fruit gets bruised process a gentler one. rently transmitted, enough to make and battered between the tree and the The computers may also prove use home television pictures as clear as supermarket. ful for measuring the forces endured those in a movie theater. The project, first publicized in New by cucumbers, pptatoes, glass and The improved signal calls for new Scientist, is the work of H. Roland Zapp, even by large medical instruments. receivers' that will have roughly one a professor of electrical engineering at Brown notes that at least one company megabyte of memory, about as much Michigan State University, and investi is considering licensing the technolo as some small personal computers, gators from the U.S. Department of gy from Michigan State and manufac says Jack S. Fuhrer, director of televi Agriculture led by Galen W. Brown. turing the devices.At a cost of sever sion research at the David Sarnoff Re Every year, according to Brown, "hun al thousand dollars each, they would search Center in Princeton, N.]. Al dreds of millions of dollars" are lost quickly pay for their keep in help though no one is yet convinced that because fruit is damaged during har ing packing houses to cut down on U.S. consumers will pay more for a vesting, packing and, to a lesser ex- bruised fruit, Brown says. -E.C

~~SCIENTIFIC AMERICAN October 1988 139~~

© 1988 SCIENTIFIC AMERICAN, INC ing a second, initially stationary ball. Assume that the balls are isolated so THE AMATEUR that we need not worry about any extra forces on them, such as fric tion from the surface over which they move. Also assume that the balls SCIENTIST collide head-on. During the collision Drop two stacked balls from waist height; some or all of the first ball's kinetic � energy is transferred to the second the top ball may up to the ceiling ball, and the second ball moves to the right. Depending on the details of the collision, the first ball may move to the right or to the left or may even be stationary. The questions are: In a given situation how much energy is transferred, and what speed is impart by learl Walker ed to the second ball? In 1968 John B. Hart and Robert B. A= Herrmann, who were then at Xavier elastic ball dropped on a hard goes almost dead on the floor; the University in Cincinnati, reported the floor may rebound almost to the· baseball reaches the ceiling. Here safe oretical studies of such collisions. height from which it was re ty precautions are a must. I once was They also conducted experiments leased. Suppose you hold a second, bruised when I failed to align the balls with steel balls of various sizes sus lighter elastic ball on top of it and properly, so that the baseball shot out pended by threads from a rod. To release the two together. How high will sideways like a cannonball, moving study how energy is transferred in a the balls go? The heavier ball may faster than I could. collision, several balls were hung in a bounce nearly as high as it did alone, If you drop a lightweight plastic Wif row, with slight separations between whereas the lighter ball can in princi fle ball instead of the baseball, the them, as in the illustration at the left ple reach nine times its release height! basketball bounces a little higher and on the opposite page. The idea was to To be sure, in most cases the lighter the Wiffle ball actually slams into the draw back a ball at one end of the row, ball will not bounce as high as that, ceiling. Even more spectacular launch release it and then see how the subse but its rebound can often be vigorous es can be made witha stack of three quent collisions transferred energy to enough so that anyone who tries the balls, provided the mass of the balls the ball at the other end. The initial demonstration should wear safety decreases toward the top of the stack. energy of the first ball was set by the goggles and take care to stay out of If all went ideally, the top ball would height from which it was released. The the way of the ball. be propelled to a height that is 49 energy finally imparted to the last ball A startling version of the two-ball times its release height. Practical mat could be measured by the height to demonstration was recently published ters reduce the height, but it can still which it swung after being hit. In this by Joseph L. Spradley of Wheaton Col be dramatic. arrangement, incidentally, the balls lege in Wheaton, IlL Hold a baseball When a falling stack of balls reaches were about as isolated as one could above a basketball (it is best to main the floor, the balls undergo a chain of hope for. tain a slight separation) and drop the collisions in which kinetic energy is Here I shall review only the theoreti pair from waist height. The basketball transferred upward through the stack. cal findings by Hart and Herrmann, The last collision reverses the top but you can check the results, as they ball's motion and increases its speed. did, with their pendulum apparatus. The height to which it then climbs Consider the case I described above in depends on the square of the speed at which a ball strikes another, stationary which it moves just after the collision. balL Two factors are important: mo If the stack has only two balls, the mentum and kinetic energy. Momen Boll:0 collision can at best triple the top tum is the product of mass and veloci moy d, rc:.och ball's speed, sending it up to nine ty; kinetic energy is half the product of nine. time..5 times the release height. With three the mass and the square of the speed. rde.oe,e. he.ight balls in a stack, the collision can at Since the balls are isolated, the mo best increase the top ball's speed sev mentum of the balls can be exchanged enfold, so that it goes 49 times higher in a collision, but the total momentum than its release height. You might must remain the same. Such a firm Rc:.leose. think the greatest height would be rule does not usually apply to the h.:.ight achieved if all of the bottom ball's kinetic energy, which is reduced when energy were transferred to the top some of it is transformed into sound ball, but that is not the case. As will be or goes into vibrations or deforma seen below, the highest bounces come tions of the balls. If there were no such when only a fraction of the bottom losses of kinetic energy, the collision ball's energy is given to the top ball. would be perfectly elastic. Everyday Exactly how is the energy trans collisions, however, are not so ideal, ferred between the balls? As a warm and they are said to be inelastic. For up for the explanation I shall consider example, you can nearly always hear a simpler collisions. For a start, picture collision, and so some energy must go How two balls may bounce one ball moving to the right and strik- into sound.

~~140 SCIENTIFIC AMERICAN October 1988~~

One way to symbolize the extent of in each one the colliding masses are the line of balls if the transfer goes in elasticity is to employ a parameter more closely matched than they were the opposite direction. called the coefficientof restitution. A in the original single collision. Hart If even more balls are inserted in the perfectly elastic collision has a coeffi and Herrmann found that the transfer line and the masses are adjusted so cient of exactly 1, whereas a complete is best when the intermediate ball has that the mass ratio between succes ly inelastic collision has a coefficient a mass equal to the geometric mean of sive balls is identical throughout the of zero. A collision of steel balls, for the masses of the other balls. (The line, the transfer nears 100 percent. example, may have a coefficientas geometric mean is the square root of The reason is that with a longer chain high as .99; a collision between a base the product of the masses.) In my the balls in each colliding pair are ball and a basketball has a smaller example, the intermediate ball should closer to being exactly matched in coefficient. Although a higher coeffi have a mass 10 times the lighter ball's mass (in which case all of the energy cient means that more energy is deliv mass. When the third ball is put in would be transferred). If the balls are ered to the second ball, this is no place, the energy transfer jumps to hung as adjacent pendulums, the re guarantee that the ball will in fact gain about 11 percent. The equation associ lease of the ball at one end sends a lot of energy. Even if the total kinetic ated with the transfer still has symme energy through the chain until the last energy remains essentially constant in try: it does not matter whether the ball finally swings out and up. During the colliSion, the first ball may trans chain of collisions begins with the the successive collisions the interme fer energy to the second ball only heaviest ball or the lightest one. Aside diate balls hardly move and there is grudgingly. from the extent of elasticity in the little evidence of the energy transfer The extent to which energy is trans colliSions, only the mass ratios affect except for the clatter that sweeps ferred depends not only on elasticity the energy transfer. along the line of balls. but also on the ratio of the first ball's The transfer may improve if even So far, the collisions have been con mass to that of the second ball. Let's more balls of intermediate mass are sidered to be perfectly elastic. The fact go back to the case in which one ball inserted into the chain. Hart and Herr that in practice most collisions are runs into a stationary second ball. If mann found that the transfer is opti inelastic changes the story. When the the mass ratio is one and the collision mum if the mass ratios of successive coefficient of restitution is less than is perfectly elastic, the full energy of balls are identical. This condition is the ideal value of 1, the transfer of the first ball is given to the second the same as requiring that each inter energy worsens if the chain of balls ball, and the firstball stops [see illus mediate ball have a mass that is equal is too long. Althougha long chain tration at right above). For any other to the geometric mean of the masses means that the balls in each colliding ratio of masses, either smaller or larg of the balls next to it. pair are nearly matched in mass, the er, the transfer is less. For example, if For example, if the ratio of the first steady drain of energy from the balls the first ball is 100 times as massive as ball's mass to the second ball's mass is into sound, vibration and deformation the second one, only about 4 percent 1.05, then the ratio of the second ball's diminishes the energy reaching the of the energy is transferred. Surpris mass to the third ball's mass should last ball. ingly, the equation that predicts this also be 1.05, and so on. That is about Hart and Herrmann calculated just transfer has a symmetry. For a given the right ratio if there are 100 balls how many intermediate balls are mass ratio it does not matter which inserted between the original two needed to maximize the energy trans ball is initially moving: the same frac balls, which have a mass ratio of 100. fer to the last ball for a given coeffi tion of energy is transferred if the The first, heaviest, ball strikes a ball cient of restitution and for a given roles are reversed and the lighter ball that is only slightly less massive, and mass ratio between the end balls. If runs into a stationary, heavier ball. the firstball gives up nearly all of its there are fewer balls in line, the conse In both cases the transfer is small energy. The second ball then collides quent larger mismatch in mass be because the masses are mismatched. with the third one, which is only tween the members of each pair de The larger the mismatch, the poorer slightly less massive, and again the creases the transfer; if there are more the transfer. transfer is nearly perfect. When the balls, the inelasticity of the collisions If a third ball of intermediate mass last ball is struck, it receives almost 95 lowers the transfer. For example, sup is inserted between the mismatched percent of the energy the first ball pose that the mass ratio of the end balls, the transfer improves. Now had initially. Symmetry still holds: the balls is again 100 but that now the there is a chain of two colliSions, and same percent of energy is sent down coefficient of restitution is .99-only

~~SCIENTIFIC AMERICAN October 1988 141~~

~~After Chain collisions~~

slightly less than perfect. The maxi tive of the firstball, as if you could dropped on the floor. The ball on the mum transfer takes place when there somehow ride along with it [see illus bottom rebounds from the floor and are 22 intermediate balls_ If the coeffi tration belowl. Before the collision the then runs into the second ball in the cient is .8 there should be only four second ball (which is actually station stack. The second ball rebounds from intermediate balls. And if the coeffi ary) appears to approach you and the the first ball and then runs into the cient is as low as .19, the best transfer first ball with a speed V. If the colli third ball, and so on until the top ball (less than 2 percent) is obtained when sion is perfectly elastic, the second is reached. In each collision in the the first ball hits the last ball directly. ball appears to bounce off the first ball chain, the energy transfer and the In all the examples, the transfer main and then move backward with a speed speed imparted to the higher ball de tains symmetry. of Vrelative to the first ball. Since the pend on elasticity and mass ratios. What conditions will maximize the first ball still has a speed that is ap The high rebound of a ball from a speed imparted to the last ball? Start proximately V, the speed of the second dropped stack of balls was first re again with the case in which there are ball is actually V+v, or 2V. In 1972 ported by Walter Roy Mellen in 1968, only two balls and the collision is James D. Kerwin of the California State not long after the introduction of the perfectly elastic. More speed is im Polytechnic University in Pomona re Super Ball by the Wham-O Manufactur parted to the second ball if its mass is ported calculations on a chain of colli ing Company. (A Super Ball is consid small compared to that of the first sions, where each collision is perfect erably more elastic than a common ball. In the limit where the mass ratio ly elastic and involves a massive ball rubber ball.) Mellen described putting is infinite, the second ball is given a hitting an infinitely lighter ball. The a small Super Ball on top of a larger speed that is twice the first ball's ini speed doubles with each collision and, Super Ball and dropping the pair. To tial speed. With such a mass ratio, if there are n intermediate balls, the keep them aligned during the fall, he however, the energy transfer is minus last ball ends up with a speed that is 2" sometimes stuck a drop of glue or a cule. The result may be perplexing. times the first ball's speed. Obvious strip of double-sided tape between How can the second ball be given its ly a long chain results in a fantastic fi them. (He said that neither technique greatest speed when it gains only a nal speed. noticeably altered the high rebound of tiny amount of energy? The answer Several lessons can be learned from the smaller ball, but my experience is lies in the fact that its mass is so small. these examples of chain collisions. that the effect is more pronounced if If it is given even a small amount of The extent of energy transfer depends there is a slight separation between energy, its speed will be large. on elasticity and mass ratios; if the the balls.) He obtained even larger re Here is one way to derive the speed masses are chosen properly, the last bounds when a table-tennis ball was of the second ball without resort to and lightest object can end up with positioned above the smaller Super any equations. Let V be the speed much of the energy or with a large Ball and the stack of three balls was of the first ball. When the mass ratio is speed, but the mass ratios required dropped. (Although a table-tennis ball very large, the speed of the first ball for those two end results differ. is larger than the smaller Super Ball, it hardly changes during the collision. These lessons apply to the chain is lighter, and it is the mass ratio that Picture the collision from the perspec- collisions when a stack of balls is counts.) Typicallythe table-tennis ball would shoot up to about 20 times the release height. Gerhard Stroink of Dalhousie Uni versity and several other authors have o suggested an easy way to picture what happens to the balls when they are dropped. Start with two balls, the up Bd'ore .spee.d relaiive per one of which has a much smaller to he.avle.rball o mass than the lower one. Assume that the collisions between ball and floor and between ball and ball are perfectly ( ,.. -, f-\ ' elastic. Let V represent the speed of the balls before the lower ball hits the � ,j �? floor. Just after the lower ball bounces, After �� it heads upward with speed Vtoward , The collision of a heavy ball with 0"a light one the top ball, which is still headed 142 SCIENTIFIC AMERICAN October 1988

© 1988 SCIENTIFIC AMERICAN, INC downward with speed V [see illustra ratio is 3.01. If the coefficient is as low Speed ,elatiY� to lower ball tion at rightJ. The balls close on each as .62, the optimum mass ratio is 3.24. �2V other at a rate that is the sum of their A basketball and a baseball have a 0 / 1 speeds, or 2V. mass ratio of about 4. When they are Imagine the impending collision dropped as Spradley recommends, the from the perspective of the lower baseball receives nearly all of the bas � ball. The second ball approaches with ketball's energy and bounces moder j2V a speed of 2 V, bounces off the lower ately high, and the basketball hardly ball and then heads upward at a speed rebounds at all. A basketball and a of 2 V with respect to the lower ball. Wiffle ball have a mass ratio of about Since the mass ratio is large, the lower 28. Since the mass ratio is so much ��'. � ball is still mOving upward at a speed larger than in the case of the baseball, OL:', of almost V with respect to the floor. the Wiffle ball probably receives much Or, Hence the top ball must have a speed less energy from the basketball than of V+ 2 V, or 3 V, relative to the floor. the baseball does. Yet the Wiffle ball Recall that the height to which a ball takes off like a rocket, climbing higher bounces depends on the square of its than the baseball does. (Of course, the speed right after the collision. In this elasticity is also likely to be different 3V case, where the second ball's speed is in the two demonstrations.) tripled by the collision, it bounces to When three balls are dropped and j nine times its release height. the collisions are perfectly elastic, o Now add a third, even lighter ball to what should the mass ratio be be the top of the stack and imagine the tween the second and third ball for a second and third balls just before they full transfer? Can you extend the anal fv collide. The second ball is headed up ysis to even more balls? If the mass ward at a speed of 3 V and the third ratio between the bottom ball and the ball is headed downward at a speed of top one in a large stack is given, can V. The balls close on each other witha you determine what masses the inter relative speed of V+ 3 V, or 4V. After mediate balls should have in order to the collision, the third ball heads up attain the maximum energy transfer? I ward with a speed of V relative to don't think anyone has yet worked out d 4 the second ball. Since the second ball the answer. has a speed of 3 V relative to the floor, Sometimes I find that certain balls the third ball must have a speed of do not bounce as I expect they will. To A collision between twodropped balls 3 V+ 4 V,or 7V, relative to the floor. In cite one example, a very small Super the ideal setting of infinite mass ratios Ball should bounce quite high when it and perfectly elastic collisions, the is dropped with a basketball, but often He described a commercially available third ball should rise to a height 49 it does not. Why not? toy that works like the bouncing balls. times its release height. You may want In 1986 D. Rae Carpenter, Jr., David j. The toy consists of a vertical rod on to continue the analysis to stacks of Rehbein and Robert]. Bonometti, all of which three cylinders slide. The cylin four or more balls. whom were then working at the United ders are of different lengths, so that Let's return now to the case in which States Military Academy at West Point, they differ in mass; they are stacked in only two balls are dropped and again devised a handy way to launch a stack order of decreasing mass. When you assume that the collisions are perfect of two balls. In their scheme a light pull the cylinders partway up the rod, ly elastic. If you want a full transfer of weight plastic ball that had been re separate them slightly and then re energy between the balls so that the moved from a roll-on deodorant dis lease them together, they bounce off lower ball stops when they collide, penser was put on top of a much the base at the bottom of the rod and you must arrange for the mass ratio heavier steel ball of similar dimen the top cylinder (the lightest one) is to be exactly three, in which case the sions. Then the balls were placed in shot so high that it flies off the rod. top ball reaches four times its release the top of a long plastic tube, support height. The rebound height is not as ed by a paper clip that ran through the dramatic as when the mass ratio is sides of the tube. When the paper clip FUR1HER READING much larger, but the demonstration is was pulled out, the balls dropped ENERGY TRANSFER IN ONE-DIMENSIONAL still surprising. Here are two balls that down the tube well aligned. Holes had COLLISIONS OF MANY OBJECTS. john B. bounce well when dropped separately, been drilled along the length of the Hart and Robert B. Herrmann in Ameri and yet when they are dropped togeth tube so that air could easily escape as can journal of PhYSics, Vol. 36, No. 1, er the lower one seemingly refuses the balls fell. The tube was placed on a pages 46-48; january, 1968. VELOCITY, MOMENTUM, ANDENERGY to bounce at all, whereas the top one hard ceramic or tile floor. The mass TRANSMISSIONS IN CHAIN COLLISIONS. bounces much higher than either ball ratio of the balls was about nine and james D. Kerwin in American journal of could on its own-evenhigher than the coefficients of restitution for the Physics, Vol. 40, No. 8, p ages the sum of the individual bounces. collisions between ball and floor and 1152-1157; August, 1972. With less elastic collisions, the opti between ball and ball were high. The SUPER BALL PROBLEM. G. Stroink in The mum ratio for a full transfer of energy plastic ball would usually shoot up to Physics Teacher, Vol. 21, No. 7, p age is somewhat larger. Spradley deter four or fivetimes its release height. 466; October, 1983. VELOCITY AMPLIFICATION IN VERTICAL mined that there can be a complete In 1982 an independent analysis of a COLLISIONS. jose ph L S pradley in bouncing stack of balls was published transfer of energy as long as the coef American journal of Physics, Vol. 55, ficient of restitution is at least .62. If by R. H. MacMillan of the Cranfield No.2, p ages 183-184; february, 1987. the coefficient is .9, the optimum mass Institute of Technology in England.

~~SCIENTIFIC AMERICANOctober 1988 143~~

© 1988 SCIENTIFIC AMERICAN, INC such a code in case messages from the COMPUTER front fell into enemy hands. One pos sible plaintext message from the Ro man general and its corresponding RECREATIONS ciphertext are given below: SEND MMCC REINFORCEMENTS On making and breaking codes: FRAQ ZZPP ERVASBEPRZRAGF Part I For such a code system to work the intended recipient of the ciphertext must be supplied with a key. In this case the letter N, which is letter num ber 13, provides the key. Knowingthis letter, the recipient can retrieve the by A K Dewdney plaintext merely by subtracting 13 from the number corresponding to

, each letter in the ciphertext. "What one man can invent another the Bombe ticked its way to a cryptan Anunintended recipient of the ci can discover." alytic victory with some help from phertext (henceforth known as the -Sherlock Holmes in "The Adven humans-including Alan M. Turing, code breaker) can attempt to decode it ture of the Dancing Men," by Sir Arthur one of the founders of computer sci by trying every possible letter key. If Conan Doyle ence. In next month's column I shall he or she attempts to decode Caesar's continue the story by relating how message by assuming B is the key, the as the famous detective's re computers are currently employed to result would be: Wmark an expression of cool encrypt and decrypt messages. confidence in his own crypt The earliest codes converted a mes TFOE NNDD SFJOGPSDFNFOUT analytic resources or a statement of sage in ordinary language (called the historic fact? Certainly from the ad plaintext) into a coded one (known as Since this makes no sense, the code vent of the written word until well into the ciphertext) by, substituting one breaker would try other possible keys this century codes that some human letter of the alphabet for another. until finally he or she hits on N, which beings have invented to conceal mes The so-called Caesar code, for exam turns the garbled message into plain sages of military or commercial im ple, does this according to a simple English. port were indeed discovered by oth numbering scheme. If one numbers At first glance it would seem that a ers. Just before World War II the en the letters of the Roman alphabet computer has no place in decoding coding process was mechanized, but (A, B, C. ..) from 0 to 25, one can specify messages enciphered with Caesar's that did little to change the situation. a particular number, say 13, and add code, because it would not be able to To paraphrase Holmes, what one ma that number to the number corre discriminate between meaningful and chine can encode another machine sponding to each letter in the plain meaningless messages each time a can decode. text. The sums represent the letters new letter key is tried. Yet a computer This month'li column, the first of that constitute the ciphertext. If a sum can be equipped with a "dictionary" two forays into the arcane world of happens to be greater than 25, one that would at least enable it to deter cryptology, ends with a discussion of must subtract 26 from it in order to mine whether the decoded message such a machine-versus-machine con get a number between 0 and 25. For contained legitimate words. There is, frontation. On one side is the Enigma example, X (letter number 23) is en however, a more powerful code-break machine used by the Axis forces 50 coded as K(letter number 10), because ing tool: statistics. years ago, and on the other is a ma 23 + 13 = 36 and 36 -26 = 10. Each letter of a language's alphabet chine called a Bombe. As we shall see, Julius Caesar is said to have used has a typical frequency with which it

~~.D .-- E~~

~~: I � ABC D E PLUGBOARD ROTOR 1 ROTOR 2 ROTOR 3 REFLECTOR LIGHTS 0 0 • 0 0~~

~~Schematic diagram of the basic Enigma machine~~

~~144 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC occurs in text written in that language. 13 �r------� For example, the first three letters of 12 the Roman alphabet account for re 11 f=' spectively 8, 1.5 and 3 percent of the z 10 -- letters found in ordinary English text. d 9 _ r-:: �0:: The most frequently occurring letter 8 �� 7 is E, appearing on the average 13 per > = u cent of the time. (A complete table of z 6 r-' - - -...... r-' -p:;:= -- UJ 5 letter frequencies is given in the illus :::> o .... .""" 1..-. -, 1_ tration at the right.) UJ 4 I=� ., 'r F 0:: - ��F In the ciphertext of Caesar's hypo u... 3 � _ -Fr--�t--4r-4- �C::· r-=F=i------l thetical message the commonest let 2 � .., • IN _ I � +- .. ter is R, which occurs four times. A '1 � .=.. 'H" . 1 '- 1- decryption program might therefore ETA 0 N I R H 5 D L eMU F P Y B G W V J K X Q Z assume that Rstands for E.Since the difference between the numerical val Frequency distribution of letters in typical English text ues of Rand E is 13, the program might further assume that the code's letter key is N a continuous string of symbols, as in by the German armed forces during Such a program would happen to be the preceding example, or in regular World War II to encode radio com correct in this case, but largely as a blocks. In either case it is assumed munications (which were themselves result of luck. In actual practice statis that the intended receiver will be able transmitted in telegraphic code) be tical forces can be fruitfully brought to separate the decoded symbols into tween field units and headquarters. to bear only if the code breaker has proper words. Because radio traffic can be intercept gathered a large volume of ciphertext. If the code breaker knows the period ed by anyone with a receiver tuned to Beyond identifying the most probable of the key (the number of letters in the the proper frequency, the need for candidate for E, such a program might key sequence) of a Vigen ere code, he encryption is obvious. also hunt for T, A and 0, which are the or she can break it by applying essen The basic Enigma machine consist next most commonly used letters. It tially the same method that is applied ed of an alphabetic keyboard, three might even match the letter distribu to crack Caesar codes. The process, "rotors," a "reflector" and a bank of 26 tions of the ciphertext against typical however, takes much longer. To de light bulbs-one for each letter of the letter distributions to determine the code the Vigenere ciphertext given alphabet [see illustration on opposite likeliest keys. above, a code-breaking computer pro page]. A rotor was a toothed wheel Blaise de Vigenere, a French cryptog gram would have to generate four sep through which ran wires that connect rapher of the 16th century, complicat arate letter distributions, one for ev ed a set of 26 contacts on one side of ed the Caesar code by proposing that ery fourth letter starting at U. one for the rotor with an equal number on the the key be changed in a periodic man every fourth letter starting at P,and so other side. The connections were ran ner. When one encodes a message a la on. The program would then compare domly assigned but fixed. In a given Vigenere, one changes the letter key each distribution with the standard position a rotor would thus represent for each successive letter in the plain letter-frequency distribution in order a particular set of permutations for text, always running in order through to guess each component letter of the the 26 possible electrical signals from the same sequence of letter keys. In key sequence. In essence the problem the keyboard (one for each letter) that essence the sequence itself is the boils downto four separate Caesar might be sent through it. For example, code's key. code decodings. If the code breaker a rotor might send a signal represent Just for fun, suppose the key se does not know the period of the key, ing the letter A to the contact repre quence happens to be CLEF, which the exercise takes even more time, senting the letter R, the signal rep corresponds to the number sequence because each possible period must be resenting B to the contact for D, and 2, 11, 4 and 5. To encode a message tried. In this case having a computer is so on. The second rotor, having a dif using this key sequence one would definitely an advantage, since it is well ferent wiring arrangement and set in divide the letters of the plaintext mes suited for such repetitive tasks. a different position, took the signal sage into groups of four and add 2 to It goes without saying that if one is from the firstrotor and induced an the number value of the first letter of dealing with short messages or rela other permutation on it. The last rotor each group, 11 to the second, 4 to the tively long key sequences, many mes similarly induced a third permutation third and 5 to the fourth. As in the sages would have to be collected be on the signal. Caesar code, the resulting sums repre fore a successful decoding attack of a After a signal had passed through sent the number values of the letters Vigenere code could be launched. Con the three rotors, it encountered the of the ciphertext. The example below versely, if only short key periods are reflector: a set of wires that connected illustrates how a Vigenere code op applied in encoding, messages do not each contact with another contact on erates on a plaintext to produce a have to be very long before it becomes the back of the third rotor, thus send ciphertext: nearly certain that the plaintext will ing the Signal back along a different emerge from the computer. path through the three rotors. In pass key: CLEFCLEFCLEFCLEF We shall now skip a multitude of ing from rotor to rotor in reverse or clever coding systems developed be der the signal underwent three more plaintext: SENDINTHECAVALRY tween the 16th and the mid-20th cen permutations. When the signal finally tury to arrive at the German Enigma reemerged from the rotor assembly, it ciphertext: UPRIKYXMGNEACWVD machine, focus of the most intense passed directly to a light bulb in the decoding effort ever undertaken up to display bank. Enciphered messages can be sent as that time. The machine was employed A key property of the Enigma ma-

~~SCIENTIFIC AMERICANOctober 1988 145~~

© 1988 SCIENTIFIC AMERICAN, INC chine was that it was self-inverse: if it coded by a differentletter permuta performed an extra permutation on happened to encode the letter Ras Q, tion. In all, 26 x 26 x 26 = 17,576 dif six or seven pairs of letters before it would-in the same state-encode Q ferent permutations were used for a their respective electrical signals en as R. The self-inverse property meant given letter before the Enigma ma tered the rotor system and again after ciphertext typed into an Enigma ma chine returned to its original state. leaving it. The Poles, stretched to the chine would emerge as the original The situation is reminiscent of the limit of their technical resources, had plaintext message if the decoding ma older Vigenere code but vastly more to give up after these modifications chine had the same initial state as the complicated. Each letter in a key se were made. encoding machine. As a consequence, quence of a Vigenere code also induc The British built on the Polish foun encoding and decoding amounted to es a permutation of the alphabet in dation by first assembling a mixed the same simple operation-as long the sense that it changes a letter in the group of cryptanalysts and mathema as the rotors were set in the correct plaintext into another, namely the one ticians (including Turing) at a Victori positions. Although it was a tremen given by the sum of the numbers cor an mansion in Buckinghamshire called dous convenience for operators of the responding to the plaintext letter and Bletchley Park. Knowing the Enigma machine, the self-inverse property the key letter. A Vigenere code, howev machine's rotor and reflector wir as we shall see-proved to be a fatal er, makes use of only as many permu ings, the group still had to discover weakness in the Enigma code. tations as there are letters in the key the machine's plugboard wiring. The What made the Enigma code so sequence before returning to the same group based its attack on what is fiendishly tough to second-guess was "state." To put it in perspective, the known as the probable-word method. that the first rotor of the machine period of the "key" for the Enigma This method exploits the fact that in rotated one step automatically after a machine can be regarded as 17,576. some contexts a particular sequence key was pressed. After the keys had It would have been virtually impos of intercepted symbols almost surely been pressed 26 times the first rotor sible to break the Enigma code if the represents a known word. Aninter returned to its original position, but British cryptanalysts had known noth cepted ciphertext broadcast from the then the second rotor moved into a ing at all about the encoding proc German naval headquarters, for exam new position. Likewise, when the sec ess. A statistical attack based on typi ple, might have had a block of five ond rotor had moved 26 times, the cal letter frequencies in German text letters that was interpreted to be-in third rotor would rotate one step. The would have been useless since a spe all likelihood-the encoded version of assembly of rotors essentially operat cific letter of plaintext would be en the German word U-boot (an abbrevi ed like the odometer in an automobile. coded as any other letter with almost ation for Unterseeboot, which means This mechanism ensured that each equal probability. Yet the British were submarine). succeeding letter of plaintext was en- not completely ignorant of how the Guessing correctly what several ci Enigma machine worked. phertext words were made it possi Before the war the French intelli ble to work out the plugboard wir gence service had obtained copies of ing merely by testing all possible wir PLUGBOARD REFLECTOR instructions for the machine and had ings and seeing which one yielded ROTORS passed that information on to the the guessed ciphertext-plaintext word Poles, who made good use of it. By pairs. Yet because there are more than analyzing German radio traffic in the a trillion possible plugboard wirings light of the instructions, Polish crypt for seven pairs of letter permutations, uD:mmJ analysts managed to deduce the wir Turing realized that only an automat ing pattern of the three rotors and the ed and relatively fast machine could reflector. Because the composite per carry out the tests. mutation comprising the net effect of Actually it was not surprising that the three rotors, the reflector and the Turing resorted to machines in try second pass through the rotors could ing to break the machine-based code. :U uuu U' be readily determined, it was now pos The Poles themselves had already em sible to decode German military mes ployed electromechanical simulators sages-if the initial state of the rotors of the Enigma machine. The simula was known. The Polish cryptanalysts tors ticked from one position to the in fact were able to ascertain the initial next, attempting to find which com states of the machines from the mes bination of rotors would produce a sages that broadcast, in coded form, given permutation. They were called o D::nrnm} the daily rotor settings. Bombes because of the ticking noise Although the British had learned all they made. of this from the Poles, the information To unravel the plugboard's wiring a was actually of limited value during new type of Bombe was therefore con 4 the war because, as the war had ap structed. The machine incorporated proached, the Germans made some circuits of relays that tested all possi o D::mID modifications to their Enigma ma ble plugboard combinations for logi chines. First, they increased the stock cal consistency. The test was simple in of rotors from three to five. Hence principle. Consider, for example, five before attempting to decode any inter Enigma machines that have been num cepted messages it was necessary to bered 1 through 5 [see illustration on determine which three of the fivein this page]. The machines have consec TD:]OOD} terchangeable rotors were in the ma utive rotor positions in order to sim chines. Second, some military versions ulate the effecta single Enigma ma A Bombe traces the plugboard logic of the machine had a "plugboard" that chine would have on each letter of a

~~146 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC five-letter word. (Remember, we are as suming that the initial rotor positions of the Enigma machine that encoded the word are known on the basis of other intelligence.) Analysts have de termined that the five-letter cipher text word CZTUC probably stands for the plaintext word UBOOT. What plug board connections were used in en coding the rest of the day's plaintext? The Turing Bombe would begin with a hypothesized plugboard wiring, say that C on the input side of the plug board was passed on as A to the first rotor. Suppose now that Enigma ma chine 1 transforms the letter A into World War 11 V-bootswere equipped with Enigma machines the letter R If the probable word is correct, the plugboard must change the Rfrom the machine into a U and, ing. At such a time the ticking would Portola Valley, Calif., has discovered a because of the self-inverse nature of stop, Signaling a coming explosion way of generating approximately the the machine, U into R perhaps-but not at Bletchley Park. same effecton a computer display That last deduction means that the The question of plugboard wiring by superposing four square grids that plugboard for Enigma machine 4 must was just part of the cryptanalytic ef are shifted or rotated with respect to also change the letter U in the cipher fort undertaken by Turing and his one another. The program, which de text word to R If machine 4 (whose wartime colleagues. The daily initial pends on Pythagorean numbers (those rotor state is shifted three steps in rotor settings, for example, also had to that correspond to the sides of a right relation to machine 1) converts the R be determined, as did other features triangle), produces an effect that is from its plugboard into an X; then the of the Enigma, which I do not have the simultaneously artistic and halluci Bombe would instantly deduce that X space to discuss. Suffice it to say that natory. One could get similar patterns and 0 are wired together, since the the group at Bletchley Park were kept by stacking window screens one on fourth letter of the plaintext word extremely busy breaking the various top of another and rotating and shift happens to be o. versions of the Enigma code employed ing them. That fact can now be exploited in by the Germans. More important per Janet A Hoskins, a computer scien the third Enigma machine, which en haps is the fact that their work, which tist at the University of Manitoba in codes the third letter of UBOOT. If it relied on machines to break the codes Winnipeg, has programmed her micro turns out that machine 3 yields an X generated by another machine, sig computer to create drawdowns, the only if it receives a P as input, then a naled the era of automated logic lead weaver's technical term for a grid plugboard connection between P and ing to modern computers. based diagram of a fabric at the in T has been established, since T is the In next month's column I shall con tersection of every warp and weft. third letter of CZTUC. tinue this cryptological theme into the Her program enables a weaver to ob Because UBOOThappens to end with present day. For now let me just say serve immediately what effectaltering a T, the Bombe would then arrive at a that there are many hobbyists who threads would have on the final woven critical juncture: Will Enigma machine practice computer cryptology in their pattern. It also creates drawdowns di 5 complete the logical loop and trans spare time. Some have even written rectly from digitized images. form P to A, so that the plugboard programs that simulate the Enigma Finally, core warriors should note then yields the C that appears in the machine and the British code-breaking that the Third International Core War final position of the corresponding effort. I am grateful to Bartosz Milew Tournament will be held on December ciphertext word? If not (as was usually ski of the University of California at 3-4 at the headquarters of the Inter the case), the hypothesis that the plug Davis for the description of his rather national Core Wars Society in Hunting board linked C with A was eliminated. comprehensive code-breaking pack ton Beach, Calif. Potential entrants The Bombe would then tick on to con age called CRYPTO.The package in may buy guidelines for writing battle sider the next hypothesis, say that the cludes a program that breaks one programs for the tournament by writ plugboard links C with B.If that hy rotor Enigma codes. Readers interest ing to William R. Buckley, 5712 Kern pothesis too is eliminated, then the ed in CRYPTOcan write to Milewskiat Drive, Huntington Beach, Calif. 92649. Bombe would try C linked to C, and so the Physics Department, University of All entries must be received by No on. In this way Turing's Bombe would California, Davis, Calif. 95616. Some vember 23, 1988. eventually discover the correct plug readers might also want to subscribe board wiring. to The Cryptogram, a newsletter pub The ciphertext word used in the ex lished by the American Cryptogram FURlHER RFADING ample is rather short and the Enigma Association, edited by Mike Barlow at CODES, CIPHERS, AND COMPUTERS: ANIN machines' letter permutations were 5052 Chestnut Avenue, Pierrefonds, TRODUCTION TO INFORMATION SECURI deliberately chosen in such a way that Quebec, Canada H8Z 2A8. lY. Hayden Book Company, 1982. the path analyzed by the consistency AlANTURING: THE ENIGMA. Andrew 1983. test could be neatly traced. In reali une's column had to do with lat Hodges. Burnett Books, ty longer messages far richer in logi ticeworks, the intricate patterns CRYPTOGRAPHY AND DATA SECURIlY. Dorothy Elizabeth Robling Denning. cal implications were used, so that one gets by weaving, according to J Addison-Wesley Publishing Company, Turing's Bombe could by sheer deduc certain geometric rules, lines that 1983. tion discover an entire plugboard wir- meander across a plane. Bob Wallis of

~~SCIENTIFIC AMERICANOctober 1988 147~~

© 1988 SCIENTIFIC AMERICAN, INC istic style And the Band Played On portrays the events and personali BOOKS ties of the early days of the epidemic. Conversations are reconstructed and A novelistic history of the AIDS epidemic events portrayed against the backdrop of a rising count of AIDS cases. This demeans both investigators and patients stylistic device lends a sense of grow ing urgency to the underlying themes of the book A "handful of heroes," Shilts writes, "risked their reputations and often their jobs to pioneer early research on AIDS." What of their col leagues? They formed a stupefied sci by William A Blattner entific establishment that "did not at first devote appropriate attention to the epidemic because they perceived AND THE BANDPlAYED ON, by Randy in meticulous journalistic detail over little prestige to be gained in study SmIts. St. Martin's Press ($24.95). the course of 605 pages, come togeth ing a homosexual affliction." Finally, er in the book's epilogue: an account in Shilts's indictment, leading scien ajor events in human mstory of the Tmrd International Conference tists "competed rather than collabo Mtend to spawn their chroni on Acquired Immunodeficiency Syn rated ... [diverting] attention and en clers: the Trojan War inspired drome, held during the summer of ergy away from the central struggle Homer, the decadence of the Roman 1987 in Wasmngton, D.C. against the disease itself." Empire was chronicled in the Satyri The Fourth International Confer This establishment-v.-antiestablish con of Petronius Arbiter and its de ence on AIDS in Stockholm this past ment theme is epitomized in the char cline was analyzed by Gibbon. The June brought us one year forward acter of a young Government scien AIDS pandemic also promises to take a from the epilogue of And the Band tist to whom the author attributes al major place in the history of our spe Played On. Unlike the tone of discord, most clairvoyant insights about the cies, but it has not yet attracted a rancor and confrontation that typified cause of the epidemic. He is, natural recorder of classic stature. Tms cir the Washington meeting portrayed in ly enough, SmIts's oracle on scientific cumstance has left the field to Randy the epilogue, there were no yellow issues. Juxtaposed to this proactive Shilts, a determined reporter who cov gloved policemen arresting death-clad hero are ms passive Harvard mentor ers the gay community for the San activists, no open-mike remarks from and a National Cancer Institute (NeI) Francisco Chronicle. politicians about "gay" men and no researcher whose discovery of the first Since its publication in October, glamorous media events where movie human retrovirus is passed off as "a 1987, And the Band Played On has stars and world leaders rubbed shoul backward scientificaffair. " sold 215,000 copies in hardcover and ders under the glare of omnipresent has gone through seven printings. A TV minicams. hilts's presentation is extremely paperback edition from Viking-Pen like each of its predecessors, the Sreadable, and it fits a common guin is scheduled for publication tms Fourth AIDS Congress reflected the romantic stereotype. Yet the ac fall. The book has been serialized in state of response to the AIDS epidemic. complishments of the scientificestab- magazines and at least one translation As such it marked an evolution paral- lishment in the seven years since the (into German) is planned. Clearly, this . leling on a societal scale the progres first cases of AIDS were recognized is the AIDS book and has been a potent sion of feelings experienced by a pa belie SmIts's assertions. It is the scien factor in the public perception of the tient confronted with a life-threaten tific establishment, not some roman AIDS problem. ing illness: denial and anger give way ticized scientific maverick, that has Written with conviction and passion, to despair, which in the best case may produced the spectacular and time the story SmIts tells does not flatter its be followed by acceptance and coping. ly current accumulation of scientific subjects. As the pandemic spreads, As scientists of 110 nations filed knowledge about AIDS. scientists and clinicians are shown en into the Stockholmsmassen, a modern The description, on page 73, of a meshed in battles over priority and convention center, they showed a unit conversation in which Shilts's clair research turf; the reaction among pol ed determination to confront AIDS and voyant hero charts the discovery of iticians and Administration officials the underlying pandemic of HIV infec the etiology of AIDSimplies too much. ranges from indifference and a preoc tion as a global problem. Luc Mon In reality the concept that a human cupation with questions of conserv tagnier and Robert Gallo spoke from T-lymphotropic retrovirus causes AIDS ative ideology to open homophobia. the same podium, their visionary talks grew out of scientificinsights devel The media exploit the lurid aspects of punctuated by the symbolic harmony oped in Bethesda and Boston. Workers the disease, playing to perceived pub of Sibelius, played by the Swedish Na who had identified HTIV-I, the first lic revulsion. These themes, explored tional Symphony Orchestra. In con human retrovirus, as one that had a trast, Shilts's book belongs to the first predilection for T cells and was trans stage of reaction: it is a story in wmch mitted by blood or sexual activity WIlllAM ABlATINER is chief of the the harpies of rancor and anger es related that finding to another obser viral epidemiology section of the Na tablish a tone so intense that it be vation, namely that certain animal leu tional Cancer Institute. This review ex comes vitriolic. kemic viruses are also immunosup presses his personal opinions and not SmIts's underlying premise is that pressive. Tms perception underlay the necessarily those of the NCI or its parent agencies. America's institutions-political, sci scientific quest, as precipitous as it entific and media-failed. In a novel- was circuitous, that in less than three

~~148 SCIENTIFIC AMERICANOctober 1988~~

© 1988 SCIENTIFIC AMERICAN, INC years proved the etiologic agent of plight of the Centers for Disease Con and Gallo that led to the cause of AIDS. AIDS to be a retrovirus, a type of virus trol (CDC) during the critical early days The facts of this literature are not that had not been reported to exist in of the epidemic is testimony to the presented by Shilts. Thus the reader of human beings until 1980. need to support basic research ade And the Band Played On is led to the As a result we have a test for the quately. As the politics of the budget conclusion that allocation of equal early detection of HIV infection that cutting process bit deeply into the credit for the codiscovery of the AIDS has made the blood supply largely core of national disease-surveillance agent to Gallo and Montagnier was the safe. Fundamental insights about the efforts at the CDC, the ability to detect result of some political compromise. viral genes have led to the develop links between geographically dispar In his epilogue Shilts refers to the ment of a therapy that is already pro ate clusters of AIDS cases was jeopar chronological information as a "pleas longing the life of some infected and dized. The absence of sufficient re ant fiction." Such an offhand dismis lethally ill patients. Such knowledge sources during those days emphasizes sal of a body of published literature is also pointing the way to additional the fact that each link of the public to which honorable men and women therapeutic strategies. Indeed, it can health and research chain is vital to have lent their names strongly sug be convincingly argued that never has the others. To be sure, the issue of gests that Shilts chose his facts care so much been accomplished so quick timely funding for research was a fully: those that support his thesis of ly in response to such a complex dis problem, which was compounded by indifference, selfishness and bigotry ease process. severe budget cuts, and it is still an are highlighted, and those that do not Reality, however, did not provide issue being hotly debated today. are played down or characterized in a a suitable foil for Shilts's anger or Whether the allocation of additional derogatory fashion. serve his antiestablishment theme. resources early in the epidemic would Shilts's rendition of the epidemio He portrays the National Institutes of have altered the timing of the discov logic sleuthing that led to the recogni Health as an intellectual country club ery of its cause-as Shilts assumes-is tion that AIDS is an infectious disease on Rockville Pike in Bethesda, Md. De hard to gauge. Experiments take time, is engaging, but he promotes mytholo tached, self-absorbed gray-haired sci and in truth there was only a very gy at the expense of reality. To be sure, entists are imagined "strolling at a small group of scientists who had the he portrays skillfully the individual leisurely pace... [lending] to the NIH proper tools, scientific background clinicians and city, state and Federal the ambience of a golf course." There and perspective for making the key epidemiologists who pulled together is only indirect concern for sick peo discoveries. Certainly there was no the firstthreads of evidence linking ple. Rather, "pure science" is pursued time to develop that expertise ab initio epidemics of Kaposi's sarcoma and in the hope that researchers "will in the course of a grave epidemic. opportunistic infections in young ho stumble across discoveries that will Finally, the response of scientists mosexual men. He shows how clini benefit humankind." In reality the NIH, themselves to such a crisis, although it cians connected these cases to similar the Pasteur Institute and a host of is a complex issue, was certainly not disease clusters among blood-product other "establishment" research insti dominated by antihomosexual prej recipients, intravenous drug abusers tutes around the world are centers udice, as Shilts charges. It is human and children. It is true too that the of excellence that draw insight from nature to accept the validity of one's story of patient "zero," the index sub often brilliant senior scientific men scientific intellectual investment. How ject from a case-linkage analysis by tors. A cadre of young and creative easy can it be to redirect this invest the CDC, provides a useful literary de scientists suffuse these institutions ment of ego and intellect, particularly vice for helping the reader to under with vitality. when the experiments are going well stand how the AIDS agent spread so and funding and publications rein rapidly and widely within the gay com t is my belief that were it not for force the importance of one's work? munity. But Shilts's tendency to per Ithe fundamental investment in ba What Shilts sees as prejudice was iner sonify leads him astray. Patient zero, a sic research made over the past 20 tia. In addressing the scientificre French Canadian airline steward, was years the discovery of the cause of sponse to AIDS, his discussion is sim not literally-as the author suggests AIDS might still elude us today. The plistic and his antiestablishment bias he was-the first patient to be infected success of science in unraveling AIDS es lead to a distorted perception of with HIV. He was only one among is stark testimony to the importance reality. These issues need to be as many contemporarIes who simultane of society's investment in the curiosity sessed in depth as science explores ously propagated the unrecognized of scientists. That instinct is crucial to and shares with the public the lessons spread of the AIDS agent. our ability to address this or any other to be learned from this unprecedented threat to survival. crisis. Unfortunately Shilts does not ne useful contribution made In turn, the rapid pace of discovery promote this process. Oby Shilts's book is its portrayal in the AIDs-research arena is creating a Shilts displays a discouraging lack of the sexually active lifestyle new body of knowledge and new tech of scnolarship. Hearsay replaces care that constitutes such an effective vec nologies that will not only advance the ful reading of the scientificlitera tor for HIV. Shilts clouds even this treatment and prevention of AIDS but ture. This is well illustrated in the un contribution to public understanding also alter fundamental insights into a critically propagated innuendo sur by distorting history. In the early variety of important diseases ranging rounding the scientific competition 1980's epidemiology and pathogen from cancer to neurodegenerative and between Montagnier and Gallo. Yet esis were blurred by diverse infor rheumatic diseases. The fruits of sci careful reading of the literature (as mation. Until the picture came into fo entific discovery, while never predict summarized in "The Chronology of cus, the fact that AIDS was a transmis able, are the product of creativity and AIDS Research," Nature, Vol. 326, pages sible disease competed with a variety rigorous inquiry. They do not result 435-436, April 2, 1987, as well as in of alternate etiologic hypotheses. Yet from random "stumbling." publications cited there) reveals the Shilts's chief scientific protagonist is Shilts's account· of the financial chain of discoveries by Montagnier portrayed as having the answer but no

~~SCIENTIFIC AMERICAN October 1988 149~~

© 1988 SCIENTIFIC AMERICAN, INC resources for discovering the retrovi tected and promising chemotherapies SCIENTIFIC ral cause of AIDS; the remainder of the and immunotherapies have been dis scientific community is either blind or covered) are the fruits of the scientific AMERICAN unwilling to accept his insight. process. If AIDS and other such chal The facts belie this assertion_ Inves lenges to our species are to be met CORRESPONDENCE tigators in Bethesda, Boston and Paris successfully this process must be un were intrigued by a retroviral cause, derstood and fostered by lay citizens but it was only one of many hypothe as well as by scientists. Offprints of more than 1,000 selected arti cles from earlier issues of this magazine, listed ses that had to be explored. When he Regrettably, the reader of And the in an annual catalogue, are available at $1.25 emphasizes the competition among Band Played On will gain little sense of each. Correspondence, orders and requests for the various workers, Shilts overlooks how scientific research is conducted. the catalogue should be addressed to W. H. the ambiguous nature of reality in Shilts focuses on controversy and per Freeman and Company, 4419 West 1980 South, another respect. Competition is part sonality rather than on process. In the Salt Lake City, Utah 84104. Offprints adopt of the scientific process, as is coop real world, scientific understanding ed for classroom use may be ordered direct eration. Significant and documenta does not proceed from insight to dis or through a college bookstore. Sets of 10 or ble cooperation existed during those covery in a straight line but follows more Offprints are collated by the publisher years, manifested by the exchange of a tortuous and sometimes convolut and are delivered as sets to bookstores. reagents and information and even ed path. Scientific discovery draws on of personnel between the laboratories failed experiments as well as success Photocopying rights are hereby gran ted by of HIV's codiscoverers. ful ones. Scientific American, Inc., to libraries and others Although Shilts's book is filled with Shilts simply does not do justice registered with the Copyright Clearance Cen novelistic detail in the tradition of In to the complexity of information that ter (Ccq to photocopy articles in this issue of Cold Blood and All the President's Men, confronted the scientific community SCIENTIFIC AMERICAN for the flat fee of $1.25 per copy of each article or any part thereof. his portrayal of people is two-dimen in tracking the elusive etiology of AIDS. Such clearance does not extend to the pho sionaL For example, Luc Montagnier of Even during the critical months in late tocopying of articles for promotion or oth the Pasteur Institute is a vague pres 1983 and early 1984 when the secrets er commercial purposes. Correspondence and ence whose contribution to science is of the cause of the epidemic were payment should be addressed to Copyright overshadowed by the more flamboy finally unraveled in Paris and Bethes Clearance Center, Inc., 21 Congress Street, Sa ant presence of his junior colleagues_ da, claims that various viruses, bac lem, Mass. 01970. Specify CCC Reference Num Here and elsewhere Shilts missed an teria, fungi and even noninfectious ber ISSN 0036-8733/88. $1.25 + 0.00. opportunity. Scientists are real people, agents (including the drug amylnitrite complex and multidimensionaL They and overexposure to sperm) were the Editorial correspondence should be ad have their faults and foibles as well as cause continued to surface on a regu dressed to The Editors, SCIENTIFIC AMERICAN, human dignity and the potential for lar basis. 415 Madison Avenue, New York, N.Y. 10017. greatness that exists in each of us_ Manuscripts are submitted at the authors' risk Shilts simplistically classifieshis he fact is that AIDS is a master and will not be returned unless accompanied universe of characters into either hero imitator. As the immune system by postage. T or villain, good or bad, fair-minded or is destroyed, a rich panoply of homophobic- The story of Dr_ Mervyn microscopic and submicroscopic or Advertising correspondence should be ad dressed to Advertising Manager, SCIENTIFIC Silverman, the former director of the ganisms find a hospitable milieu. A AMERICAN, 415 Madison Avenue, New York, San Francisco Department of Public major challenge was to sort out what N.Y. 10017. Health and current president of the was cause and what was effect. That American Foundation for AIDS Re was the challenge when Montagnier Address subscription correspondence to search, is a case in point. According first cultured and photographed the Subscription Manager, SCIENTIFIC AMERICAN, to Shilts, Silverman "had left an am causative agent. Was this retrovirus P.O. Box 3187, Harlan, IA. 51593. The date of biguous legacy" as he grappled with yet another passenger? In fact, were it the last issue on subscriptions appears at the the politically charged AiDS-preven not for the earlier discovery of HTLV-I right-hand corner of each month's mailing tion decisions of the earliest days of and the development of associated label. For change of address notify us at least the epidemic in San Francisco. Shilts's techniques, it is doubtful that anyone \ four weeks in advance. Please send your old ultimate judgment Dr_ Silverman's would have believed that a human address (if convenient, on a mailing label of a story demonstrates that "people of retrovirus existed, much less that it recent issue) as well as the new one. good intentions would ultimately do could be the cause of AIDS. far less harm. __than. __people of bad In place of this complexity the au Name intentions_" In this regard, Silverman thor dramatizes the plight of his sci New Address becomes a symbol, losing his human entific protagonist. Like his index case, ity to Shilts's portrayaL Furthermore, Shilts's clairvoyant scientific hero is a Street to the detriment of many people, once literary figment who restructures re City Shilts identifies his heroes they are ality for a good read. deified in a kind of pantheon; the vil Another recurring oversimplifica State and ZIP lains he consigns to Hades never get a tion is the concept of before and after. second chance_ The most prominent example is the The story of AIDS is still in its ear public disclosure of Rock Hudson's Old Address ly stages; how it will end cannot be AIDS illness. In the case of Hudson's described with anything approaching death the "before" was the long period Street certainty_ Yet the positive aspects of of indifference that persisted within City the response to AIDS (the agent has important segments of the nation's been identified, the blood supply pro- political leadership. The "after" was State and ZIP

~~150 SCIENTIFIC AMERICAN October 1988~~

© 1988 SCIENTIFIC AMERICAN, INC the response of politicians, the press and society itself to this highly publi cized event. Exercise There is a better example of the before-and-after paradigm. Four re ports from Gallo's laboratory were More L ess published together within a year of with Montagnier's paper. Those reports -MORE EFFECTIVE By -LESS TIME Because proved beyond a shadow of a doubt duplicating the motion of NordicTrack is so efficient, that HIV was the etiologic agent. Be cross country skiing, the you burn more calories and fore those publications in the May 4, world's best exercise, get a better aerobic workout 1984, issue of Science there was no NordicTrack provides the in less time. clear cause. After that date all research could focus on preventing infection by ideal aerobic workout. understanding the modes of transmis other exercise sion, developing rationally targeted Unlike bikes and machine burns therapies and searching for a vaccine. other sitdown more calories Yet "before and after" is an over exercisers, than NordicTrack simplification that does not do jus NordicTrack ... 50 you can tice to the intricacies of the research exercises all lose weight paths, followed by many scientists, the body's faster with that led to Montagnier and Gallo's fun major muscles out dieting. damental discovery. This utterly naive assertion that "the AIDSvirus was for a total _NO not a particularly difficultmicrobe to body workout. IMPACT find" trivializes the scientific process; _MORE Running and it demeans the brilliance of the scien CALORIES some aerobic tists who grappled with this formida BURNED In workouts can ble adversary. tests at a major uni cause painful and And The Band Played On appears to versity, NordicTrack potentially harmful be a weighty tome. Yet it is oddly burned more calories jarring. A repetitive, even static, in its develop than an exercise bike and NordicTrack workout ment. Although the themes are de a rowing machine.* is completely jarless. fined early and often, these issues too do not grow and evolve as one pro _MORE CONVENIENT . _NO SKIING EXPERI gresses through the 600-plus pages. With NordicTrack, you can ENCE REQUIRED Even if Instead they are restated in a heavy exercise in the comfort of your you've never skied, in a few handed way. Among those injured by home. NordicTrack easily minutes you'll.be "tracking" this approach are the men and wom folds, requiring storage space your way to better health. en whose poignant lives and deaths of only 17" x 23". arouse Shilts's anger and compassion. *Scientific test results included in fFREE BROCHURE AND VIDEO His need to prove a point converts NordicTrack brochure. I Call Toll Free Or Write: these individuals into thematic sym 1-800-328-5888 bols. In his overriding effort to brow In Minnesota l-8lJll.422·5l45 In Canada l-8lJll.433-9582 beat the reader with the failings of 141 Jonathan Blvd. N., Chaska, MN 55318 o Please sen" free brochure society's response to AIDS, he man NordIc/rack D Also free video tape D VHS D BETA ages to dehumanize the very people Name ______THE BEST WA Y TO FITNESS Bill Koch whose stories bring home the tragedy. Olympic Street ______Silver Medalist City __State __Zip ___ To me the ultimate sadness of this A CML COMPANY © 1988 NordicTrack Phone () 32OJ8 book is that it represents a lost oppor tunity. Shilts's position and accom plishments as a journalist who could gain entry both into the gay world and into the world of science and public FREE SCIENCE BOOKS CATALOG policy presented a unique opportuni Send for your free catalog of new and reccnt.publications from W. H. Freeman and ty. He could have helped his fellow Company, the book publishing arm of Scientific Americanfor more than 20 years. citizens to share in the effort to cope Discounts and bonus books offered. with AIDS and to understand the trage o dy of those afflicted with the disease, Yes, I'd like a free copy of your latest science book catalog. so that this challenge and others like o Please send literature about the ScientificAmerican Library, too. it can be surmounted. Perhaps, back in 1987, emotion precluded the writ Namc ______ing of such a book. Perhaps anoth Address ______er chronicler will find the positive City, State, Zip ______threads in the AIDS story; they are strong enough to produce unity, and ,Mail to: Gail Harleston - W. H. Freeman and Company, 41 Ma dison Avenue, New York, NY JOOJO therefore hope.

~~SCIENTIFIC AMERICANOctober 1988 15 1~~

© 1988 SCIENTIFIC AMERICAN, INC of retroviruses such as HIV. What is become one of the liveliest fields in ESSAY urgently required-is indispensable, basic immunology long before the ap in fact-is some new and very deep pearance of AIDS,and what is now AIDS: information about the intimate details needed is an intensification of the An unknown of retroviruses and the enzyme sys research. In my own view (perhaps distance still to go tems that enable them to penetrate biased because of my background in and multiply within the target cells immunology), it is the most urgent that are their specialty. and potentially promising of all cur Second, we need an abundance of rent approaches to the AIDSproblem. new information about how the hu To sum up, AIDSis a scientific re man immune system can neutralize search problem, to be solved only by

HIV. Even if and when an antiviral drug basic investigation in good laborato is in hand that really works to control ries. The research done in the past few by Lewis Thomas infection in individual cases, the only years has been elegant and highly pro imaginable way to prevent the contin ductive, with results that tell us one uing spread of HIV will be by means of sure thing: AIDSis a soluble problem, n a long lifetime of looking at bio a vaccine. The design of a vaccine calls albeit an especially complex and diffi Imedical research, I have never seen for better understanding of the molec cult one. No one can predict at this anything to touch the progress ular labels at the surface of the virus stage how it will turn out or where the that has already been made in labora and knowledge of which among these really decisive answers will be found, tories working on the AIDSvirus. Con labels represents a point of vulnerabil but the possibilities are abundant and sidering that the disease was recog ity for an immune response. Since this the prospects are bright. nized only seven years ago and that its particular virus has the strange prop It is particularly encouraging that agent, HIV, is one of the most complex erty of changing its labels from time the basic research most needed is be and baffling organisms on earth, the to time-even at different stages of ing conducted by collaborative groups achievement is an astonishment. the disease in the same patient-this in both academic and industrial estab If AIDS had firstappeared 10 or 15 will be no easy task. A few vaccine lishments. That is a new phenomenon years ago, before the research techno trials are already under way in small in this country, well worth noting in logies of molecular biology had devel cohorts of human subjects. There is the present context. Until just recent oped the marvelous tool of recombi no reason to be optimistic about these ly-the past decade or so-the univer nant DNA, we would still be complete at the present time, nor is there any sity laboratories and their counter ly stuck, quite unable even to make way to hurry things up. With a lot of parts in the pharmaceutical industry intelligent guesses about the cause of luck, some laboratory may succeed in tended to hold apart from each other, the disease. Thanks to the new meth identifying a stable and genuinely vul indeed rather looked down their noses ods, which emerged from entirely ba nerable target molecule in HIV, and at each other. It took the biological sic research having nothing at all to do ttlen a vaccine will be feasible. revolution of the 1970's, and specifi with any medical problem, we now A third line of research involves the cally the new technologies of recombi know more about HIVs structure, mo human immune system itself, the pri nant DNA and monoclonal antibodies, lecular composition, behavior and tar mary victim of HIV. Most, if not all, to bring scientists from both commu get cells than about those of any other patients with AIDS die from other nities into a close intellectual relation. virus in the world. The work, in short, kinds of infection rather than from Now the lines we used to think of as is going well. But it is in its early any direct, lethal action of the virus separating basic and applied research stages, and there is an unknown dis itself. The process is a subtle one, into two distinct categories have be tance still to go. At the moment three something like an end game in chess. come more and more blurred. Aca lines of research seem to me to hold What the virus does, selectively and demic and industrial scientists recog the most promise, and already there is with exquisite precision, is to take out nize that they are in the same line of a conspicuous shortfall in the funds the population of lymphocytes re work, and research partnerships are needed for each of them. sponsible for defending the body being set up all over the place. One approach, the most direct of the against all sorts of microbes in the I take this to be an exceedingly three but perhaps the most difficult world outside, most of which are healthy transformation in our institu and unpredictable, is in the field of harmless to healthy human beings. In tions. One response to the develop pharmacology. We need a new class of a sense, the patients are not dying ment will have to be the recruiting and antiviral drugs capable of killing off because of the HIV virus; they are training of more bright young people viruses inside the cells they invade, being killed by great numbers of other for the work ahead. As an academic, I without killing the cells themselves. bacteria and viruses that can now am delighted to see so many universi These drugs must be comparable in swarm into a defenseless host. Re ty scientists eyeing new horizons and effectiveness to the antibiotics that search is needed to gain a deeper thinking of career possibilities in in began to be deployed against bacterial understanding of the biology of the dustry. It is a good sign for the future infections 50 years ago. There are a immune cells, in the hope of preserv of this country in our competition few partially active drugs that may ing them or replacing them by trans with others in pharmaceutical science, turn out to be the primitive precur planting normal immune cells. This and a good sign as well for the solu sors of such a class, but their effective may be necessary even if viricidal tion to the AIDSproblem. ness is still incomplete, they are tempo drugs are developed: by the time such rarily palliative at best and their toxici drugs destroy the virus in some pa LEWIS THOMAS is president emeritus ty is unacceptable. However, there are tients, the immune system may al of the Memorial Sloan-Kettering Cancer no theoretical barriers to the develop ready have been wiped out, and the Center and scholar in residence at the ment of decisively effective antivirals, only open course will be to replace it. Cornell University Medical College. including drugs to stop the replication This third line of investigation had

~~152 SCIENTIFIC AMERICAN October 1988~~