All the animal species surrounding the AIDS virus (center) are targets of AIDS-like diseases. The slow viruses, or Ientiviruses, responsible for these diseases attack the cells of the host’s immune system. In the background are T4 cells, the primary target of the AIDS virus. The cells are stained with toluidine blue to identify nucleoproteins. The black dots, produced by radioactive probes, show the location of viral RNA in these infected cells. hy AIDS research at Los outlines the basic dynamics governing models are sadly lacking and often hard Alamos? In 1981 when the the epidemic in the United States. The to collect. Moreover, some data that wfirst AIDS cases were pub- model is based on two unique features have been collected are unavailable. licized, Stirling Colgate, a physicist of the AIDS case data from the Centers Seeing this deficiency, the Los Alamos at Los Alamos, was among those who for Disease Control (CDC). First, the group suggested in a commentary in Na- foresaw that a disease that undermines number of AIDS cases has not grown ture that a national database of complete the human immune system and is trans- exponentially with time (as happens and unfiltered information from diverse mitted through sexual contact could ex- when all members of a population are sources be established and made avail- pand into a worldwide pandemic. The equally at risk) but rather as the cube able to researchers and health officials threat seemed to him nearly as serious of time. Steady cubic growth between involved in surveying and forecasting as the threat of nuclear war, requiring 1982 and 1987 has occurred not only the course of the AIDS epidemic. Af- the kind of conceptual and quantitative among the total population but also ter the appearance of the commentary, approach characteristic of research in among groups defined by sexual pref- Beverly Berger of the Office of Sci- physics. erence, race, and geographical origin. ence and Technology Policy (OSTP) and Stirling explains: “Our dedication to Second, the CDC data indicate that the Scott Layne of Los Alamos organized a understanding the growth of the AIDS average risk behavior (number of sexual workshop entitled “A National Effort to epidemic received extra impetus in 1986 partners per year) of those developing Model AIDS Epidemiology.” The work- from the contrast between the popular AIDS was extremely high at the start shop brought together a diverse group view that the probability of progressing of the epidemic and has subsequently of modelers, statisticians, biologists, from infection to AIDS was as small decreased with time. clinicians, sociologists, and computer as 10 to 15 per cent and the epidemi- The model reproduces both the cu- scientists to assess what is known and ological evidence from Walter Reed bic growth of AIDS cases and the pro- what needs to be known to make accu- Army Hospital and Germany that the gression of the disease from the highest rate predictions. Although the meeting conversion probability was at least 90 risk individuals by assuming that peo- started with some tension among partic- per cent, and more likely, almost 100 ple tend to choose sexual partners who ipants from different fields, the interac- per cent. Another misconception at that are like themselves in sexual activity. tive format of the workshop created an time was that the slowing growth of Thus the model predicts that the disease atmosphere that was described in a pub- the epidemic relative to the expected will spread most rapidly among highly lic letter by one participant as: “Above exponential growth was a sign that the active high-risk individuals. However, and beyond the immediate payoffs of epidemic was dying out. because there is some mixing between the report on which we are working, we “A quantitative understanding of the risk groups, the epidemic will gradually have created a critical mass of scien- dynamics of the epidemic was desper- spread to lower and lower risk groups. tists from disparate areas who are now ately needed to develop a consensus The authors hope that the pattern they speaking to each other in a way that among scientists. Only then could a ra- have identified will dispel any wishful was not possible before.” Unfortunately, tional national policy be established. thinking that the threat of AIDS is not no plans exist at present for continuing Without knowing whether the number of universal. The recent reports of HIV the type of interdisciplinary communica- AIDS cases in the United States would infection among college students (esti- tion facilitated by the meeting. The flow continue to increase, the dedication of mated to be 1 in 500) gives us reason to of information among AIDS researchers resources required to defeat such a com- look carefully at the Los Alamos model. is still reduced by sensitive political, plex virus would be unlikely.” All models of the AIDS epidemic are legal, and ethical issues. “’AIDS and a Risk-Based Model” attempts to answer certain basic ques- One of my observations at the OSTP by Stirling Colgate, Ann Stanley, Mac tions. How many people are infected workshop was the unfamiliarity of re- Hyman, Scott Layne, and Cliff Quails now? How many will be infected in searchers from outside the hard sciences the next decade? What groups are most with the power of quantitative analysis. at risk? Where and what kind of inter- vention strategies will be most effective at stemming the course of the disease? Data to validate the epidemiological

Los Alamos Science Fall 1989 The power of such analysis is evident of various chemical agents designed to own) to develop a traditional vaccine not only in the opening article (“AIDS control the spread of infection within an against the AIDS viruses. The conclu- and A Risk-Based Model”) but also in individual. Until now, infectivity assays sion he reaches is that such approaches two other research articles in this is- from different laboratories have been have only a marginal chance of succeed- sue. “Genealogy and Diversification very difficult to compare to one another. ing. He turns finally to animal models of the AIDS Virus” by Gerry Meyers, The kinetic model developed by Scott of host adaptation (such as those of the Randy Linder, and Kersti MacInnes Layne, Micah Dembo, and John Spouge African green monkey and the chim- discusses a mathematical determina- describes the infection by free virus and panzee) as a possible source of inspi- tion of the genetic distances among other competing processes occurring in ration for developing a strategy against various HIV strains and between HIV infectivity assays. It also defines stan- the AIDS and AIDS-like viruses. An- and other immunodeficiency viruses. dard experimental techniques for de- other possible source of inspiration are It traces not only the evolutionary his- termining the rate constants of those isolated human populations in Africa tory of the AIDS virus but also the processes from the assay data. The pos- that may have evolved and still are in present epidemiology of the disease. sibility of standardizing interpretation equilibrium with the AIDS virus. Gerry Meyers of Los Alamos started the of infectivity assays and gaining more Our modem western culture has prob- Laboratory’s effort to collect and ana- detailed knowledge of the kinetic pro- ably broken social and evolutionary bar- lyze DNA sequences of these viruses cesses is attracting the attention of labo- riers previously operative in culturally in 1986. Through this unique effort we ratory scientists around the country. isolated populations that kept viruses, can monitor the mutations in HIV and One of those is Peter Nara of the such as HIV, under control. In many identify unequivocally which strains are National Cancer Institute. His quanti- such epidemics of the past, evolution spreading and where. One important tative HIV infectivity assay is partic- has selected immunologically stronger finding related to disease diagnosis is ularly suited to validating the kinetic hosts and less virulent mutants of the that the present test for HIV antibodies model. Peter, a doctor of veterinary pathogen, but only through the toll of in the blood (the ELISA test) is based medicine as well as a Ph.D. in virol- countless deaths. At present, AIDS is on a different strain of the virus than ogy, has been very generous in writ- spreading rapidly among inner city pop- the one that may be most prevalent at ing down for us his expansive view of ulations in this country and is spreading this time. Although ELISA detects anti- where the AIDS virus fits into our un- in many areas of Africa. The World bodies against new strains, we have an derstanding of viruses and their role Health Organization estimates that be- early warning that the test may have to in evolution and disease. In “AIDS tween 5 and 10 million people are now be altered to keep up with the mutations Viruses of Animals and Man: Nonliv- infected worldwide. Are we to repeat of this virus. ing Parasites of the Immune System” the experiences of epidemics in cen- The other quantitative article ("The we learn that the AIDS virus is one of turies past? Are we, who have seen Kinetics of HIV Infectivity”) concerns a group of “slow” viruses whose strat- twentieth-century medicine conquer nu- a theoretical framework for interpreting egy for survival is to develop slowly merous infectious diseases, too confident viral infectivity assays. Such labora- in the host and thereby assure continu- or too complacent to see the extent of tory experiments are the principal means ity of the host-virus relationship, These of measuring the virulence of differ- lentiviruses have probably evolved over ent viral strains and the effectiveness eons of time within the oldest and most crucial cells present in the immune sys- tems of all vertebrate animals. As such, they have developed many deceptive strategies for outsmarting the immune system. After describing both clinical manifestations of disease and immune dysregulation caused by the lentiviruses, Peter reviews attempts (including his NUMBER 18

AIDS and a Risk-Based Model ...... 2 Los Alamos Science Staff by Stirling A. Colgate, E. Ann Stanley, James M. Hyman, Clifford R. Quails, and Editor Scott P. Layne Necia Grant Cooper A model that assumes people choose partners of similar sexual activity reproduces the observed Managing Editor cubic growth in AIDS cases, whereas most models predict exponential growth. A general dis- Roger Eckhardt tribution of sexual activity along with biased mixing are identified as the factors driving the Science Writer epidemic from the highest to lower and lower risk groups. Nancy Shera Mathematical Formalism Art Director by James M. Hyman and E. Ann Stanley Gloria Sharp Numerical Results of the Risk-Based Model Design, Illustration, and Production by James M. Hyman, E. Ann Stanley, and Stirlitrg A. Colgate Gloria Sharp Katherine Norskog The Seeding Wave Photography by Stirling A. Colgate and James M. Hyman John Flower

Circulation Dixie McDonald Genealogy and Diversification of the AIDS Virus ...... 40 by Gerald L. Myers, C. Randal Linder, and Kersti A. Maclnnes

Comparison of the DNA sequences of HIV from various AIDS victims reveals a genealogy for Other Contributors the virus that agrees with the epidemiology of the disease.

IS-9 Photography Group Viruses and Their Lifestyles Tech Reps Inc. Smith and Associates, Inc. An HIV Database Printing Guadalupe D. Archuleta AIDS Viruses of Animals and Man: Nonliving Parasites of the Immune System ...... 54 by Peter Nara of the National Cancer institute

Address Mail to A class of “slow” viruses has evolved a full bag of tricks allowing them to use the immune cells Los Alamos Science of animals and man as a comfortable ecological niche and then to outsmart vaccines designed to Mail Stop M708 evict them from that niche. Los Alamos National Laboratory Los Alamos, New Mexico 87545 The Search for Protective Host Responses

The Kinetics of HIV Infectivity ...... 90 Los Alamos Science is published by Los Alamos National Laboratory, an Equal Op- by Scott P. Layne, Micah Dembo, and John L. Spouge portunity Employer operated by the Univer- sity of California for the United States De- A first attempt to model the kinetics of viral infectivity in culture should help standardize labo- partment of Energy under contract W-7405- ratory experiments and help evaluate various treatment strategies for AIDS. ENG-36. Mathematical Considerations