Searchlightsummer/Fall ’98

SEARCHLIGHTSummer/Fall ’98

QUARTERLY NEWS FROM AIDS RESEARCH ALLIANCE The National Leader in Fast-Track AIDS Research

AIDS RESEARCH A L L I A N C E Board of Directors Kenneth C. “Cam” Davis Financial Advisor Sanford C. Bernstein & Co. Chair H. Smith Richardson, III Vice-Chair What’s News— Chuck Williams Chuck Williams & Associates Treasurer * * * * * * Tim Engel Senior V. P. of Production Clinical Research People & Developments Walt Disney Feature Animation Secretary Daniel Bowers, M.D. Pacific Oaks Medical Group VaxGen, Inc. has selected AIDS RES E A R C H AIDS RESEARCH Alliance received national press Nancy Bresler Alliance to participate in the world's first large-scale coverage of our first inoculation of a volunteer in Sandy Bresler Talent Agent study of a preventative AIDS vaccine, AIDSVAX™. VaxGen, Inc.’s preventative AIDS vaccine study. Bresler, Kelly & Associates Bruce Cochran, Atty. A total of 5,000 HIV-negative people at risk for sex- Television, radio, and newspaper reporters wit- Tim Corrigan ually-transmitted HIV infection will be enrolled at nessed and photographed the injection, which was Executive V.P. Bates Worldwide approximately 40 sites throughout North America followed by a large press conference. Steve Martin, Friley Davidson Entrepreneur in this 3 year, double-blind, placebo controlled mayor of West Hollywood, and West Hollywood city David Hart, M.D. st u d y . councilman Sal Guarriello were also on hand to Wilbert Jordan, M.D. Director, Oasis Clinic (Coverage Begins on Page 4) lend their support. & AIDS Programs King/Drew Medical Center * * * Arnold Kassoy * * * Partner The Holiday Card Campaign is now underway for Manatt, Phelps & Phillips Virco, N.V. has selected AIDS RESEARCH Alliance Matt Redman to participate in a study that will determine the 8th consecutive year. We are offering 4 new McCown-Redman Design and inspiring selections—"Guardian Angel" (a Robert Winters, M.D. whether anti-HIV drug choices made with prior Chief Executive Officer knowledge of the drug resistance properties of drawing by Amy Dakos), "Still Window" (a collage Gregory S. Britt by Louella Hill), "Candle" (a photo by A r m o n d Director of Clinical Research patients' virus can improve the patients' responses Stephen J. Brown, M.D. Ba g d a s a r i a n ), and "Unknown Angel" (a photo by Medical Director to their medications. We are currently enrolling George C. Fareed, M.D. this open-label, randomized trial that will take Jayme Thornton)—in addition to a popular design Medical and Scientific Advisory Committee place in 20 centers nationwide. that we have retained from last year ("City Star"). Harvey Abrams, M.D. Bisher Akil, M.D. (Article on Page 13) H. Aaron Aronow, M.D. (Article on Page 3) Victor Beer, M.D. Aron Bick, M.D. * * * Joseph Church, M.D. * * * Gary Cohan, M.D. AIDS RESEARCH Alliance's Institutional Review Richard Cooper, M.D. Four AIDS RESEARCH Alliance staff members con- George Fareed, M.D. Erik Fleishman, D.O. verged upon the 12th World AIDS Conference in Board (a.k.a. IRB), which ensures the highest stan- Parkash Gill, M.D. Jonathan Goldsmith, M.D. dards of ethical treatment of study participants, has Michael Gottlieb, M.D. Geneva, Switzerland this summer to uncover areas Edward Grant, M.D. expanded its membership and undergone a David Hardy, M.D. of HIV/AIDS science now ripe for clinical investi- Scott Hitt, M.D. change in leadership. Three new members have John James gation. In this issue, we provide extensive coverage A. Kay Kalousek, D.O. Mark Katz, M.D. of major advances in our understanding of been elected to serve on the IRB, and S t e p h e n Peter Kraus, M.D. James Lee, D.O. Fefferman, M.F.C.C. was voted in as chairman. Albert Lerner, M.D. HIV/AIDS as presented at the conference. Aliza Lifshitz, M.D. We extend our gratitude to his predecessor, Fa t h e r Thomas Lockner, M.D. * * * Thomas Magee, M.D. Douglas Glassman, for 5 years of dedicated service Steven Miles, M.D. Michael Moret, M.D. Frequently, clinical trial results for anti-HIV drugs Phillip A. Musikanth, M.D. as a member, and later chairman, of the IRB. Gregg Olsen, M.D. fail to reflect the probable outcome for the average Amit Patel, M.D. (Article on Page 11) Henry Poscher, Ph.D. patient that uses these drugs after they receive FDA Eugene Rogolsky, M.D. Peter Ruane, M.D. approval. This has implications for how communi- * * * Jesse Sanders, M.D. Karen Sandler, D.O. E Anthony Scarsella, M.D. ty members should interpret clinical trial results Circle of Hope, AIDS R SEARCH Alliance's major Michael Scolaro, M.D. Elyse Singer, M.D. and potentially for how future studies should be donor campaign, kicked off with a bang in '98, Brian Smith, D.C. Brian Terry, M.D. designed and analyzed. The article, " C l i n i c a l adding 27 new members to the program. We are James Thommes, M.D. Daniel White, M.D. Trials to Clinical Reality", on page 23 discusses grateful to all those who have contributed to our Herbert Wiesinger, M.D. Kevin W. Williams, M.D. these issues in depth. mission of finding a cure for AIDS. Ronald Wing, M.D. Founders In Memorium * * * * * * Paul Rothman, D.O. Matthew Rushton 2

SEARCHLIGHT quarterly news from AIDS RESEARCH Alliance The growing complexity of the epidemic— A National Leader in Fast-Track AIDS Research It’s a multi-factorial disease (stupid)

AIDS RESEARCH Alliance is a national leader in cutting- edge AIDS research dedicated to finding more effective, better-tolerated treatments for HIV, and a cure for everal years ago, there were members of the scientific community who repeated the AIDS. AIDS RESEARCH Alliance recognizes that aggres- sive science is the only hope for saving the lives of the S mantra “it’s the virus, stupid”. This oft-quoted catch phrase served to imply millions of people infected with HIV worldwide. that 100% of the pathogenesis of HIV disease could be attributed directly to the virus (i.e. remove the virus, cure the patient). EXECUTIVE EDITOR Gregory S. Britt EDITOR Numerous scientific presentations at the XII World AIDS Conference held recently Andrew Korotzer, Ph.D. in Geneva, Switzerland served as a poignant reminder that HIV disease is a highly MEDICAL EDITORS complex multi-factorial disease. Data were presented demonstrating that total sup- George C. Fareed, M.D. pression of the virus does not result in rapid immune restoration. While the virus Stephen J. Brown, M.D. may be the igniter of the gradual depletion of the immune system, it is far from the EDITORIAL CONSULTANT Michael Slattery only factor as the disease progresses. Our basic assumptions of how the virus behaves have been revised. The virologists have finally acknowledged that they may CONTRIBUTORS TO THIS ISSUE Andrew Korotzer, Ph.D. need the assistance of the immunologists (and other specialists) in order to win the Gregory S. Britt war against AIDS. Michael Slattery Stephen J. Brown, M.D. Karen J. Wellenkamp Beware of the person with simple solutions to a complex problem (or of the person PRODUCTION COORDINATOR with an elixir that cures “all that ails you”). Despite the numerous proponents of Karen J. Wellenkamp the simplest solution always being the best solution, it has been shown repeatedly SUBSCRIPTION COORDINATOR throughout history that highly complex problems typically require complex solutions. Carlo Danielson The ultimate solution to the AIDS epidemic will be no different. ART DIRECTOR Chris Davies The real news presented in Geneva were the advances made in the areas of basic ART PRODUCTION Mad Macs Communications science—which have served to better inform our future strategies for blocking HIV’s DIGITAL PRE-PRESS STUDIO entry into the cell, fighting viral resistance, and rebuilding the immune system. Fontographics However, the details of these advances didn’t make it into the mainstream media AIDS RESEARCH ALLIANCE because the complexities cannot be reduced to a savory headline. MEDICAL EXECUTIVE COMMITTEE Robert Winters, M.D., Chair Peter Anton, M.D. The only “stupid” scientists working in AIDS research are the ones who have the Daniel Bowers, M.D. arrogance to assert that they have all the answers. I will happily indulge their James Corti, R.N. George C. Fareed, M.D. arrogance the day that they present us with the cure. Until then, the rest of us will David Hart, M.D. continue to feel our way around in the dark attempting to shed as much light in as Wilbert Jordan, M.D. many places as possible until we find a definitive solution to this epidemic. Ian McGowan, MB, D. Phil, MRCP Michael K. Wensley, M.D. Se a r c h l i g h t is published quarterly for the HIV community by AIDS RESEARCH Alliance, a California nonprofit corporation which is solely responsible for its content. Noncommercial reproduction is encouraged provided the appropriate credit is given. Circulation: 16,000. Copyright© 1998 AIDS RESE A R C H Alliance. All rights reserved. Gregory S. Britt Chief Executive Officer AIDS RESEARCH Alliance 621A North San Vicente Blvd. West Hollywood, CA 90069 Telephone: (310) 358-2423 Fax: (310) 358-2431 @ PRINTED BY ACUPRINT ON RECYCLED PAPER

S U M M E R / F A L L ’ 9 8 S E A R C H L I G H T NEW

C L I N I C A L T R I A L S 3

Treatment based on prior knowledge of viral drug res i s t a n c e — VI R C O ’ s Antivi ro g ra m ™ An open-label, randomized trial to determine w he t h e r the Antiv i ro g ra m ™ (“immediate phenotyping”) can lead to improved treatment c ho i c e s .

LOS ANGELES, August 20, 1998— ed drugs. In theory, one can mini- 2) >2000 HIV-1 RNA copies/ AIDS RESEARCH Alliance has mize the likelihood of failure by mL . been selected as a clinical site for determining ahead of time which 3) Stable on one’s antiretroviral Virco, N.V.’s study to evaluate the drugs each patient’s particular treatments for at least one Antivirogram™ as a clinical tool in strain is susceptible to, and choos- month prior to screening. designing patient-specific drug reg- ing these drugs for that individ- 4) Experience with at least two imens. Subjects are being recruit- ual’s treatment regimen. nucleoside RT inhibitors, ed from 20 centers nationwide. Accordingly, the primary objec- and currently on one pro- As described in an article in the tive of the trial is to evaluate tease inhibitor for at least Summer/Fall 1997 issue of whether making treatment choices one month. No other pro- S e a r c h l i g h t, the Antivirogram™ based upon prior knowledge of tease inhibitor experience, determines the degree of sensitivi- viral phenotype leads to signifi- and naive to all non-nucleo- ty or resistance (the “phenotype”) cantly improved drops in viral load side RT inhibitors. of the subject’s virus population to compared with making these deci- 5) No previous phenotypic HIV specific antiretroviral drugs, and to sions without phenotype informa- drug sensitivity testing. combinations of drugs. With this tion. Secondary objectives include information, the treatment regi- changes in CD4 counts and CD4%. Exclusion Criteria (partial list). men for each patient should be As many as 400 patients will be 1) History of alcohol or drug optimized by ensuring that individ- enrolled across all study sites. us a g e . uals only receive medications that Participants must have an HIV viral 2) Life expectancy < 6 months the virus is susceptible to. load >2000 copies/mL, be on sta- or diseases such as (but not To perform the phenotyping ble antiretroviral treatment for 1 limited to) lymphoma or test, 200 microliters (about 2 month prior to screening, be naïve Kaposi’s sarcoma, that could drops) of blood are drawn. to non-nucleoside RT inhibitors interfere with end point Standard molecular biology tech- and be experienced with only one niques are then applied to isolate protease inhibitor. Other inclu- as s e s s m e n t s . the subject’s viral reverse transcrip- sion/exclusion criteria will also 3) No prior protease inhibitor tase (RT) and protease genes. A ap p l y . therapy and no prior treat- CD4+ cell line is then outfitted ment with two or more pro- with a custom-made HIV virus, a Testing and tr ea t m e n t . tease inhibitors. viral construct from which the RT Subjects will be assigned to and protease genes are deleted, receive either standard HIV treat- # Patient Slots. plus the subject’s isolated RT and ment or a treatment regimen 8 - 20 protease genes. The viruses pro- based on the results of the duced by these cultures can rapidly Antivirogram™. Subjects will St a t u s (within 5 - 10 days) be tested for receive virologic and immunologic Currently enrolling. susceptibility to all approved anti- assessments from 8 visits over a 16- retroviral drugs. week period. Principal Inves t i g a t o r : Resistance is the major cause of Stephen J. Brown, M.D. antiretroviral failure, and strains of Inclusion Criteria (partial list). virus are being transmitted that 1) Male or female > 13 years of For more information, contact already express resistance to assort- ag e . Corigan Castro at (310) 358-2429.

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4 C L I N I C A L T R I A L S

AIDS vaccine gets its day in the sun.

The road to phase III trials for a preventative effectively neutralized by vaccine-induced anti-

AIDS vaccine has been a long one. It has been bodies. Some argue that a T cell response

fraught with controversy, as scientists, regulators needs to be elicited in addition to an antibody

and activists have debated the issues. Today, no response. Such scientists favor vaccine candi-

consensus exists in the scientific community dates designed to elicit both cellular and anti-

about the expected efficacy of preventative vac- body responses, but these candidates are not yet

cines based upon the gp120 viral protein. But ready for full-scale testing.

with the FDA’s blessing, VaxGen will now test a On the other hand, AIDSVAX™ has been

carefully developed vaccine candidate on a shown in chimpanzee studies to provide protec-

large number of volunteers. tion against a challenge of high concentrations

It seems reasonable to say that providing any of HIV. Because the currently enrolling trial

level of protection in inoculated individuals is involves HIV-negative individuals at risk of

better than none at all. So the question is, why infection, any protective effect of the vaccine

delay the testing of a vaccine candidate? In the could save many lives during the course of the

case of VaxGen’s AIDSVAX™ vaccine, there is trials. Should the vaccine fail, on the other

no chance of a volunteer becoming infected hand, much will be learned from studying the

from the vaccine itself, since it is not formulated reasons for failure. This information will likely

from an attenuated or killed virus, but from a lead to more efficacious vaccines and will clarify

protein. further the immunology of AIDS.

Some scientists in the AIDS research commu- The need to prevent the spread of HIV is as

nity have lined up in passionate opposition to crucial as the need to treat those already infect-

moving forward with the AIDSVAX™ study. ed. In developing countries, where 90% of new

Some argue that the high mutation rate of HIV infections occur, an effective vaccine might be

could result in virus against which the vaccine is the only affordable solution to the epidemic.

ineffective. It is not known whether an antibody However the results turn out, the trials on

response, such as AIDSVAX™ produces, offers AIDSVAX™ will take us further down the road

protection from infection. Unlike laboratory towards the identification of an AIDS vaccine

strains, many transmitted strains may not be that will reduce HIV infections worldwide.

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C L I N I C A L T R I A L S 5

The first phase III trial of a preventative HIV vaccine— VaxGen’s AIDSVAX™ B/B A double-blinded, placebo-controlled, multi-center study to evaluate the efficacy of the AIDSVAX™ B/B vaccine in adults at risk of sexually transmitted HIV-1 infection.

LOS ANGELES, August 20—AIDS single strains of virus. Some indi- A total of 5,000 people will be RESEARCH Alliance has been viduals that had been inoculated selected to participate; 3,335 will selected as the Los Angeles site with such formulations of vaccine receive vaccine and the remainder for VaxGen’s Phase III study to subsequently became infected will receive placebo. However, determine whether AIDSVAX™ with HIV-1. For most of them, since the study is double-blind, B/B can offer protection from the infecting strain was not the neither the researchers nor the HIV infection to HIV-negative one the vaccine was designed to participants will know who is individuals at risk for infection. provide protection from. The receiving the vaccine and who is This trial will be the first large- current formulation is believed to receiving placebo. Participants scale phase III study of an HIV be superior in that it contains may be male or female; they must preventative vaccine. be HIV-negative At least 40 sites will and at risk of infec- eventually be involved. “Obviously, a vaccine is absolutely essential to tion through sexual A similar trial in transmission (see Thailand is scheduled stop this epidemic. The major question is Inclusion Criteria). to begin later this whether this vaccine is effective, and to what year. Side Effects The vaccine con- degree. Now we’re going to find out.” Extensive Phase I tains recombinant and II trials in the gp120 protein from —Dr. Donald P. Francis, U.S. and Thailand two different viral (>1000 human vol- strains that induce an President VaxGen, Inc. unteers) have been antibody response. conducted utilizing Gp120 is an envelope vaccines with similar protein that functions in viral antigens from the two most com- formulations to AIDSVAX™ B/B. attachment to host cells. Another mon strains circulating in the These vaccines differ from component is an adjuvant, in this United States. AIDSVAX™ B/B with regard to case aluminum hydroxide. An The primary objective of this the strains of virus employed. adjuvant is simply a substance trial is to determine whether the They appear to be safe and well- that enhances the immune vaccine protects subjects from HIV- tolerated, with the adverse reac- response to a vaccine. 1 infection. Secondary objectives tions reported being those com- In earlier trials, AIDSVAX™ include determining whether the mon to many vaccines, such as vaccines have reliably produced vaccine can reduce viral load in pain or inflammation at the injec- antibody responses in trial partici- those subsequently infected with tion sites. pants. These antibodies neutral- HIV-1, and further confirmation of ize HIV in test tubes. the vaccine’s safety. There will also Dose Previous versions of the be evaluation of possible immuno- A single intramuscular injec- AIDSVAX™ vaccine contained logical markers associated with tion will be administered during 7 recombinant gp120 protein from protection from HIV-1 infection. visits over a 30 month period.

continued on page 6

S E A R C H L I G H T S U M M E R / F A L L ’ 9 8 NEW

VaxGen’s AIDSVAX™ B/B— continued from page 5 Each injection will contain 300 micrograms of recom- Inclusion Criteria. binant gp 120 from each HIV strain plus adjuvant 1) Male or female 18 to 60 years of age. (vaccine group) or adjuvant alone (placebo group). 2) HIV-negative at time of screening. 3) M e n : Those who have anal intercourse with Testing other men, excepting those in a continuous Blood samples will be collected for assessment of monogamous sexual relationship with the same immunogenicity (the immune reaction induced by seronegative partner. the vaccine) during visits for each immunization and W o m e n : Those currently in a sexual relation- during visits that will occur two weeks after each ship with an HIV-positive male partner, OR immunization. Assessment of HIV-1 infection will those who have had > 1 male sexual partner and occur at each visit for immunization by testing for at least one documented sexually transmitted seroconversion to 2 or more non-vaccine antigens. disease within the past 12 months. Subjects who become infected with HIV-1 during the course of the study will be followed for more exten- Exclusion Criteria. sive immunological and virological testing. 1) Injection drug use, now or in the past. 2) Those who have previously received any HIV vaccine. 3) Women who are pregnant. 4) History of immunosuppressive disease, immunosuppressive therapy.

# Patient Slots At least 150.

VaxGen, Inc. Status VaxGen Inc. was founded in 1995 with the Currently enrolling. mission of developing a vaccine against HIV. At the time, the National Institutes of Health had Principal Investigator: Stephen J. Brown, M.D. recommended against moving forward with current vaccine candidates, and private industry For more information, contact Corigan Castro at (310) had been curtailing vaccine research efforts. It 358-2429. was in this context that VaxGen was formed by Drs. Donald Francis and Robert Nowinski with other former members of Genentech, Inc.’s HIV vaccine research unit. The Genentech team had already accomplished much of the groundbreaking research into a gp120-based vaccine and they felt the necessity of continuing ❖ their development of this vaccine candidate. VaxGen improved Genentech’s formulation and conducted small-scale safety and efficacy trials of that vaccine candidate. As a result of their research, AIDSVAX™ is the first preventative AIDS vaccine to undergo large-scale Phase III clinical trials.

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As the Pendulum Swings—

XI International “Bridging the Gap” XII World AIDS Conference on AIDS Conference Vancouver, Canada Between Vancouver and Geneva Geneva, Switzerland July, 1996 June, 1998

hile there was plenty of good and hopeful news foundations for new treatment possibilities. Some of W to be found at the XII World AIDS Conference these new therapies are already being developed, and in Geneva, Switzerland, you had to look hard, listen show great promise. carefully, and wake up early in order to find it. You But to temper these expectations (as, in hindsight, had to look hard because the good news was embed- the expectations about the new antiretroviral thera- ded between the lines of several “basic science” track pies reported in Vancouver should have been tem- presentations. You had to listen carefully because the pered), several years and much work will realistically information that was presented was extremely com- be required to bridge the gap from these new scien- plex and sometimes hard to follow—even if you were tific foundations to new therapies. Even as the mech- an M.D. or Ph.D. biologist. You had to get up early anisms underlying AIDS are being clarified greatly, it because some of the most up-to-date and compelling must be kept in mind that the immune system is information was presented at 6:30 AM “satellite” ses- incredibly complex and subtle, and new questions sions hosted by various industry sponsors. emerge as rapidly as old ones are answered. These factors have contributed to many summing up the conference in negative terms. The fact is that after many came close to declaring HIV/AIDS all but Between the Headlines— cured after remarkable data about protease inhibitor- Ideas Whose Time Has Come containing regimens was presented at the XI World AIDS Conference in Vancouver, there was perhaps The mood swing that has occurred between the XI no where to go but down. and the XII World AIDS Conferences has garnered The promise of Vancouver—eradication of virus much media attention. Less notice has been paid to from the body—we now know to have been unrealis- the continuity in the development of crucial research tic. And the great leaps in AIDS therapy from over the last several years. Vancouver have given way to baby-steps forward in As an example, at the forefront of today’s Geneva, with advances reported being in relatively HIV/AIDS science are issues of immune reconstitu- mundane areas such as dose optimization for reduction and new therapeutic approaches for immune sys- ing pill burden and the relative advantages of differ- tem control of HIV. In many ways, the last two years ent drug combinations. have been watershed years for these issues. However, despite the somber impact of some of Presentations on these subjects are featured promi- the clinical treatment realities, leaps were made in nently in our reporting of the XII World AIDS Geneva. They were made in the area of basic science, Conference in Geneva. and in our understanding of how the virus and the It seems surprising to realize in retrospect that immune system interact. These leaps provide real there was as much emphasis on these topics at the XI

continued on page 8

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“Bridging the Gap” Between Vancouver and Geneva— continued from page 7

World AIDS Conference in Vancouver as there was in our understanding of the disease. It is perhaps appro- Geneva. Looking back through the program guide priate that the gap between treatment possibilities for the Vancouver conference, one notes that there and treatment realities should cause the public mood was a talk by Dr. William Paul, then director of the to swing like a pendulum, but this gap does not rep- Office of AIDS Research, entitled, “Can the Immune resent the complete picture. Although it is easy to System Control HIV?” There were also two entire ses- become mired in elation or despair as results are cov- sions of talks dedicated to immune-based therapies ered in the press, the work that makes real progress and immune reconstitution—the same number that does not always make headlines. there were in Geneva. The breakthroughs in antiretroviral therapy naturally stole the show in Vancouver. Far from the lime- light, however, steady progress had been occurring in OUR GENEVA COVERAGE other areas. As a result, we have now come to the point where it is realistic to test strategies for training The Immune System Strikes Back. . . . . 9 ravaged immune systems to participate in natural suppression of HIV. Clinical Trials to Clinical Reality . . . . . 23

The Gap and the Pendulum Take Home Messages From Geneva . . 25

Each World AIDS Conference historically becomes Preventative Medicine for associated with only a few particular new developments, but HIV/AIDS research comprises a number White Blood Cells...... 29 of interrelated fields that are constantly advancing

t the 12th World AIDS Conference in Geneva, a vast amount of information was presented on Anearly every aspect of the pandemic. But in keeping with our mission of indentifying more effective and better tolerated therapies, our coverage of the conference will focus on emerging issues in the science of HIV/AIDS, and promising areas of developments for new therapeutic compounds. For

excellent coverage of current treatment issues, we refer the reader to B E T A, the National AIDS Treatment Advocacy Project (NATAP), Treatment Issues, and AIDS Treatment News. BETA is published

quarterly by the San Francisco AIDS Foundation (tel. 415-487-8060) and can be found on-line at

www.sfaf.org/beta.html. NATAP’s website is NATAP.org, and the phone number is 212-219-0106. Treatment Issues is a publication of the Gay Men’s Health Crisis in New York (212-367-1528). John James’

AIDS Treatment News can also be accessed on-line (www.immunet.org), or call 415-255-0588.

S U M M E R / F A L L ’ 9 8 S E A R C H L I G H T GENEVA

Turning the table on HIV— The Immune System Strikes Back

BY ANDREW KOROTZER, PH.D. lacked a full understanding of the ically against it. The immune sys- complex interactions that lead to tem achieves its incredible speci- he most compelling informa- the immunodeficiency of AIDS, ficity both by producing antibod- Ttion to emerge from the XII and this has limited their contribu- ies to particular molecular targets World AIDS Conference was in tions to clinical solutions. Finally (antigens), and by dedicating each the basic science arena. Our in Geneva, a great deal of investi- mature T lymphocyte to respond understanding of how HIV inter- gation has culminated in extensive to a particular antigen. With acts with and impacts the immune discussion and exploration of ther- regard to defense against viruses, system is becoming clarified to apeutic concepts for reconstitut- CTLs activated by antigen kill cells such an extent that immunolo- ing the immune system. infected with virus when alerted to gists are beginning to design their presence by activated helper approaches to counter the multi- Im m u n o d e f i c i e n c y is more sub- T cells. The ability of the immune ple strategies HIV uses to destroy tle than we wer e awar e system to mount a potent defense the immune system. The path to The pathological hallmark of against a broad range of immune reconstitution is being the immunodeficiency of HIV/ pathogens depends not just on the paved. Ultimately, this work AIDS is the loss of CD4+ T cells sheer number of T lymphocytes, might turn the table on HIV by (also known as helper T cells). but on the breadth of the set of producing immune-based thera- Since these cells play a pivotal role antigens for which there are pies that empower the immune in both antibody and cellular responsive cells. system to participate in suppress- responses to infectious agents, the ing the virus. immunodeficiency was initially Those T cells dedicated to respond blamed on their loss. In fact, the to HIV remain continuously activated Though there is no doubt that loss of CD4+ T cells over time is a substantial factor in broad-based by the virus. In the case of CD4+ T immune function can be improved by immunodeficiency, but now it is cells, the activated state makes them antiretroviral therapy, this improve- acknowledged that more subtle vulnerable to infection. In the case of changes in surviving T lympho- ment is incomplete. The virologists CD8+ T cells, continuous activation have brought us this far, now the cytes (including the CD8+ cytolytic T lymphocytes, also known as eventually makes them unresponsive. immunologists are taking the baton CTLs) are important determinants Either way, immune function is lost. and running. of how immune function survives or fails under the burden of HIV. When patients successfully In combating most infections, The real and measurable gains respond to HAART, their immune the activation of CD4+ and CD8+ made in the suppression of HIV systems are strengthened. Such cells is a good thing; in the case of are making the concept of immune patients experience dramatically HIV infection, however, it under- therapy feasible. New, highly active reduced rates of opportunistic mines immunity by at least two antiretroviral therapy (HAART) infections, because their defense mechanisms. First, activated can relieve patients’ immune sys- against a broad range of CD4+ cells are most readily infect- tems of the burden of a heavy viral pathogens has returned. But the ed by HIV, so it is precisely those load. The release from the improvements to their immune helper cells that initiate the unremitting assault of HIV is like systems do not include effective defense against HIV that are most the lifting of a siege. Only when immune responses to HIV itself. vulnerable to it. And, since the the battering stops can the damage To place these phenomena into virus is never eliminated, T cells be assessed and repairs made. a larger framework, immunity to are chronically activated. When At previous World AIDS an invading pathogen normally mature T cells of either subtype Conferences, the immunologists requires a defense designed specif- remain activated long enough in

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S E A R C H L I G H T S U M M E R / F A L L ’ 9 8 GENEVA

The Immune System Strikes Back— continued from page 9 the presence of the antigen they Paris, France has shown that in responses to HIV itself (lost very are meant to recognize, they sim- patients for whom HAART has early in most HIV-infected per- ply become unresponsive to it. suppressed viral load, non-HIV sons) appears crucial for main- The resulting dynamics from recall antigens can induce memo- taining the LTNP state. these interactions are complex. ry cell clonal proliferation. This is HAART falls short of restoring Immediately following infection consistent with the reduced rate the body’s defenses against HIV. (the period known as primary of opportunistic infections in suc- However, the viral suppression infection), the body is swamped cessfully treated patients. induced by HAART might provide with a very large plasma viral load However, when helper cells from a window of opportunity for recon- (viremia). Within weeks, large these patients are grown in cul- stituting the immune system’s abili- numbers of activated CTLs are ture and presented with HIV- ty to respond to HIV antigens. found in the blood and, probably recall antigens, proliferative New data on the pathogenesis of due to their activity, the viremia responses do not occur. Since HIV during primary infection indi- subsides. However, in the mean- HIV-specific CD4+ T cells are par- cate that HIV-specific immune time, the viral reservoir has been ticularly vulnerable to attack from responses are lost very soon after established, HIV-specific helper HIV, it does not seem surprising infection. These data also indicate cells have become infected, and that their responses do not return that those responses can be pre- the CTLs remain chronically acti- even as broad-based immunity served if HAART is initiated within vated until they become unre- does. Since helper cells are cru- weeks after infection, and that the sponsive. The usual clinical cial in eliciting an effective preserved HIV-specific responses course is the eventual large-scale immune response against a can contribute to controlling the loss of CD4+ cells and progression pathogen, the continued absence virus. Thus, helper responses to to AIDS. of helper cell responses to HIV HIV recall antigens, the keystone means that viral suppression can- of immunity, are retained, and the The immune system: down but not be maintained without contin- aberrantly maintained activation of not out uous HAART. The immune sys- CTLs (a mechanism by which T The immunodeficiency caused tem remains blind to the contin- cell responsiveness is lost) is also by HIV includes the loss of ability to ued presence of HIV in its midst. reversed. This phenomenon is respond appropriately to antigens associated with the retention of seen previously (known as recall When the table is turned: CTL responses to HIV. antigens). In healthy people, recall immune systems controlling Although this information is antigens elicit a much stronger HIV obviously crucial to individuals immune response than occurred The significance of HIV-specif- who can be diagnosed within the during the initial antigen presenta- ic helper cell activity can best be period of primary infection, most tion. This response involves the seen in studies of long-term non- infected people cannot be, limit- division of T cells that remember progressors (LTNPs) conducted ing the direct impact of these having seen the antigen, and are by Dr. Bruce Walker and col- findings on clinical outcomes. therefore called memory cells. Any leagues at Massachusetts General The real significance of these mature T cell and its progeny have Hospital. LTNPs are a very small studies is that immune control of exactly the same antigen-specificity minority of infected people that HIV is not necessarily compro- because they are clones, and so maintain good viral control for mised by chronic infection, but recall antigens normally induce many years without antiretroviral by conditions established during large numbers of memory T cells therapy. Helper cells from LTNPs primary infection. One would reactive to those antigens. The loss exhibit very strong proliferative expect, therefore, that by revers- of clonal proliferation of memory T responses to HIV recall antigens. ing the effects of primary infec- cells in HIV/AIDS is one cause of The more vigorous the helper cell tion, immune based therapies im m u n o d e f i c i e n c y . responses, the longer the delay to could lead to viral suppression Dr. Brigitte Autran’s laboratory progression to AIDS. Thus, the without requiring eradication of at the Hopital Pitie-Salpetriere in maintenance of strong immune virus from the body.

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S U M M E R / F A L L ’ 9 8 S E A R C H L I G H T PE OP LE DEV E LOP M E N TS FACES &• PLACES • EVENTS Ensuring Ethical Consideration of Study Parti c i p a n t s — AIDS RESE A R CH Al l i a n c e ’s Institutional Review Boa r d (IRB)

n addition to several levels of scientific review and approvals that must be achieved prior to the initiation of new I res e a r ch projects, all clinical trials conducted at AIDS RESEARCH Alliance must also be approved by a human subjects protection committee that ensures the ethical and equitable treatment of all study participants. Following is an ov e r view of the role of this committee—the Institutional Review Board (IRB)—and an introduction to the individuals that comprise this all-important grou p . An IRB is a committee of individuals who are responsible for ensuring the ethical treatment of participants in human clinical res e a r ch studies. The IRB accomplishes this by carefully reviewing prior to initiation (and on an on-going basis) all res e a r ch protocols, informed consent documents and advertisements used to promote participation in a study. The IRB is charged with being an advocate and protector of the rights and welfare of potential study parti c i p a n t s — ensuring that studies are designed to minimize risk and maximize potential benefit to patients. In accordance with Federal regulations, all res e a r ch conducted using human subjects must be reviewed and approved by an IRB (also known as a Human Subjects Protection Committee). Theref o r e, most institutions that conduct a large amount of res e a r ch maintain their own IRB. The AIDS RESEARCH Alliance IRB meets monthly to review new clinical trials protocols, informed consent documents, proposed study advertisements, and all on-going clinical studies. It is common for the IRB to request changes to the study protocol itself and particularly the informed consent document.

John J. Duran, Atty. Proposition 215; People v. ACT UP Orange County, John has been active on defending ACT UP members from criminal prosecu- our IRB since 1996. He is a tion for First Amendment demonstrations against founding partner of Du r a n , Reverend Lou Sheldon and Congressman Bill Loquvam & Robertson, one Dannemeyer; and Boland v. L.A. County Sheriff, repre- of Southern California’s senting Deputy Bruce Boland, first openly gay sheriff leading law firms on gay/les- who was wrongfully terminated from the Sheriff’s bian rights and AIDS law. De p a r t m e n t . He was born in Los He has been an equally energetic human rights sup- Angeles, California, grew up porter in his political activities. He was a member of in East Los Angeles and went to California State Lieutenant Governor Leo McCarthy’s Commission on University/Long Beach, receiving his B.S. for Business Hate Crimes, drafting legislation and recommenda- Administration in 1982, with a double major in Human tions to curtail hate crimes based on race, religion, eth- Resources and Marketing. He went on to receive his nicity and sexual orientation. From 1995 to 1997, John Juris Doctor degree in Law from Western State served on the National Board of Directors of the Un i v e r s i t y in Orange County, California. National Gay and Lesbian Task Force. Since 1986, he In his professional career, Mr. Duran has been an has been a member and advisor to the Political Action extremely active proponent of human rights and social Committee of the Human Rights Campaign Fund, and equality in both the gay & Latino communities. He has he continues to be active on the Board of Directors of won significant, high-profile cases in recent years, A. N . G . L . E . , a gay political group that, among its many including People v. Perkins, the first test case of medical activities, produces an election year slate card for distri- marijuana defense since the passage of California’s bution to 400,000 gay and lesbian voters statewide.

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S E A R C H L I G H T S U M M E R / F A L L ’ 9 8 12

Meet the IRB— William Matchett, continued from page 11 M. D . Dr. Matchett is a recent addition to our IRB; he is a Stephen Feffe rm a n , psychiatrist in private prac- M. F. C . C . tice in Sherman Oaks, Stephen Lloyd Fefferman, California. Since 1996, he M.F.C.C., working with has been a Board member Charles Wilcox, M.F.C.C. of Van Nuys-based and Dr. Paul Rothman, was B r i d g e F o c u s, a community one of the founding mem- development and counseling organization, as well as bers of AIDS RES E A R C H the volunteer Medical Director of the Temple Beth A l l i a n c e in 1990 (formerly Hillel Guidance and Crisis Center. called “Search Alliance”). He William was born in Philadelphia, Pennsylvania, joined the IRB in 1996 and was voted Chairman after and moved to Denver, Colorado as a young boy, grow- the departure of Chairman Father Douglas Glassman in ing up until leaving for Princeton University in New early 1998. Jersey. He graduated from Princeton with a B.A. in Stephen was born and raised in Thousand Oaks, French Literature in 1959 and went on to Y a l e California. He attended San Jose State University, Medical School, graduating in 1964 with his M.D. He receiving his B.A. in Psychology in 1978. He achieved completed his internship at the University of his Master of Science in Psychology at the U n i v e r s i t y Colorado Medical Center in Denver. of LaVerne in Claremont, California in 1984 and was He then spent two years as a General Medical licensed as a Marriage, Family, Child Therapist in Officer with the United States Peace Corps in Turkey, 1986. With an office located in Sherman Oaks, and another year with the U.S. Indian Health Service Stephen has developed a successful practice that has on the Navaho reservation in Window Rock, Arizona. attended to the needs of the Gay & Lesbian community He went back to complete his residency in psychiatry for the past 14 years. at the Yale School of Medicine, returning to Denver In 1989, Stephen made it possible for L.A. Shanti for two years of private practice. He then became an to open its first San Fernando Valley office, making it Assistant Professor of Psychiatry at Yale, followed by an the first AIDS service organization to physically associate professorship in psychiatry at the University branch out into the Valley community. While serving of Tennessee College of Medicine in Memphis. as Clinical Director of the Community Consultation Dr. Matchett moved to the Los Angeles area in C e n t e r, he assisted a Los Angeles Unified School 1978, working for Kaiser Permanante, first at their D i s t r i c t school, Langdon Elementary, in developing Harbor City facility for several years, spending six an HIV Awareness program for fourth graders. years at their Panorama City facility and then practic- Stephen is a long-time volunteer with the Gay & ing at their Woodland Hills facility as Chief of Lesbian Community Service Center (G.L.C.S.C.). In Psychiatry for the next ten years. He left Kaiser’s 1985, along with his one-time associate Charles employ in 1996 to open his current private practice in Wilcox, he developed the first group therapy Sherman Oaks. approach in working with men who were HIV positive, known at that time as the “worried well”. He continues to volunteer his services to the G.L.C.S.C., see- Ver onica Matos ing low-fee clients on their referral and supervising Veronica joined our IRB M.F.C.C. interns. He has been an AIDS Project Los at the beginning of 1998. She Angeles volunteer since 1988, and an active member has just taken a position as of the San Fernando Valley Child Abuse Council Executive Director of since 1993. Gramercy Housing Group, a Stephen is currently working on his Doctorate in mid-city non-profit organiza- Psychology at Ryokan College in Santa Monica. He tion providing affordable has also written a book for children concerning issues housing and offering training of relationships and molestation, which he hopes to and counseling to young sin- have published in the near future. gle-parent families. She has a solid core of HIV knowledge

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S U M M E R / F A L L ’ 9 8 S E A R C H L I G H T 13

DEVELOPMENT NEWS

HO L I D A Y PROM OT I O N

Giv e the gift of hope— ‘98 Holiday Car d Cam p a i g n

IDS RESEARCH Alliance will repeat its popular and successful Holiday Card campaign for Athe eighth year in a row . Last year’s campaign brought in over $22,000 to support AIDS res e a r ch. This year our supporters will have four completely new designs to choose from as well as a favorite card from last year’s campaign.

esigner and illustrator Amy Dakos D donated her inspiring “Guardian Angel” for this year’s holiday card program. Rendered in dark, rich, saturated oil pastels, it depicts a young, sweet-faced angel reaching for a skyful of swirling stars. We are also offering a repeat of “City Star”, one of last year’s most successful cards, created and generously donated by Amy as well.

GUARDIAN ANGEL

C I T Y S T A R

eventeen-year-old Louella Hill produced the peaceful Sand serene holiday image “Still Window” especially for AIDS RESEARCH Alliance. This collage is rendered in soft greens, browns and reds and evokes the stillness of a snowy day seen from the comfort of a warm and well-lit room.

continued on page 14 STILL WNDOW

S E A R C H L I G H T S U M M E R / F A L L ’ 9 8 14

‘98 Holiday Card Campaign— continued from page 13

ur final new image comes from the O camera of Jayme Thornton. We came upon “Unknown Angel” by sheer chance and found it delightful—a street painter had decorated the side of a building with this exuberant color painting of an angel, and photographer Jayme Thornton captured it for our use.

he image for our third card Tcomes from Armond Bagdasarian, Creative Director of jazz record label MAMA Records, who photographed this deeply-muted color shot of a solitary candle in full flame. The photograph inspires us with the image of steady illumination possible from the light from just one small source.

e’d like to thank everyone who donated images to make the ‘98 Holiday Card Campaign a success. W Our thanks go to Ar men Baghdassarian of Alco Printing for design and production consultation. We’d also like to extend our appreciation to Len Hendry and Doug Wic h e r t of the Regency Fine Art Gallery for their tireless effo r ts in searching through the Regency collection for a likely illustration for our use. To order cards or for further information, call Karen J. Wellenkamp at (310) 358-2423.

S U M M E R / F A L L ’ 9 8 S E A R C H L I G H T 15

ABOUT THE ARTISTS

Ar mond Bagdasarian studio. They have a house in Tarzana where they The creative director live with their son Evan, age 7 and daughter Audrey, for MAMA Foundation/ 4 1/2. MAMA Records, a non- profit jazz archive record Louella Hill label in Studio City, At age 17, Louella is California, Armond took fairly new to both the busi- photos for Bobby Shew’ s ness of commercial illus- upcoming CD “Salsa tration and volunteerism. Caliente”. He shot this She created and gave to year’s poignant holiday card “Candle” especially for AIDS RESEARCH Alliance AIDS RESEARCH Alliance. the collage “Still Window” Armond was born in Teheran, Iran and moved while working as a nanny here with his family in 1979. He went to high school to a family on Lake in Van Nuys, California, and attended the University Winnipesaukee in New Hampshire. She will return to of Redlands and U C L A for music composition and her hometown of Bisbee, Arizona to attend her final piano performance. He has worked variously as a year of high school. typesetter, layout artist, designer, writer and editor; Louella was born and raised in Bisbee and has he employs all of these skills in his work at MAMA been drawing and painting as long as she can remem- Records. He studies photography and drawing while ber. She is quite an active letter writer, and began working full time. decorating and embellishing her letters with illustra- tions at a young age. Her interest and skills grew over Amy Dakos time, and now she anticipates seeking a career in the A freelance art director, art world. She plans on working on her portfolio designer and illustrator, starting in the fall and applying to art schools. Amy created and donated Her paternal grandfather is watercolor artist Tom last year’s popular “City Hill, and her father Christopher is an artist and iron- Star”; this year she painted smith. Louella attributes much of her present skill the unique “Guardian and interest in creating art to the life-long support of Angel.” She has given her mother, Patricia. freely of her work before to charitable institutions; she created the “Save the Rainforest” T-shirt that Jayme Thornt o n went on the Paul McCartney tour in 1990 and earned There are years when our staff has to search high almost a half million dollars for Friends of the Earth. and low for novel, interesting and appropriate artistic Born in Baltimore, Maryland, Amy moved to works for use in our holiday card campaign. And Southern California when she was six months old. sometimes we serendipitously stumble upon on image She attended UC Santa Barbara and graduated from that we feel is irresistible. It is through pure coinci- UCLA with a B.S. in sociology. She studied illustra- dence that we found this endearing image of an angel tion at the Art Center in Pasadena and design, print- painted on the side of a corrugated steel warehouse. making and illustration at California State University While we, through much investigative work, have dis- at Northridge. She has her own graphic design busi- covered that Jayme Thornton is the artist, attempts to ness, creating album covers and corporate identity contact him to learn more about his inspiration for and collateral for such clients as Walt Disney this piece have been unsuccessful. No matter...as we S t u d i o s, D r e a m w o r k s, MAMA Records, the G y p s y are content to enjoy this image as it is and have aptly K i n g s (Electra Records) and General Electric. Her named the piece “Unknown Angel”. We hope you husband, Walter Mladina, runs his own photography feel that it is as special as we do.

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DEVELOPMENT NEWS

CIRCLE OF HOPE David Hart, M.D. Alliance through the Grace Jones Edward J. Judd Richardson Trust in Atlanta. We IDS RESEARCH Alliance’s Arnold D. Kassoy offer our heartfelt thanks for their A1998 Circle of Hope Camp- James L. O’Connor consistent support of our work. aign is off to a successful start with Marion Rosenberg the addition of the following Carl Scott/Warner Bros. Records Video Industry AIDS Action donors. We express our deep Trimeris, Inc. Committee (VIAAC) appreciation for their generous Jeff Jenest, Chair of the VIAAC contributions towards our mission. RANTS Beneficiary Committee helped G AIDS RESEARCH Alliance secure FOUNDER’S CIRCLE a $5,000 unrestricted grant. ($25,000 AND ABOVE) $30,000 Anonymous P l a y b o y Vice-President Jeff Jenest Anonymous Foundation Grant is a member of APLA’s governing Estate of Matthew Rushton AIDS RESEARCH Alliance Board and a long-involved and received an anonymous founda- CHAIRMAN’S CIRCLE ardent supporter of AIDS tion grant to further our investiga- ($10,000—$24,999) research activity. We would also tion of lymphocytosis-promoting Michael Chang like to thank ARA Board member factors. Our thanks to them, as Estate of Paul R. Johnson Tim Engel, who was instrumental well as to Donald H. Smith, who in our receipt of this grant. PRESIDENT’S CIRCLE facilitated our receipt of this ($5,000—$9,999) grant. Christopher A. Marlett BEQUESTS Mr. and Mrs. David Payntner The Carr Foundation & H. Smith Richardson The Carr Foundation, a family Paul R. Johnson Estate (Grace Jones Richardson foundation started by Dr. Omar J. AIDS RESEARCH Alliance Trust) F a r e e d and Martha Carr Fareed, received $17,776.97 from the Thomas Schumacher awarded us a $1,500 grant to assist Estate of Paul Johnson. Paul had & Matthew White in expansion of our trials in been a donor since 1991, begin- Video Industry AIDS Southern California. We’d like to ning his association with us by Action Committee thank Dr. George Fareed f o r donating memorial funds in DIRECTOR’S CIRCLE assisting us with this donation. honor of ARA co-founder D r . ($2,500—$4,999) Paul Rothman. We wish to thank Debbie Avnet Michael Chang Mr. Johnson for remembering us Celgene Corporation AIDS RESEARCH Alliance in his will and express our appre- Tim Engel received a $10,000 gift from ten- ciation to his executrices V i c t o r i a Jeff Iorillo nis pro Michael Chang in support and Debra Cordano for expedit- Donald Schwartz of our clinical trials. This is the ing this bequest. Danilo Terribili /Allegro second such gift from Michael; he Partners, L.P. awarded us a similar unrestricted Matthew Rushton Estate FRIENDS grant of $10,000 in 1996. Our We received an additional ($1,000—$2,499) appreciation goes to Dr. George $45,021.15 in funds from the Es t a t e Larry Breeding Fareed for facilitating this award. of Matthew Rushton, one of AIDS Stephen Brown, M.D. RESEARCH Alliance’s founders George Fareed, M.D./The Carr Grace Jones and former Board of Director’s Foundation Ri c h a r dson Trus t Chair. This brings the total monies John Humphrey Gilbert Special thanks go to Mr. and received from this bequest up to Elliot P. Graham Mrs. David Payntner and H. Smith over $164,000. Richard F. Habic R i c h a r d s o n for a $5,000 unre- Matthew was the Executive & Mildred Naatz stricted grant to AIDS RESEARCH Producer of the blockbuster movie

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Mrs. Doubtfire, and passed away from complications arising from at the Beverly Center Macy’s AIDS in 1995. Our appreciation on Saturday, September 27th goes to William Zimmerman, and Sunday the 28th. trustee of Mr. Rushton’s estate and former ARA Board mem- Purchasers will also be entitled ber, for facilitating these dis- to 10% discounts at the West bursements. We also extend our Hollywood Sunset V i r g i n thanks and good wishes to Macy’s Passport Megastore. Matthew’s parents Marjorie and A I D S RESEARCH Alliance Arthur for their continued sup- will receive the $10 ticket pur- port of our work. Instore Event chase price, as well as an addi- IN-KIND IDS RESEARCH Alliance tional $3 per each ticket A will join several other Los redeemed through attendance Lowe Fox Pavlika Angeles AIDS organizations as at the Instore event. ARA will An employee at Lowe Fox participants in Macy’s Passport also receive an additional $3 P a v l i k a, a Manhattan-based Instore Event this fall. for each person checking in at advertising agency, saw one of Sponsored by H o m e Macy’s on Saturday or Sunday S e a r c h l i g h t’s recent advertise- Magazine, Metropolitan and then using their coupon at ments soliciting Macintosh H o m e Sports Illustrated computers and donated ten , a n d Virgin Megastore. assorted Macs, including Vanity Fair, in association with Macy’s will also host Pa s s p o r t LCIIs, Quadras and peripher- E v i a n, O d w a l l a and V i r g i n ‘98: “Different Together: An als. Our thanks to this charita- M e g a s t o r e, this event will sup- Evening of Fashion and ble firm and their Office port area AIDS groups, includ- C o m p a s s i o n ”, a V.I.P. fashion Services Manager D a v i d ing Being Alive, B i e n e s t a r show fundraiser with food and Greenwald, who facilitated this Latino AIDS Project, D r e a m live music on Saturday, much-needed donation. S t r e e t, Homestead Hospice September 26th in the evening, Peet’s Coffe e and Shelter, and the L o s including a special appearance We received 30 pounds of Angeles Gay and Lesbian by k.d. lang. “Different Together” organically-grown coffee from Center, among many others. is hosted by Founding Chair Pe e t ’ s , a Berkeley-based coffee Each participating group Elizabeth Taylor and Event Chair distributor that recently opened up shop here in Los Angeles. will sell special $10 discount Magic Johnson; proceeds benefit Our gratitude goes to Manager coupons entitling the purchas- numerous area AIDS organiza- Andrea Raynor and the gener- er to 15% off purchases for use ti o n s . ous folks at Peet’s for helping keep all of us here at ARA just a little bit more awake. We also wish to thank A d r i a n Stephen Wat k i n s OUR HEROES Van Deudekom of D i s n e y l a n d f o r his continuing efforts on our In another response to our behalf; Adrian has been tireless in S.O.S. for Macintosh comput- We would like to express our his solicitation of donations to ers, Stephen Watkins of Ve r t e x deep appreciation to D a n i l o AIDS RESE A R C H Alliance since his Ph a r m a c e u t i c a l s gave us a Mac Terribili, who has given us 10% of own first donation to us in 1994. powerbook with peripherals, the proceeds of three seatings A l t o helping us to keep linked to weekly in his restaurant Palato our network while on the move. since January of 1998, making a grand total of over $4,400 ❖ We offer our appreciation to this year. Mr. Watkins for this timely gift.

S E A R C H L I G H T S U M M E R / F A L L ’ 9 8 18

AIDS RESEARCH Alliance— New Talent to Meet the Challenges

ur regular Searchlight readers will have noticed that the volume of clinical res e a r ch being O conducted at AIDS RESEARCH Alliance has increased dramatically. Of course, this increa s e in activity has necessitated growing our staff. However, we remain committed to being a “lean and mean” operation. In fact, as our organization has grown and our staff size and level of activity has in c r eased, our administrative overhead expenses continue to decline on a percentage basis.

He attended Notre Dame High moved to Philadelphia, Pennsylvania S c h o o l, and at age 16, received a when he was ten. He attended the Macintosh Quadra 660AV; he start- University of Pennsylvania f o r ed his own internet account and communications, transferring to ran a Mac chat room. He left high Temple University and graduating school in 1997, passing his equiva- from their School of Radio, lency test that same year. He was Television and Film in 1989 with a hired as a full-time Technical B.A., with minors in sociology and Support Representative for English. During his senior year of E a r t h l i n k in Pasadena in February college, he substitute-taught at inner- of 1997 and worked there until he city schools for the Philadelphia pub- Joe Bergs t ro m began classes at Los Angeles Valley lic school system, as well as for the Ma n a g e r , Information Systems C o l l e g e, which he continues to Catholic Archdiocese of at t e n d . Ph i l a d e l p h i a . oe, a self-trained computer Carlo moved to San Francisco in Jwhiz, began work for AIDS October of 1989, where he began RESEARCH Alliance in February his long association with non-profit 1998. Since his arrival, Joe has organizations. He volunteered at overseen ARA’s computer system the Larkin Street Youth Center changes and upgrades and estab- for Homeless Youth, as well as at lished our in-house and external the Center on Juvenile and e-mail systems. At 19 years of age, Criminal Justice (CJCJ), and soon he is the youngest member of our after began a full-time position at s t a f f . CJCJ, starting in direct client ser- He was born in North vices and moving into administrative Hollywood and received his first work. He next worked for T e l l i n g computer (a Commodore 64C) at P i c t u r e s, creators of such films as age 7. He attended computer Carlo Danielson The Life and Times of Harvey Milk an d camp each summer at M e a d o w Co n t ro l l e r / O f fice Manager The Celluloid Closet, working in both Oaks in Calabasas for the next five production and post-production years, switching to Apple comput- Carlo started working for AIDS operations. His last position in San ers and pursuing his growing RESEARCH Alliance in April, Francisco was as Business and interest in computer technology 1998, and has been busy managing Systems Manager for the S a n and software. He was given a the foundation’s finances and Francisco International Film Macintosh LC for his 12th birth- supervising the extensive office re- F e s t i v a l, where he was responsible day and joined Prodigy network; organization precipitated by the for the fiscal planning and opera- by age 14, he had started experi- recent addition of numerous staff tions of the 1997 Festival, as well as menting with modems and begun me m b e r s . for oversight of the festival’s com- his own Bulletin Board System Brooklyn, New York is Carlo’s puter network design, installation (BBS). birthplace; however, he and his family and maintenance.

S U M M E R / F A L L ’ 9 8 S E A R C H L I G H T 19

Carlo moved to Los Angeles in combined interest in science and jobs until starting at Bank of December 1997 to find a position writing. Dr. Korotzer brings a America International Banking, in film production, but found him- strong science writing background where she was employed from 1974 self drawn back to non-profit to S e a r c h l i g h t, and contributes his until 1980. She developed an inter- employment; he plans to attend expertise in biology and basic sci- est in law and studied medical-legal school for non-profit management. ence to our clinical research devel- secretarial skills, working for vari- He is an avid film-goer and sup- opment. ous attorneys from 1980 until 1991, porter of independent films; he Andrew is an accomplished musi- acquiring many paralegal skills and also enjoys writing fiction. cian and likes to play blues guitar. increasing her secretarial capabili- ties. She studied micro-computer systems at the Computer Learning C e n t e r, and found she was drawn to social service and non-profit organizations, working at A m e r i C o r p s, the Glendale School S y s t e m and Bridges from School to Work, L.A. Helen lives with her husband Bernardino in Los Angeles. She enjoys playing piano, listening to music, reading, writing and watch- An d r ew Korot z e r , Ph.D. Helen Macias ing old movies. Di re c t o r , Scientific Re c e p t i o n i s t / Co m m u n i c a t i o n s / Administrative Assistant Ed i t o r , Search l i g h t Helen started working for ndrew began working as our AIDS RESEARCH Alliance in A Director of Scientific Commun- March of 1998; she was hired ications and S e a r c h l i g h t Editor in through the Career Planning June, 1998; he began his tenure at C e n t e r of Marina Del Rey. In AIDS RESEARCH Alliance by attend- addition to serving as our recep- ing and reporting on the XII World tionist and office assistant, Helen AIDS Conference in Geneva, translates many of our informed Switzerland. (Please see this issue of consent documents and public Searchlight, page 7.) relations material into Spanish. Michelle Simek He was born and grew up in the She was born in Mexico City, Clinical Research Assistant/ Bronx, New York, attending N e w Mexico, moving with her family to Patient Recrui t e r York University and receiving a Spain at age two and returning at B.A. in Psychology in 1985. He age 6, where she lived until she fin- Michelle joined our staff in the holds a Doctorate in the Biological ished high school. Born to a beginning of June, 1998 as Clinical Sciences from the University of German mother, Helen is multilin- Research Assistant and Patient California, Irvine, and completed gual, speaking both German and Recruiter. She will be expanding a post-doctoral position in molecu- Spanish in her youth. At age 16, our “Clinical Trials Priority lar biology at Colorado State she lived in Cuba for a year. She Notification Program” and building U n i v e r s i t y in Fort Collins, returned to Mexico City, married at our alliances with local physicians, Colorado. 19 and moved to Florida with her community groups and AIDS service His doctorate work was on the husband in 1965. In 1967, Helen organizations. She brings counseling pathological mechanism underly- and her husband moved to New skills, as well as Spanish expertise ing Alzheimer’s disease, which Jersey, where she gave birth to their and administrative skills to AIDS resulted in an impressive publica- son Edward. RESEARCH Al l i a n c e . tion record. After completing his Helen moved to Los Angeles in She was born in Chicago, Illinois, post-doc, he decided to pursue a 1971, working at various secretarial and moved to the San Francisco Bay

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ARA Staff— continued from page 19

area while still a baby; in 1980 she physical exams to patients, in addi- and her family moved to Los tion to coordinating several of the Angeles. She graduated from S a n t a clinical trials currently underway. AI D SRE S E A RC H Monica High School, and went on Michele grew up in New A L L I A N C E to attend Santa Monica College, Brunswick, New Jersey and moved transferring to University of to Milwaukee, Wisconsin to attend C a l i f o r n i a , Los Angeles and grad- Marquette University, receiving STAFF uating in 1993 cum laude with a her B.S. in biology in 1974. She B.A. in Spanish and departmental moved to San Francisco, California Chief Executive Officer ho n o r s . in 1975, worked as a lab assistant GRE G O R Y S. BRI T T After graduation, she found her- for Kaiser Hospital and attended self drawn to women’s issues, espe- the College of Marin in Kentfield, Director of Clinical Research cially those of health, and went to California for nursing. STE P H E N J. BRO W N , M.D. work as a pregnancy & birth con- After graduating from nursing trol options and HIV counselor at school in 1979, she moved to Medical Director Planned Parenthood. She went on Mission Viejo, California, working GEO R G E C. FAR E E D , M.D. to work for the American Lung as an R.N. at St. Joseph’s Hospital Director, Scientific Association as a program assistant. in the City of Orange until 1982. Co m m u n i c a t i o n s Michelle found the issue of HIV She re-located to Santa Monica, AND R E W KOR O T Z E R , PH.D . health compelling and missed California to enter the U n i v e r s i t y doing hands-on work in the com- of Southern California’s Assistant Director, Research Development munity; she felt that she could use Physician’s Program, graduating MIC H A E L SLA T T E R Y her HIV knowledge, counseling in 1983 with a P.A. certificate. and other skills to further our mis- From 1983 to 1988, Michele was Clinical Trials sion at AIDS RESEARCH Al l i a n c e . employed at the Santa Monica Co o r d i n a t o r / M n g r . She plans to continue her educa- H o s p i t a l’s Family Practice SER G I O COD I N A , R.N. tion and study for her Master’s Program teaching outpatient Degree in public health. medicine to medical residents. Clinical Trials Coordinator She is an avid reader and plays a She left in 1988 to practice outpa- MIC H E L E VER T U C C I , PA-C “mean game of air hockey”. tient medicine at Santa Monica Family Physicians. Manager, Information Systems In 1989, she joined M i c h a e l JOE BER G S T R O M Roth, M.D. in private practice in Santa Monica, focusing primarily Controller/Office Manager on HIV medicine; Dr. Roth’s prac- CAR L O DAN I E L S O N tice later merged with P a c i f i c Oaks Medical Group, where she Executive Assistant worked until 1996. She then KAR E N J. WEL L E N K A M P entered private practice with Doctors Phillip Musikanth a n d Clinical Research Assistant Cyril Gautier, where she worked COR I G A N CAS T R O until joining the staff of ARA. Michele Ver tucci, PA- C Michele lives with her partner Clinical Research Assistant/ Clinical Trials Coordi n a t o r Elliot, their five-year-old son Joshua, Patient Recruiter two dogs, three cats and two tanks MIC H E L L E SIM E K AIDS RESEARCH Alliance wel- of fish in Westchester, California. comed Michele to its clinical staff She enjoys reading, especially mys- Re c e p t i o n i s t in June, 1998. As a Physician’s tery novels, as well as walking and HEL E N MAC I A S Assistant, she is able to provide doing crossword puzzles.

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Meet the IRB— in Mobile, Alabama. He left Mobile for Charlotte, North Carolina to attend Davidson College, transfer- continued from page 12 ring after one year to begin his architecture studies at and experience, having worked in the field for the Auburn University in Auburn, Alabama. John graduat- last eight years. ed with a B.A. at the top of his class in 1973. She was born in San Juan, Puerto Rico and spent He began his professional career after graduation at her childhood and early school days in San Juan, the Atlanta architecture firm of Heery and Heery, leav- Trinidad and Tobago and the Fiji Islands. She moved ing in 1978 for La Jolla, California, where he opened to Wellington, New Zealand to attend V i c t o r i a his own office. John has designed for such clients as University, receiving a B.A. in psychology and sociolo- Forrest Gump director Robert Zemeckis, Penny gy in 1988. She returned to Fiji for a year at the M a r s h a l l, writer (Field of Dreams) Phil Robinson a n d Women’s Crisis Center in Suva. singer/songwriter Carole King. He also designed the Veronica moved to Boston, Massachusetts in 1987, Los Angeles A d v o c a t e headquarters with publisher working for several years at the United South End David Goodstein. Se t t l e m e n t , a multi-service community agency, where John is HIV positive and has been active in AIDS she became Childcare Supervisor. She came to Los and gay political and community work for many years. Angeles in 1989 and was employed by the Sickle Cell Disease Research Foundation as a Counselor and Health Educator, before working at AIDS Project Los Paul G. Tel l s t r ö m An g e l e s as an Intake Specialist. She next worked for Paul became a member the Valley Community Clinic as their Resource of our IRB in February of Coordinator and was promoted to Coordinator of 1998. He is Pastor of the Mt. HIV Services. In 1994, she took a position as the Lo s Hollywood Congregational Angeles Gay & Lesbian Center’s Deputy Director of C h u r c h in Hollywood, Health Services, and remained there until she became Ca l i f o r n i a . Project Angel Food’s Program Director in 1997. He was born in Syracuse, She has offered numerous presentations on lesbian New York. Later, he moved health care issues, HIV education and lesbian & HIV to Fayetteville and then issues for such conferences as the National Lesbian and Binghamton, New York, where he attended high Gay Health Association Annual Conference, the Na t i o n a l school. He traveled to Oneonta, New York to attend Latino Lesbian and Gay Organization Encuentro Hartwick College, and transferred after two years to Na c i o n a l , and the Los Angeles County Women and HIV Syracuse University, where he graduated in 1977 with Co n f e r e n c e . Ms. Matos has been a Board member of the a B.S. from the School of Visual and Performing Arts. Greater Los Angeles YWCA Lesbian Health Advisory He moved to New York City to pursue an acting B o a r d and the Susan B. Komen Breast Cancer career, working in stage, film and television commer- Fo u n d a t i o n and is presently a member of the Na t i o n a l cials, appearing with Rita Gam in a stage performance Latino Lesbian and Gay Organization Health Advisory of Chekov’s The Seagull, and touring with Jesus Christ, Gr o u p and the LAUSD Project 10 speaker’s bureau. S u p e r s t a r and Joseph and the Amazing Technicolor She currently resides in West Hollywood with her Dr e a m c o a t . He was invited to be a guest artist for the partner Amie and her son Sean. She says she “loves New Jersey State Council on the Arts in Atlantic City, being a mom”, is a great cook and is enthusiastic about where he coordinated the first Martin Luther King, Jr. music and books. event ever in Atlantic City. Paul met his partner of 13 years, Carl Whidden, in 1985 and they moved to Los Angeles, California in John Powell 1986. Paul became a member of the American Society John was a member of of Interior Designers and was involved in design and the first AIDS RES E A R C H home furnishings, which he did in conjunction with A l l i a n c e (then “Search Carl’s real estate firm Whidden Realty. Alliance”) IRB in 1990. He In 1994, Paul decided to return to school to earn his has maintained his own pri- Master of Divinity Degree, entering the C l a r e m o n t vate architecture practice School of Theology in Claremont, California. He was since 1978. licensed as a minister in 1995 at the First Congregational He was born and raised Church of Los Angeles, where he served an internship

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Meet the IRB— Therapy in 1994 and began private practice in Sherman Oaks, CA. He is a Certified Diplomate of the continued from page 21 American Psychotherapy Association and is a Doctoral and chaired their Board of Deacons from 1995 until Candidate in Clinical Psychology, having completed 1997. He graduated from Claremont with honors in his course work at Pacifica Graduate Institute in Santa 1997 and received the Claremont Distinguished Preaching Barbara, CA where he is currently finishing his disser- A w a r d. He was ordained as a minister at the First tation. James is also a founding partner of D i s p u t e Congregational Church of Los Angeles in 1997. Resolution Professionals, a divorce mediation service He is presently a doctoral candidate at Claremont, in Southern California. with his dissertion topic on “Homospirituality”. On June 7th, 1998, Paul was called as minister of the Mt. Hollywood Congregational Church, an “Open and Sy Young, M.D. Affirming, Just Peace” church of the United Church of Dr. Young has been a Christ. member of our IRB since 1997. He is a Board-certi- James E. Walton, MA, fied neurologist working in his Beverly Hills private M. F .C.C., D.A.P.A . practice; he worked with Another recent addition AIDS RESEARCH Alliance to our IRB, James is a as a consultant on G l a x o Licensed Family Therapist W e l l c o m e’s 1592U89 study with a private practice in for HIV-infected individuals with AIDS Dementia Sherman Oaks, California. Co m p l e x . He was born in Salem, Sy was born and grew up in the New York City area, New Jersey and later moved leaving after high school to attend Cornell University to Philadelphia, Pennsyl- in Ithaca, New York. He received a B.S. with vania with his family. After spending his childhood in Distinction in Biology from Cornell in 1982, and Philadelphia, he left to attend Dickinson College i n achieved his M.D. at S t o n y b r o o k in New York State. Carlisle, Pennsylvania where he was a volunteer for the He completed his general internship at Tufts New federally-sponsored W. I. C. program, assisting migrant England in western Massachusetts, and went on to fin- farming families in improving their living conditions. ish his residency in neurology at the University of He received a Bachelor of Arts in economics in 1982 Massachusetts in Worcester, Massachusetts. He contin- after spending his junior year studying sociology in ued his training by completing a neurology fellowship Medellin, Colombia. at UCLA. He continued his education at the A m e r i c a n He then began what he describes as his “communi- Graduate School of International Management i n ty-based private practice”, as well as running and teach- Glendale, Arizona and was awarded his Master’s in ing at the Outpatient Neurology Clinic at the V.A. International Management in 1984 after completing Medical Center in Sepulveda, California. He has vol- his studies at the European Business School i n unteered for numerous community projects and has Vesbadden, Germany and European Management spent the past ten years as the neurology consultant for Centre in Brussels, Belgium. the Venice Family Clinic. In 1985 and 1986 he served as a translator providing technical services as a Latin American Consultant for ❖ American researchers in Peru at the Cultural Ministry of Cuzco. He moved to Los Angeles and joined the Father Douglas Glassman was a member of the AIDS World Immunological Network as an administrative RESEARCH Alliance IRB for five years; for the last 3 years he assistant and attended the Third International served as Chairman. He resigned in the beginning of 1998 Conference on A.I.D.S. in Stockholm, Sweden. due to work-related obligations, and Stephen Fefferman, In 1991 he completed his Masters Degree in M.F.C.C. was voted in as Chairman. Marriage and Family Therapy from The California We thank Doug for his years of hard work and commit- Family Study Center (now known as The Phillips ment and wish him godspeed in his ministry at Saint Graduate Institute). He received his license in Family Monica’s Parish.

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“Bridging the gap” between science and the patient— Clinical Trials to Clinical Reality

BY ANDREW KOROTZER, PH.D. tative of the population in gener- prompt management of adverse al. Second, trial sites extend ser- effects as they arise. In general, The media hype surrounding vices to patients that can factor sites have a vested interest in the success of protease inhibitor- into the level of care. Third, liber- aggressively supporting their containing regimens as reported al analytical techniques can por- patients. This level of attention at the XI World AIDS Conference tray data in ways that appear to naturally has an impact on how in Vancouver has evolved into favor the regimen studied. participants handle their treat- somber reports from Geneva on Selection criteria for trials are ment regimen. the realities of drug resistance, often biased towards patients like- Another significant factor in compliance management, and ly to respond well to treatment. evaluating an anti-HIV drug is the adverse side effects in the general Inclusion criteria often require limit of detection of the viral load patient population. This “gap” is participants to be naïve to anti- assay used in the study. The highlighted by a recent report retrovirals. Conditions that could detection limits can vary by more which shows that participants of make adverse effects more likely than an order of magnitude, HIV+ clinical trial volunteers live longer than HIV+ patients in routine care. How could careful scientific investigation fail to accurately predict outcomes in the clinic? clinical trials live longer and are frequently grounds for exclu- depending on which assay is used. progress more slowly to AIDS than sion. The result is a relatively For example, Chiron’s “branched the average patient in routine healthy population (even taking chain DNA” test can quantify viral care (Ferrigno et al., 1997). Since CD4 counts and initial viral load load down to 400 copies per milli- the objective of clinical trials is to into account) that presents mini- liter of plasma, although a new identify strategies that are effec- mal drug resistance problems. version of this test just released tive in routine care, this disparity There is also a self-selection effect; for investigational use can go is cause for concern. How could patients who volunteer tend to be down to 50 copies/mL. Organon carefully-controlled scientific more proactive with their treat- Teknika’s NASBA test can detect investigation fail to accurately pre- ment. down to 80 or to 400 copies/mL, dict outcomes in the clinic? These selection biases imply depending on how much sample At a satellite symposium of the that many of those who respond is used. Roche’s FDA-approved XII World AIDS Conference spon- well in the context of a clinical Amplicor test can go down to 200 sored by F. Hoffmann-La Roche trial would have responded equal- copies/mL, although a newer, Ltd., Dr. Melanie Thompson of ly as well in a routine treatment experimental version of the test the AIDS Research Consortium of setting. There are also ways in called the Ultra Sensitive Atlanta, Georgia, presented an which participation in a study Amplicor can quantify HIV at con- excellent overview of the reasons actively improves the patient’s centrations as low as 50 why patients in clinical trials do care. Clinical trial sites provide copies/mL. better. She provided three gener- diligent attention to volunteers, A treatment regimen evaluated al arguments. First, participants including follow-up phone calls, with a detection limit of 400 in many studies are not represen- compliance monitoring, and copies/mL might work well

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Clinical Trials to Clinical Reality— continued from page 23 enough to be deemed successful, only the patients that actually There has been irrefutable but the clinical utility of this “suc- receive treatment for the full progress in the clinical manage- cessful” regimen might be mini- course of the study and tend to ment of HIV disease in the last mal. A recent report (Gunthard show the possible, not necessarily several years, and this progress et al., 1998) has shown that there probable, benefit of the treat- can be understood in terms of the is evidence of low-level viral repli- ment. This means that this analy- expanded possibilities for treat- cation in patients whose viral load sis technique ignores the data ments and our improved compre- was less than 400 copies/mL, but from patients who were non-com- hension of the biology of AIDS. higher than 20 copies/mL (mea- pliant, withdrew due to side Between Geneva and the XIII sured with especially sensitive mol- effects, or simply dropped out of World AIDS Conference in South ecular techniques). However, the study. On the other hand, the Africa, the challenge will be to patients with a viral load under 20 more conservative “intent-to-treat” complete the picture and trans- copies/mL showed no evidence of analysis includes all patients late that progress into better rou- ongoing viral replication. Since assigned to treatment groups, tine care. In addition to showing even low-level replication is associ- even those who had to drop out what’s possible to achieve in the ated with the eventual develop- during the study for any reason. treatment of HIV in clinical trials, ment of drug resistance, one Therefore, clinical trial results we look forward to seeing data might expect substantial differ- which present data utilizing an from these studies that better pre- ences in the durability of patient “intent-to-treat” analysis will more dict what is probable in the thou- responses to treatment when their accurately predict the clinical sands of patients who will take viral load is below 20, as opposed response of the general patient these drugs after the trials are to 400, copies/mL. population. completed. In a clinical trial, if a patient’s After Ziagen (Abacavir), Sustiva viral load goes down to the assay’s (Efavirenz),and Adefovir (bis-POM References detection limit, the patient is con- PMEA) receive FDA approval later Ferrigno L et al. (1997) Survival sidered successfully treated. If the this year (as expected), it will be and progression of disease in HIV- patient began with a viral load possible to prescribe anti-HIV infected individuals in interventional only 10-fold higher than the drugs in 1028 possible triple thera- treatment studies as compared to an observational cohort. 37th Interscience detection limit, that patient may py combinations. When you con- Conference on Antimicrobial Agents have experienced only a one log sider that 4, 5 and even 6 drug and Chemotherapy. Abstract I-179. drop in viral load. As a result, the combinations are becoming widely number of trial participants for prescribed, the number of possible Gunthard H et al. (1998) Human whom a regimen is successful can drug regimen configurations grows immunodeficiency virus replication depend substantially on the assay logarithmically. While some of and genotypic resistance in blood and used to test viral load. Certainly, these combinations will be studied lymph nodes after a year of potent an average patient in routine care in phase IV post-marketing trials, it antiretroviral therapy. Journal of can achieve a degree of viral would be impossible to study them Virology, 72:2422-2428. reduction consistent with that all. Against this backdrop, patients seen in studies and yet not go and their physicians are faced with below detectable limits. the challenge of constructing the In addition, clinical trial optimal regimen to meet the ❖ reports utilize different methods patient’s needs. The gap between of data analysis, which materially the published clinical literature affects the reported outcome. and the usual clinical experience “On-treatment” analyses consider complicates this task.

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Take Home Messages From Geneva— The Good, the Bad, and the Ugly

BY ANDREW KOROTZER, PH.D.

The entire spectrum of emotions could have been elicited by the presentations in Geneva, depending upon which information or data one chose to focus on. There was plenty to be hopeful about, and also some less than encouraging news. The chart on pages 26 and 27 outlines most of the major points in clinical and basic research to emerge from the meeting. These developments range from good to bad to downright ugly.

New targets, no drugs Life cycle targets: transcription is an inherently Many scientists acknowledge a brief primer complicated biochemical reac- that effective viral suppression will, For HIV to infect a cell, it first tion. The enzyme requires help in fact, ultimately require inhibi- attaches to the cell surface from other proteins, including tion of several steps of the viral life through specific chemical interac- nucleocapsid (NCp7), to work cycle simultaneously. (The viral tions (See “Preventative Medicine for effectively. The newly created life cycle refers to the series of Blood Cells”, page 29). Human pro- viral DNA must be integrated events necessary for a virus to teins called chemokine receptors into the cell’s DNA, a reaction infect cells and result in the pro- mediate these attachment events, catalyzed by the enzyme inte- duction of new live viruses). A which result in the injection of g r a s e . multi-pronged pharmaceutical viral RNA in association with viral Integrated viral DNA serves as approach is less likely to result in proteins into the cell. The attach- a template for the eventual pro- viral “breakthrough” due to the ment events represent a discrete duction of RNA that contains the development of drug resistance. step that is being investigated by same genetic information, a Currently available anti-HIV anti-HIV drug development labo- process known as transcription drugs target two enzymes (the ratories throughout the world. (the opposite process, the con- reverse transcriptase and the viral The next several steps of the version of viral RNA into DNA, is protease) that catalyze events life cycle are the conversion of called “reverse” transcription). that occur once a cell has been viral RNA into DNA, and the inte- This viral RNA is translated into infected. The remaining steps of gration of that DNA into the cell’s proteins that will serve in the cre- the life cycle are performed by a nucleus. New viral proteins can- ation of new viral particles. number of other proteins encod- not be manufactured until these Normally, RNA that is tran- ed by the virus’ genetic material. steps are completed. This work, scribed from DNA is chewed up Because each step in the life however, requires specialized viral by the cell after it has been trans- cycle is required for infection proteins (including several lated into new proteins. This cre- and subsequent viral replication enzymes), so these proteins enter ates a problem for the virus. It to occur, interference with any or the cell as a package along with must find a way to reproduce all of these steps will suppress the the RNA. itself in the form of newly tran- v i r u s . HIV must convert its RNA into scribed RNA and smuggle that Several new targets for thera- DNA because it utilizes normal RNA out of the nucleus. peutic intervention actively being cellular mechanisms for making Like worker bees taking care explored by scientists are listed in proteins from its genes, and cells of their queen, a group of pro- the chart on pages 26 and 27. store their genes in the form of teins are responsible for ensuring What follows is a brief description DNA. The well-known viral that newly transcribed viral RNA of where these targets fit in the enzyme reverse transcriptase cat- is escorted out of the cell nucleus viral life cycle. alyzes this reaction, but reverse and packaged into new infectious

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26 TAKE HOME MESSAGES

NEW TARGETS, NO DRUGS NEW DRUGS, OLD TARGETS Chemokine Receptors: We now have a much greater understanding of how chemokine receptors are utilized by HIV Preliminary data indicate that new drug to gain entry into and infect cells. combinations lacking a protease Identification of effective, non-toxic inhibitor (PI) may be as potent as a PI- chemokine receptor inhibitors is a top containing regimen. priority for most HIV drug development labs. None are in clinical trials yet.

There are a number of proteins that The "next generation" of drugs that are required by HIV to infect cells and inhibit reverse transcriptase and protease replicate. The molecular properties of appear to be much more potent than these proteins are being defined to great their predecessors. precision.

Preliminary data indicate that many of Examples include i n t e g r a s e, which inte- the "next generation" drugs will be at grates viral genes into the cell's DNA, least partially cross-resistant with their and nucleocapsid, which plays several sig- predecessors in the same drug class (ie. nificant roles in the viral life cycle. new PIs will likely be cross-resistant with old PIs).

Detailed study of these targets is a first step towards the development of agents that can potently inhibit their activity without affecting normal cellular activity.

Most experts agree that HIV must be Effective HAART without PIs may pro- attacked at numerous points of its life vide more options for salvage therapy by cycle in order to achieve optimal inhibi- staving off the development of resistance tion of viral replication. to the entire PI drug class.

Drugs for these targets may offer many PI-sparing strategies are not relevant for advantages over current drug classes, individuals who have already developed including potentially less drug resistance. PI resistance.

Individuals just now initiating therapy There are no drugs in human clinical tri- will have more potent compounds to als that inhibit these targets (excepting choose from and will be able to design one small study of an integrase inhibitor), therapies that will maximize future treat- meaning it will likely be at least several ment options. However, cross-resistance years until such compounds might be between new and old drugs of the same av a i l a b l e . class will impair options for those currently failing available drugs.

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TAKE HOME MESSAGES 27

OLD DRUGS, NEW PROBLEMS NEW OPPORTUNITIES, NEW CHALLENGES

Patients’ inability to comply with unwieldy treat- HAART improves the immune system's ability to ment regimens is a major contributor to sub-opti- deal with pathogens that may lead to opportunistic mal treatment outcomes (not achieving sustained infections. However, immune responses to HIV "undetectable" viral load) and to the development itself do not improve. Therefore, viral suppression of viral resistance to drugs. continues to require powerful anti-HIV drugs.

Viral strains that are already resistant to current medications are being transmitted to newly- When patients are treated with HAART within infected individuals—potentially leaving these weeks of infection, immune responses to HIV are "drug-naïve" patients with few or no treatment retained. options to begin with.

Resistance to a drug frequently confers partial to REMUNE™, an immune-based therapy, may complete resistance to other drugs of that class, enhance viral suppression by helping to re-direct leaving patients with few alternatives for salvage the immune system to better recognize HIV anti- therapy. gens.

Significant side effects, particularly for PI-containing regimens, are a growing concern and include IL-2, GM-CSF and possibly other cytokines or lipodystrophy (redistribution of fat in the body), immuno-therapies may help to rebuild immune kidney stones, liver problems, cardiovascular com- function lost to HIV. plications and neuropathy.

HAART, by reducing the continual onslaught of The challenges outlined above underscore the viremia which overwhelms the immune system, urgent need for new drugs for new targets and new makes the concept of immune restoration distinctly therapeutic concepts. possible.

Observations of improved immune function under HAART have led to improved understanding of how the virus causes immunodeficiency, leading to more rational strategies for immune reconstitution.

The clinical impact of the basic science advances will eventually be substantial for patients at all stages of infection, though its impact may not be felt in the immediate future.

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Take Home Messages From Geneva— continued from page 25 HIV. Nuclear export is handled side effects. comitantly with advances in other by a protein called r e v, which is The inadequacies of current areas. New reverse transcriptase being studied in molecular virol- drug choices notwithstanding, and protease inhibitors can be ogy labs, but for which an their achievements go beyond useful in this regard if they are inhibitory drug has yet to be that of extending the lives of a more potent than their predeces- developed. Another key protein number of infected patients. sors, and especially if they act on in these steps is NCp7. Because Antiretroviral therapy can sup- novel sites on these enzymes. NCp7 has several crucial func- press the virus sufficiently in some Regimens incorporating such new tions in the viral life cycle, it is a people to raise the possibility of drugs along with established anti- particularly favorable candidate reconstituting their immune sys- retroviral drugs can be improved for drug development. tems. Ongoing work might lead upon by determining drug combi- to immune–based therapies that nations that minimize adverse side New drugs, old targets. make possible the participation of effects and viral drug resistance. Old drugs, new problems. the patients’ own immune systems Opportunities are now avail- Nowhere is the mixture of in controlling the virus. These able to us to raise treatment possi- good and bad news more evident concepts are truly revolutionary, bilities to the next level. These than in the state of the art of anti- and are explored in detail in an opportunities are also challenges retroviral therapy. As noted in article entitled “The Immune to the scientific community, to The inadequacies of current drug choices notwithstanding, their achievements go beyond that of extending the lives of a number of infected patients. Antiretroviral therapy can suppress the virus sufficiently in some people to raise the possibility of reconstituting their immune systems.

the chart, current drug choices System Strikes Back,” in this issue methodically pursue multiple are associated with a myriad of (page 9). research strategies to achieve problems. In fact, the basic these goals. approach of antiretroviral therapy New opportunities, —suppressing the causative agent new challenges of AIDS—has brought us to a cul- It is becoming increasingly de-sac; at least for now this clear that solutions to the global approach will not produce the AIDS epidemic will require an cure for HIV/AIDS. New drugs effective attack on all fronts. are expected to be approved by Methods are required to break the FDA in the near future. They the viral life cycle at numerous ❖ act on the same targets as current- points. At the same time, it is cru- ly approved drugs, and won’t pro- cial that we seize the opportuni- vide long-term solutions. ties afforded us by current anti- However, they could potentially retroviral therapies for exploring offer relief from two particularly immune based approaches. ugly problems associated with pro- Therefore the pursuit of tease-inhibitor containing regi- improved antiretroviral medica- mens: drug resistance and severe tions needs to be continued con-

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Keeping HIV from infecting healthy cells— Preventative medicine for white blood cells

BY ANDREW KOROTZER, PH.D. this “co-receptor” is the same pro- Re-thinking the CD4/ tein that normally binds the sig- chemokine relationship urrently available treatments naling molecules known as Dr. Gallo suggests a conceptual Cfor HIV interfere with chemokines. shift in our understanding of the enzymes that the virus needs after Chemokines attract white roles of CD4 and chemokine recep- it has infected a cell. As Dr. blood cells to sites of inflamma- tors. In his view, CD4 represents a Robert Gallo, director of the tion. Macrophages and lympho- “facilitator” that helps HIV find the Institute of Human Virology, cytes differ in their responsiveness true receptor, the chemokine recep- pointed out in a talk at a plenary to various chemokines, and this is tor. This is based in part on studies session in Geneva, consideration due to the differential expression of some CD4- cells that are suscepti- is only now being given to cell sur- of chemokine receptor types. ble to HIV infection despite lacking face events as targets for therapeu- Because macrophages and helper CD4. Sugar residues known as gly- tic intervention. These cosaminoglycans on the events include the cell surface substitute for binding of the virus to Developing drugs that block viral attach- CD4 to promote viral the cell surface and the binding in these cases. subsequent fusion of ment to cells is not a straight-forw a rd Most types of cells the viral membrane express elaborate sugar with that of the cell, molecules on their sur- resulting in the injec- p rocess. However, there have been pro m i s- face that help the cell tion of viral RNA into interact with molecules the cell. Drugs that ing advancements in drug design. bathing it in the sur- block this process rounding fluid. One might offer advantages class of these sugars, the over current treatments, since T cells express different glycosaminoglycans, functions nor- recent evidence indicates that chemokine receptors, strains of mally to sequester chemokines HIV gene products can impede HIV differ in terms of the cell type from the blood to regions of the normal cellular activity even in they prefer to infect. M-tropic cell surface near their receptors, the absence of viral replication. virus readily infects macrophages providing a large local concentra- HIV primarily infects cells that via the macrophage-associated tion. Apparently, not only can gly- express the CD4 protein on their chemokine receptor known as cosaminoglycans direct chemo- surface. CD4 is expressed by CCR-5, whereas T-tropic virus kines to the chemokine receptors, macrophages and by a subset of readily infects helper T cells that but HIV as well. lymphocytes, the helper T cells. express the chemokine receptor Initial viral attachment can be Since HIV binds to the CD4 pro- CXCR-4. to either CD4 or to glycosamino- tein, and CD4+ cells are lost in For those infected through sex- glycans—but either way HIV must AIDS, CD4 has been thought to ual transmission, macrophages in then bind to the chemokine recep- be the primary receptor mecha- the mucosal lining where the virus tor. For this reason, Dr. Gallo sug- nism for binding and entry into enters are the first cells to be gested that we raise the status of cells. infected. For this reason, M-trop- chemokine receptors from “co- But there are cells that express ic virus predominates early in the receptor” to “real” receptors. CD4 and yet cannot be infected course of infection. The muta- by HIV. This means that CD4 is tions necessary to confer T-tro- Blocking viral binding to not in itself sufficient to allow pism require a long time to devel- chemokine receptors. infection, and that HIV must find op. Eventually T-tropic strains Given the primary role of a second attachment point on the emerge and this is associated with chemokine receptors in the bind- cell surface. We now know that progression to AIDS. ing of HIV to cells, it is not sur-

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Preventative medicine for white blood cells— continued from page 29

prising that identifying com- the pharmacological constraints The chemical structures of pounds to block that binding for developing chemokine recep- chemokines need only minor event is a priority in many HIV tor drugs are more approachable modifications to abolish their sig- drug development laboratories. for a single receptor than for sev- naling properties while retaining Since the target of such com- eral receptors. their affinity for binding to their pounds are cell-associated rather However, selectively blocking receptors. And in a report cur- than viral proteins, it is assumed CCR-5 could place selective pres- rently in press, a graduate student that there would be minimal sure on the virus population to named Jennifer Burns in collabo- problems with viral resistance to mutate more rapidly toward the T- ration with Drs. Tony DeVico and such drugs. tropic strains that are associated George Lewis in Dr. Gallo’s lab But developing drugs for this with progression to AIDS. show that incubation of target is not an easy or straightfor- Whether such mutations would chemokines with an excess of gly- ward process. Normal inflamma- actually occur remains an unan- cosaminoglycans forms a large tory responses require chemokine swered question, and may not be molecular complex that increases receptor activation. Drugs known without clinical testing of a the antiviral action of the designed to block HIV binding to potent CCR-5 receptor blocker. chemokines while blocking signal- these receptors might interfere A further complication is that ing. with normal immune functioning the simple M-tropic/T-tropic Inhibition of viral attachment is if these drugs also block dichotomy is not absolute. Other the next great frontier in the chemokines from binding. chemokine receptors are expressed development of anti-HIV com- Aberrant signaling that compro- by macrophages and helper T cells pounds. Given the difficulties of mises cellular function can occur that also allow HIV binding. There attacking this target, it is perhaps if a compound blocks HIV bind- are also “promiscuous” strains of not surprising that no lead com- ing but activates the chemokine HIV that are functionally dual-trop- pound is currently ready for the receptor. A good drug for this ic; they can infect macrophages clinic. But for cells as well as for target will therefore have a phar- and helper T cells equally well. people, preventing the initial macological profile of blocking Promiscuous HIV, like T-tropic infection will be an integral part HIV binding to the chemokine strains, is associated with faster pro- of the solution to HIV/AIDS. receptor yet allowing access for gression to AIDS. chemokines to the receptor, while Two “natural” experiments not activating the receptor itself— argue that blocking CCR5 will not a tall order for a compound to accelerate disease progression. achieve. People born with a mutant copy Studies have shown that mice of the CCR5 gene do not exhibit can develop and live quite nor- faster progression to AIDS than mally and not experience any those with normal CCR5. Those apparent immune deficits without who naturally overproduce the the CCR-5 receptor, implying that chemokines that bind to CCR5 do ❖ blocking this receptor might not not progress to AIDS faster than compromise patients’ health. those with normal chemokine Since the strains of virus that are production. Both findings are usually transmitted from person contrary to what one would to person are M-tropic and utilize expect if the virus population was this receptor, it might seem that being forced to become T-tropic CCR-5 is a particularly promising or promiscuous by the unavailabil- therapeutic target. In fact, a num- ity of CCR5. ber of researchers have been There have also been promis- focusing on CCR-5, mindful that ing developments in drug design.

S U M M E R / F A L L ’ 9 8 S E A R C H L I G H T GENEVA

Immune System Strikes Back— continued from page 10 There are no data on whether Response Corporation, aims to adult dose (4 children, 100 µg) of a sufficiently vigorous immune restore HIV-specific immune REMUNE™, and followed for 18 response could allow patients on responses. It contains an inactivat- months. For both groups of chil- HAART to safely go into a more ed virus that lacks the viral enve- dren, viral load had dropped con- relaxed treatment regimen. lo p e . siderably as a result of the anti- However, a recent animal study The T lymphocytes from the retroviral drugs. However, the suggests that when HIV-immuni- patients in the REMUNE™ group children given the low dose of ty is spared with antiretroviral exhibited significantly greater pro- REMUNE™ experienced viral treatment of primary infection, liferative responses to recall anti- rebound, a result consistent with a therapy might not be needed gens from a variety of HIV strains regimen lacking a protease indefinitely. In one experiment, (clades). In previously published inhibitor. Importantly, the 4 chil- macaques were inoculated with data, it had already been shown that dren given the adult dose of HIV-2 and provided immediate responses to p24 antigen were REMUNE™ did not experience treatment with d4T. Viral loads boosted by REMUNE™. P24 is well- viral rebound during the 18 remained low and CD4 counts conserved across viral strains, so this months of the study. Although never declined. When the result itself implies that cross-clade this study involved a small number macaques were removed from responses could be elicited. More of patients, it does suggest that an treatment after 16 weeks, CD4 direct evidence for cross-clade immune based therapy can help counts stayed high and viral load action was presented in Geneva. maintain the low viral load estab- never increased. The virus used in REMUME™ con- lished initially by antiretroviral The macaque study must be tains clade G p24 and clade A enve- therapy, under conditions where interpreted cautiously. For one lope, and yet it boosted the prolifer- failure was likely to occur other- thing, it is a study of macaques, ative response to BaL antigen wise. and non-human primates do not derived from clade B virus. The hype following the XI respond to HIV as humans do. World AIDS Conference in Also, although helper cell “The role of HIV-1 specific immune Vancouver included the belief that HIV could be eradicated responses to HIV are correlated based therapies is to enhance T helper with good viral control, correla- from an infected person’s body. tion does not prove cause and and CD8 effectors against the virus. We now know that eradication effect. But if we assume that a This should translate clinically into cannot be accomplished with potent immune response can prolonged viral suppression for HAART alone. However, recent investigations of long-term non- participate in HIV suppression, patients on HAART,” says Dr. the question is whether it can be progressors and those treated dur- induced in patients with Ronald Moss of the Immune Response ing primary infection show that advanced infections. Corporation. eradication may not be necessary for immune reconstitution. Training the immune system to HAART has not been an ultimate control HIV In Geneva, Dr. Ronald Moss solution to the epidemic. But by In a “late-breaker” session in of the Immune Response clarifying the role of the immune Geneva, Dr. Fred Valentine of New Corporation presented data from system in its own defense against York University Medical Center a small study that extends these HIV, and establishing the first presented data from a 43 patient findings of enhanced HIV-specific necessary condition (viral suppres- double-blind multi-center study, in responses to improved viral sup- sion) for immune reconstitution, which lymphocytes from patients pression. Nine HIV-positive chil- HAART has provided a window of receiving HAART alone were com- dren who were being treated with opportunity for developing better pared to those from patients receiv- AZT and ddI (at the time, the pre- weapons against the virus. ing HAART plus REMUNE™. ferred antiretroviral therapy for REMUNE™, developed by the late children) were given either a low ❖ Dr. Jonas Salk at the Immune dose (5 children, 25 µg) or an

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