WINTER 2007 | VOLUME 17, No. 2 AIDS RESEARCH SEARCHLIGHT ALLIANCE A NATIONAL LEADER IN FAST-TRACK AIDS RESEARCH In This Issue– 2 Message from the CEO 3 News and Views 5 HIV Viral Reservoirs: Barriers to a Cure 10 Viral Eradication: A Continuing Debate 12 Measuring The HIV Reservoir 14 Current Research and Clinical Trials at ARA 16 Can Animals Help? 17 Interview with Robert Siliciano, M.D., Ph.D. 18 Health Literacy: A Tool for People Living With HIV/AIDS 20 AIDS Research Alliance Welcomes New Members to the Board of Directors 21 Friends of AIDS Research Alliance Busy This Fall 25 An Evening with Nobel Laureate David Baltimore, M.D.M.D. 27 Combined Federal Campaign (CFC) THE CHALLENGE OF EMPTYINGEMPTYING THE HIV RESERVOIRRESERVOIR MESSAGE FROM THE CEO SEARCHLIGHT HIV VACCINE RESEARCH: A RISKY BUSINESS NEWS FROM AIDS RESEARCH ALLIANCE A NATIONAL LEADER IN FAST-TRACK AIDS RESEARCH AIDS RESEARCH ALLIANCE was one of the clinical sites for the Merck vaccine study that recently was halted by the Data Safety Monitoring Board (DSMB). In VISION collaboration with the National Institute of Allergy and Infectious Diseases AIDS Research Alliance (ARA) envisions a future in which HIV and (NIAID) and the HIV Vaccine Trials Network (HVTN), Merck conducted a its effects on health are eliminated, and new infections are prevented. MISSION STATEMENT phase IIb study of an aden- ovirus (common cold) based AIDS Research Alliance exists to develop a cure for HIV/AIDS, medical modalities to prevent new infections and better treatments vaccine designed to stimulate for those living with HIV. cell mediated immunity in RESEARCH BUSINESS MODEL healthy patients at higher risk The core areas of the AIDS Research Alliance non-profit research of contracting HIV. The clini- model include: 1. Independent clinical research, without regard to profit. cal trial of the vaccine was ter- 2. Clinical trials for innovative anti-HIV technologies and treat- minated prematurely when ments, and for vaccines, microbicides and other biomedical pre- vention research. data from the trial showed that 3. The development of treatments for HIV-related conditions. it was not effective in prevent- 4. Collaborations and strategic partnerships with other scientific organizations (including academic institutions, biotech and phar- ing HIV infection (compared to maceutical companies and governmental agencies). patients on placebo). Nor did it lower the viral load in patients who contracted EDITORIAL BOARD HIV during the course of the study. As one of the investigative sites for the Stephen J. Brown, MD Merck study, AIDS Research Alliance will continue to follow up with study vol- Carolyn H. Carlburg, JD Vincent M. Cummings unteers who participated in the trial. Marjan Hezareh, PhD Due in large part to our involvement in the clinical trial, AIDS Research Ava Lena Waldman, MHS Alliance was hopeful that the Merck vaccine candidate — one of about 30 HIV MANAGING EDITOR & PRODUCTION COORDINATOR vaccines currently in clinical trials — would demonstrate some degree of effec- Bernice Schacter, PhD tiveness of the underlying concept of cell mediated immunity. The fact that it did CONTRIBUTORS not is troubling because the majority of vaccine candidates currently in clinical Marc Borzelleca Herminio R. Reyes, PhD trials are based on the same concept. But the failure of the Merck vaccine should Stephen J. Brown, MD Peter Salveson be placed in perspective. One of the most respected scientists in the field, Dr. Marjan Hezareh, PhD Bernice Schacter, PhD Donald Herman Dave Schwep Anthony Fauci, the Director of NIAID, which is part of the National Institutes of Joe Jennings Lisa Vasey Health (NIH), framed the issue when he said, “Clearly this [the termination of ART DIRECTOR & ART PRODUCTION the Merck study] indicates the failure of a product. Whether or not it indicates Chris Davies / Shout, Inc. the failure of a concept, we don't know at this point.” PRE-PRESS & PRINTING Other leading scientists have weighed in on the issue. Dr. David Baltimore, Southwest Graphic Services Nobel Laureate for the shared discovery of reverse transcriptase, and former Searchlight is published for the medical research and HIV community president of the California Institute of Technology, recently said, “If you are by AIDS RESEARCH ALLIANCE, a California nonprofit corporation which is solely responsible for its content. Noncommercial reproduction is going to think about the most complicated issues in science, then you must be encouraged, provided the appropriate credit is given. prepared to be wrong. That doesn't ameliorate the awful disappointment at the CIRCULATION: 16,000 failure of the phase IIb Merck HIV vaccine trial…The greatest difficulty facing COPYRIGHT © 2007 AIDS RESEARCH ALLIANCE ALL RIGHTS RESERVED. vaccine researchers has been that none of their laboratory subjects (chimpanzees ISSN 1932-2526 and/or mice) are affected by HIV in precisely the same way as humans, making AIDS RESEARCH ALLIANCE it nearly impossible to tell how a vaccine will work in a human population.” 621-A North San Vicente Blvd. West Hollywood, CA 90069 This is not the first time that HIV vaccine research has suffered a major TAX I.D. 95-4264845 setback. In 1999, AIDS Research Alliance was a leading investigative site for the Telephone: (310) 358-2423 first Phase III preventative HIV vaccine candidate, VaxGen. In that case, the Fax: (310) 358-2431 underlying concept was that certain antibodies could be produced that would www.aidsresearch.org [email protected] confer immunity against HIV. When VaxGen failed, as AIDS Research Alliance @ Medical Director Stephen J. Brown has pointed out, “there was more informa- PRINTED ON RECYCLED PAPER continued on page 26 2 WINTER 2007 | SEARCHLIGHT NEWS AND VIEWS 4TH INTERNATIONAL AIDS SOCIETY IAS CONFERENCE ON HIV PATHOGENESIS, TREATMENT AND PREVENTION, SYDNEY, AUSTRALIA, JULY 22-25, 2007 HIV Antiretrovirals in Pipeline 2007 CLINICAL TRIAL NAME COMPANY PHASE TYPE PATIENTS Raltegravir Merck Co Approved Integrase inhibitor* Treatment naïve and (Twice daily) experienced with multi- drug resistant Elvitegravir (GS-9137) Gilead Phase III Integrase inhibitor Treatment naïve and (Once daily) experienced with multi- drug resistant Rilpivirine (TMC278) Tibotec & J&J Phase III NRTI** Treatment naïve Maraviroc Pfizer Approved CCR5 inhibitor *** Treatment naïve and experienced with multi- drug resistant Vicriviroc Schering Plough Phase II CCR5 inhibitor Treatment naïve and experienced Pro 140 Progenic Phase I CCR5 monoclonal Treatment naïve and antibody experienced Etravirine (TMC125) Tibotec and J&J Phase III NRTI Treatment experienced Bevirimat (PA-457) Panacos Stopped due to lack of Maturation inhibitors Not Determined correct formulation **** continued on next page SEARCHLIGHT | WINTER 2007 3 NEWS AND VIEWS continued from page 3 CLINICAL TRIAL NAME COMPANY PHASE TYPE PATIENTS TNX-355 Tanox Stopped due to dosing CD4 monoclonal anti- Not Determined issue body ***** BILR-355 Boehringer Ingelheim Phase I NNRTI ****** Not Determined Racivir Pharmasset Phase II NRTI Treatment-experienced Lamivudine-resistant virus Reverset Pharmasset Phase II NRTI Treatment-experi- enced, NRTI-resistant virus Amdoxovir RFS Pharma Phase II NRTI Treatment-experi- enced, NRTI-resistant virus Apricitabine (AVX754) Avexa Phase II NRTI Treatment-experi- enced, NRTI-resistant virus Elvucitabine Achillion Phase I NRTI Not Determined pharmaceuticals * The enzyme Integrase is required for productive infection of target cells and assembly of progeny virions. ** Nucleoside Reverse Transcriptase Inhibitor, blocks replication of the virus. *** CCR5 is a receptor for entrance of HIV into macrophages and some T cells. **** Maturation inhibitors prevent HIV from properly assembling and maturing, from forming a protective outer coat, or from emerging from human cells. ***** CD4 is a receptor that HIV uses to infect T cells. ****** Non-nucleoside Reverse Transcriptase inhibitor blocks replication of the virus. 4 WINTER 2007 | SEARCHLIGHT BASIC SCIENCE HIV VIRAL RESERVOIRS: BARRIERS TO A CURE Since 1996, remarkable advances in the Inhibitors, Protease Inhibitors and Entry/Fusion Inhibitors. treatment of human immunodeficiency Different combinations of three or more of these drugs, virus (HIV-1) have decreased progres- known as highly active antiretroviral therapy (HAART), sion to AIDS and the death rate among produce sustained suppression of viral replication in most HIV positive patients. Four classes of patients. Prolonged viral suppression raised hope for virus antiretroviral medications are currently available for the eradication. However, in 1997, three separate research treatment of HIV: Nucleoside Reverse Transcriptase groups, using sensitive co-culture techniques, were able to Inhibitors, Non-nucleoside Reverse Transcriptase recover replication competent HIV from purified CD4+ lymphocytes of patients on long-term HAART, despite BY MARJAN HEZAREH, Ph.D. prolonged undetectable virus in the plasma (<50 Dr. Hezareh has been AIDS Research Alliance’s Scientific copies/mL) [1-3]. The first estimation of the half life of Director since 2001. these reservoirs demonstrated that the reservoir decays SEARCHLIGHT | WINTER 2007 5 very slowly, with a long half-life of 44 months in patients needed. To this end, it is worth examining the nature of on HAART with sustained viral suppression for 7 years, viral reservoirs. rendering the eradication of HIV infection impossible with A latent reservoir is defined as a cell type or anatomical currently available