Friends of Aids Research Alliance Stay Busy This Fall

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 adenovirus (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 prevention 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-experienced, NRTI-resistant virus

Amdoxovir RFS Pharma Phase II NRTI Treatment-experienced, NRTI-resistant virus

Apricitabine (AVX754) Avexa Phase II NRTI Treatment-experienced, 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 antiretroviral drugs [4]. However, a site in which a form of the virus persists, without actively recent study showed that in patients who initiated antiviral producing virus while retaining the capacity to do so. therapy early in infection, the reservoir half-life was esti- The best-characterized cellular reservoirs for HIV are mated to be 4.6 months. Therefore, it would take 7.7 years resting memory CD4+ T-cells. The establishment of laten- of continuous therapy to completely eliminate latently cy in these cells and its stability are consistent with the infected resting CD4+ T-cells in these individuals [5]. biology of memory CD4+ T-cells [6,7]. In an HIV-infected individual, some HIV-infected CD4+ T-cells may survive THE NATURE OF THE VIRAL both the cell killing effect of the virus and the HIV specific RESERVOIR immune responses, and enter a resting state with HIV-1 provirus in their genome (Figure 1) [6,7]. The transcription Since the long term use of HAART is associated with of HIV genes, the conversion of the DNA form into infec- metabolic disorders, and considering that HIV medications tious RNA virus particles, depends on the activation state are costly, development of new strategies or therapeutic of CD4+ cells. The integrated HIV DNA is transcription- agents targeting elimination of viral reservoirs are urgently ally silent in these cells, and therefore unaffected by

Antigen IL-7 OKT3 Prostratin

Figure 1. The mechanism of HIV infection and establishment of latency in resting memory CD4+ T-cells. The antigen-activated CD4+ T-cells are the primary targets of HIV infection. The productively HIV-infected CD4+ T-cells generally die within a few days due to direct cell killing effect of the virus or the cell killing immune mechanism. But some HIV-infected CD4+ T-cells may survive longer to revert to a resting state with integrated HIV DNA proviruses in their genome, thereby establishing a stable latent reservoir of HIV in resting memory CD4+ T-cells.

6 WINTER 2007 | SEARCHLIGHT HAART. Once these cells encounter a protein or carbohy- major concern with phorbol esters as possible therapeutic drate capable of stimulating an immune response, they agents is their ability to promote the development of become activated and begin to produce virus. The stability tumors. Prostratin (12-deoxyphorbol 13-acetate) is a rela- of HIV reservoirs is consistent with long-term survival of tively water soluble phorbol ester, which displays the memory CD4+ cells (over 20 years), the presence of wild- unique characteristic of non-tumor promotion [19-21]. The type and drug-resistant HIV strains in reservoirs, and the unique biological activity of prostratin is due to the lack of hypothesis that a low level of virus replication is continuous- hydroxyl group at the C12 position [21]. Prostratin and ly reseeding the reservoirs in patients on HAART [6,8-11]. other water soluble phorbol esters inhibit HIV infection It is noteworthy that other potential cellular (e.g., and stimulate HIV replication in latently infected cells monocytes and dendritic cells) and anatomical reservoirs [18,19,22,23]. Thus, the lack of tumor promotion of pros- (e.g. central nervous system) may exist, but have not yet tratin, coupled with its dual activity on HIV infection been fully characterized. (antiviral and activator of HIV provirus DNA), makes this compound a candidate and prototype for development as a POTENTIAL STRATEGIES TO new class of anti-HIV drug targeting viral reservoirs [24]. ELIMINATE VIRAL RESERVOIRS In 2001, AIDS Research Alliance inlicensed prostratin from the National Institutes of Health. Most of the pre-clinical Since the discovery of viral reservoirs, several HIV studies required for submission of an Investigational New reservoir elimination strategies have been investigated. Drug Application (IND) to the Food and Drug Admin- One strategy involves the activation of HIV replication in istration (FDA) for prostratin have been performed, and latently infected cells in the continued presence of submission in 2008 is planned. HAART. The rationale for this strategy is that such cells Kulkosky and colleagues investigated HAART intensi- will die more rapidly due to the cell killing effect of the fication in order to eliminate the low level of HIV replica- virus or will present viral components on their surfaces. tion responsible for replenishing the viral reservoirs in This in turn will make them more detectable by the patients with undetectable plasma viremia [25]. They immune system and/or render them more susceptible to showed that in patients with an undetectable plasma viral targeted destruction by the immune system cell toxins and load (<50 copies/mL), intensification of HAART (addition other potential therapeutic agents designed to bind selec- of Didanosine and hydroxyurea) and simultaneous stimu- tively to viral products. Most attempts to activate latently latory therapy using OKT-3 and IL-2 can alter the HIV infected cells have focused on immune system signal proviral reservoir in vivo, but full eradication and elimination teins, cytokines such as the T-cell growth factor IL-2, of reservoirs could not be achieved. lipopolysaccharides (complex lipid, sugar and immune sys- A new approach to eliminate viral reservoirs was tem activators from bacteria), and anti-CD3 antibodies investigated by Shen and colleagues, who showed that in a (OKT-3) [12-14] . However, most if not all of these agents macaque/simian immunodeficiency virus (SIV) model for are highly toxic and have undesirable side effects due to HIV-1 latency, proviral DNA can be activated through the damage to the immune system [6,15]. Recently an in vitro co-stimulatory CD2 pathway of T-cell activation without study with the immune system signal protein Interleukin the engagement of the T-cell receptor (TCR) with the (IL-7) showed promise since IL-7 is able to activate latent Major Histocompatibility Complex (MHC) [26]. This reservoirs without stimulating T-cell replication and prolif- approach may eliminate undesirable side effects due to eration [16,17] global activation of the immune system. Another agent that has shown promise with cultured Another strategy investigated by Lehrman and col- cells is prostratin. Prostratin was initially isolated as the leagues was based on the mechanism that restricts HIV active constituent of extracts of the tropical plant, expression in latently infected cells [27]. Several studies Homalanthus nutans, used in traditional Samoan herbal showed that changes in the cell’s DNA and associated pro- medicine for the treatment of “yellow fever” (i.e., hepati- tein might decrease transcription of HIV. They hypothe- tis) [18]. Prostratin is a 12-deoxyphorbol ester and an acti- sized that binding of specific transcription factors to the vator of the enzyme protein kinase C (PKC) [18]. The HIV-1 Long Terminal Repeat (LTR), the sequence of DNA

SEARCHLIGHT | WINTER 2007 7 at either end of the latent virus, may recruit the enzyme, a reservoir for HIV-1 in patients on highly active antiretroviral ther- histone deacetylase 1 (HDAC 1). Inhibition of HDAC leads apy. Science 1997;278:1295-1300. 3 Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina to induction of HIV gene expression in latently infected CA, Richman DD: Recovery of replication-competent HIV despite cells [28-30]. A recent pilot study investigated the effects of prolonged suppression of plasma viremia. Science 1997;278:1291- an HDAC inhibitor, valproic acid (VA), administered in 1295. conjunction with HAART and enfurvitide in four HIV pos- 4 Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick itive patients [27]. The frequency of replication-competent JB, Kovacs C, Gange SJ, Siliciano RF: Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting HIV in resting CD4+ cell declined in 3 out of 4 patients. CD4+T cells. Nat Med 2003;9:727-728. The authors suggested that such an approach in combina- 5 Chun T-W, Justement JS, Moir S, Hallahan CW, Maenza J, Mullins tion with intensified HAART might eliminate viral reser- JI, Collier AC, Corey L, Fauci AS: Decay of the HIV reservoir in voirs in suppressed patients (viral load < 50 copies/ml). patients receiving antiretroviral therapy for extended periods: However, another study in patients with undetectable Implications for eradication of virus. J Infect Dis 2007;195:1762-1764. 6 Blankson JN, Persaud D, Siliciano RF: The challenge of viral reser- plasma virus levels continuously receiving valproic acid (3 voirs in HIV-1 infection. Annual Review of Medicine 2002;53:557-593. months) did not show any decrease in the number of 7 Pierson T, McArthur J, Siliciano RF: Reservoirs for HIV-1: latently infected cells [31]. These authors noted several dif- Mechanisms for viral persistence in the presence of antiviral ferences between the two experimental approaches that immune responses and antiretroviral therapy. Annual Review of might account for discrepancy of results, including the use Immunology 2000;18:665-708. 8 Chun TW, Lucy Carruth, Diana Finzi, Xuefei Shen, Joseph A. of enfurvitide, the concentration of valproic acid adminis- DiGiuseppe, Harry Taylor, Monika Hermankova, Karen Chadwick, tered, and assays to detect latently infected cells. Further Joseph Margolick, Thomas C. Quinn, Yen-Hong Kuo, Ronald studies investigating long-term follow-up effects of val- Brookmeyer, Martha A. Zeiger, Patricia Barditch-Crovo & Robert proic acid are needed. F. Siliciano: Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection Nature 1997;387:183-188. FINAL REMARKS 9 Ruff CT, Ray SC, Kwon P, Zinn R, Pendleton A, Hutton N, Ashworth R, Gange S, Quinn TC, Siliciano RF, Persaud D: The presence of HIV latently infected cells constitutes Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pedi- a barrier to a cure for HIV. Understanding the mechanism atric patients with extensive antiretroviral exposure. J Virol of latency will allow us to investigate novel strategies tar- 2002;76:9481-9492. geting viral reservoirs without producing life-threatening 10 Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F, damage to the immune system. To accomplish this, we Macken CA, Perelson AS, Markowitz M, Ho DD: The decay of the latent reservoir of replication-competent HIV-1 is inversely correlat- need an appropriate in vitro model to investigate the mech- ed with the extent of residual viral replication during prolonged anism of latency and an in vivo model where various elimi- anti-retroviral therapy. Nat Med 2000;6:82-85. nation strategies can be tested and validated. Viral reser- 11 Bailey JR, Sedaghat AR, Kieffer T, Brennan T, Lee PK, Wind-Rotolo voirs act as an archive of HIV drug resistance in latently M, Haggerty CM, Kamireddi AR, Liu Y, Lee J, Persaud D, Gallant infected cells and can compromise treatment options. JE, Cofrancesco J, Jr., Quinn TC, Wilke CO, Ray SC, Siliciano JD, Nettles RE, Siliciano RF: Residual human immunodeficiency virus Development of an assay to determine the genotype of type 1 viremia in some patients on antiretroviral therapy is domi- viruses in latently infected cells is also warranted. nated by a small number of invariant clones rarely found in circulat- ing CD4+T cells. J Virol 2006;80:6441-6457. 12 Chun T-W, Engel D, Mizell SB, Ehler LA, Fauci AS: Induction of REFERENCES HIV-1 replication in latently infected CD4+T cells using a combination of cytokines. J Exp Med 1998;188:83-91. 1 Chun T-W, Stuyver L, Mizell SB, Ehler LA, Mican JAM, Baseler M, 13 Kutsch O, Benveniste EN, Shaw GM, Levy DN: Direct and quanti- Lloyd AL, Nowak MA, Fauci AS: Presence of an inducible HIV-1 tative single-cell analysis of human immunodeficiency virus type 1 latent reservoir during highly active antiretroviral therapy. reactivation from latency. J Virol 2002;76:8776-8786. Proceedings of the National Academy of Sciences USA 1997;94:13193- 14 Moriuchi H, Moriuchi M, Fauci AS: Induction of HIV-1 replication 13197. by allogeneic stimulation. J Immunol 1999;162:7543-7548. 2 Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson 15 Chun T-W, Fauci AS: Latent reservoirs of HIV: Obstacles to the RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, eradication of virus. Proceedings of the National Academy of Sciences Markowitz M, Ho DD, Richman DD, Siliciano RF: Identification of USA1999;96:10958-10961.

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16 Brooks DG, Hamer DH, Arlen PA, Gao L, Bristol G, Kitchen CMR, therapy for human immunodeficiency virus type 1 reservoirs in Berger EA, Zack JA: Molecular characterization, reactivation, and infected persons receiving virally suppressive highly active anti- depletion of latent HIV. Immunity 2003;19:413-423. retroviral therapy. J Infect Dis 2002;186:1403. 17 Scripture-Adams DD, Brooks DG, Korin YD, Zack JA: Interleukin-7 26 Shen A, Yang H-C, Zhou Y, Chase AJ, Boyer JD, Zhang H, induces expression of latent human immunodeficiency virus type 1 Margolick JB, Zink MC, Clements JE, Siliciano RF: Novel pathway with minimal effects on T-cell phenotype. J Virol 2002;76:13077- for induction of latent virus from resting CD4+T cells in the simian 13082. immunodeficiency virus/macaque model of human immunodefi- 18 Gustafson K, John H. Cardellina II, James B. McMahon, Robert J. ciency virus type 1 latency. J Virol 2007;81:1660-1670. Gulakowski, Junichi Ishitoya, Zoltan Szallasi, Nancy E. Lewin, 27 Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand Peter M. Blumberg, Owen S. Weislow, and et a: A nonpromoting A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, phorbol from the samoan medicinal plant homalanthus nutans Bosch RJ, Margolis DM: Depletion of latent HIV-1 infection in vivo: inhibits cell killing by HIV-1. J Med Chem 1992;35:1978-1986. A proof-of-concept study. The Lancet 2005;366:549-555. 19 Hezareh M: Prostratin as a new therapeutic agent targeting HIV 28 Han Y, Lassen K, Monie D, Sedaghat AR, Shimoji S, Liu X, Pierson viral reservoirs. Drug News Perspective 2005;18:496-500. TC, Margolick JB, Siliciano RF, Siliciano JD: Resting CD4+ T cells 20 Zayed S, et al.,: New tigliane and daphnane derivatives from pime- from human immunodeficiency virus type 1 (HIV-1)-infected indi- lea prostrata and pimelea simplex. Experentia 1977;333:1554-1555. viduals carry integrated HIV-1 genomes within actively transcribed 21 Szallasi Z, KW Krauz and PM Blumberg: Non-promoting 12- host genes. J Virol 2004;78:6122-6133. deoxyphorbol 13-esters as potent ihibitors or phorbal 12-myristate 29 He G, L Ylisasigui and DM Margolis: The regulation of HIV-1 gene 13-acetate induced acute and chronic biological responses in cd-1 expression: The emerging roll of chromatin. DNA Cell Biol mouse skin. Carcinogenesis 1992;13:2161-2167. 2002;21:697-705. 22 Gulakowski RJ, McMahon JB, Buckheit RW, Gustafson KR, Boyd 30 Williams S, Lin-Feng Chen, Hakju Kwon, Carmen M Ruiz-Jarabo, MR: Antireplicative and anticytopathic activities of prostratin, a Eric Verdin,and Warner C Greene: NF-κB p50 promotes HIV laten- non-tumor-promoting phorbol ester, against human immunodefi- cy through hdac recruitment and repression of transcriptional initia- ciency virus (HIV). Antiviral Research 1997;33:87-97. tion. EMBO J 2006;25:139-149. 23 Kulkosky J, Culnan DM, Roman J, Dornadula G, Schnell M, Boyd 31 Siliciano JD, Lai J, Callender M, Pitt E, Zhang H, Margolick JB, MR, Pomerantz RJ: Prostratin: Activation of latent HIV-1 expres- Gallant JE, Cofrancesco J, Jr., Moore RD, Gange SJ, Siliciano RF: sion suggests a potential inductive adjuvant therapy for HAART. Stability of the latent reservoir for HIV-1 in patients receiving val- Blood 2001;98:3006-3015. proic acid. J Infect Dis 2007;195:833-836. 24 Hezareh M: Prostratin as a new therapeutic agent targeting HIV viral reservoirs. Drug News Perspect 2005;18:496-500. 25 Kulkosky J, Nunnari G, Otero M, Calarota S, Dornadula G, Hui Z, Malin A, Sullivan J, Yan X, DeSimone J, Babinchak T, Stern J, VVV Cavert W, Haase A, Pomerantz RJ: Intensification and stimulation

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BASIC SCIENCE

VIRAL ERADICATION: A CONTINUING DEBATE

“A close monitoring of the size of viral reservoirs in Readers following the debate among researchers patients who initiated antiretroviral therapy early in about the possibility of “curing" AIDS may be excused for feeling alternatively elated and deflated following quotes infection after successful control of HIV for longer in the press these last few months, especially surrounding than 8 years and who elect to discontinue therapy will the International AIDS Society Annual Conference in be of considerable value in assessing the feasibility of Australia in July, 2007. eradication of HIV”. WELL, WHICH IS IT? Drs. Chun, Justement, Moir, Hallahan, Searchlight took a look at the recent brief report by Maenza, Mullins, Collier, Corey and Fauci Dr. Fauci and colleagues in the Journal of Infectious Diseases Journal of Infectious Diseases to clarify the issue of whether advances towards a cure for AIDS were being made. At issue is the determination of 2007;195:1762-1764. the rate of natural decay or attrition of the latently infected cells in the reservoir and whether this decay can be extrap- “It's time the world stopped talking about a cure for olated to actually empty the reservoir over time. Chun et al report recent findings on a cohort of AIDS.” patients who began Highly Active Antiretroviral Therapy, Dr. Anthony Fauci (HAART) soon after infection [1]. In an earlier publication Sydney Morning Herald the initial cohort consisted of 10 individuals who began on HAART early in infection, at times ranging from 0.3 July 22, 2007 - 8:29 A.M. months to 4 months after symptomatic primary HIV infection [2]. The initial therapy consisted of AZT, 3TC, and “The integrase inhibitors are particularly potent indinavir. The focus in the initial report was to show that despite early treatment, a reservoir of latently infected drugs and I think you will start to see that eradica- resting CD4+ T-cells was established in all patients. Initial tion will return to the agenda with these new agents responses to therapy showed that five patients had virus and new ways of using them”. levels below 50 copies/mL. An additional four patients had virus levels less than 400 copies/mL and one patient, Dr. David Cooper despite having a 3 log drop in virus level, had about 1000 National Centre in HIV Epidemiology and copies/mL at the time of the original study. Clinical Research, Australia Interestingly, despite HAART, ongoing viral replication as evidenced by higher levels of un-integrated DNA Agence France Presse observed in 9 of 10 patients. Un-integrated DNA is unsta- July 9, 2007 ble and so its presence indicates recent HIV infection of target cells. Despite the focus on early treatment, the time from BY STEPHEN J. BROWN, M.D. primary infection symptoms to initiation of HAART, as Medical Director, AIDS Research Alliance well as time spent on HAART, did not correlate at all with

10 WINTER 2007 | SEARCHLIGHT the measurements of the HIV reservoir in the resting of ongoing viral replication seen in the original paper may CD4+ T-cells. point to the activity of a more intact immune system in Nearly 9 years later, the cohort (now seven patients) is assisting with viral reservoir decay. This in turn would the focus of a study on the decay of the HIV reservoir in argue for the continued priming of the immune system, patients receiving HAART for extended periods. One can for example, by exposure to viral antigens through thera- assume the regimens have changed although the designa- peutic vaccinations, as a way to keep the pressure on. tion of this as a “Brief Report” greatly limits accompanying More recent treatments, particularly those that pre- data. Calculations for this small population of patients vent viral entry, or integration of virus into the host cell treated early showed a mean half-life of 4.6 months. After DNA, may present significant advances in HIV treatment, estimating the size of the entire reservoir at about 1x106 and prevent residual “cryptic replication” being a source of cells, the authors estimate that elimination of the cellular reservoir replenishment and new viral production seen in component of the HIV reservoir could be achieved in 7.7 some patients. years [1]. Lastly, these reports all rely on the use of HAART The authors conclude that since antiretroviral therapy alone in decay and eradication efforts. While HAART may has been widely available for 10 years, large numbers of be improving in the facilitation of the decay of reservoirs, patients exist who may have started treatment early after it would be short sighted to rely on such interventions infection, and that this may allow assessment of the feasi- alone in the quest for a cure. bility of eradication of HIV in these individuals. Several comments can be made with respect to this paper. As pointed out in the editorial commentary, in at REFERENCES least some of these patients the data seem to show a second, slower decay phase rather than a single linear curve 1 Chun TW, Justement JS, Moir S, Hallahan CW, Maenza J, Mullins JI, Collier AC, Corey L, Fauci AS: Decay of the HIV reservoir in patients [3]. That suggests that the earlier, faster decay may be fol- receiving antiretroviral therapy for extended periods: Implications for lowed by a second or third slower rate of decay. Some eradication of virus. J Infect Dis 2007;195:1762-1764. studies have found evidence for different decay rates, 2 Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS: Early which may be related to earlier treatment or more success- establishment of a pool of latently infected, resting CD4(+) T cells ful treatment without any “blips” in viral load that indi- during primary HIV-1 infection. Proc Natl Acad Sci USA cate incomplete suppression of viral replication. A logical 1998;95:8869-8873. extension of these findings is that the possibility of a cure 3 Margolis DM, Archin NM: Eliminating persistent HIV infection: in the sense of an antibiotic for pneumonia may not apply. Getting to the end of the rainbow. J Infect Dis 2007;195:1734-1736. Instead, there may be a continuum of patients, some close to depleting their reservoir, while others have continuing replication and are thus unable to deplete their reservoirs. The slowing of the reservoir decay over time could reflect cellular compartments with differential decay half- lives, or could point to the importance of immune system actions in facilitating decay. The shorter half-life of the VVV measured cellular reservoir found in the face of evidence

SEARCHLIGHT | WINTER 2007 11 BASIC SCIENCE

MEASURING THE HIV RESERVOIR

MEASUREMENT OF HIV-1 VIRAL RESERVOIRS AND THEIR INTRINSIC DECAY

In patients receiving highly active antiretroviral therapy (HAART) to suppress viral replication, HIV remains latent or nonproductive in several pools of cells. Among these are resting CD4+ T-cells, and macrophages. These cells are most easily found in the blood, but also are found in larger numbers in lymphoid tissue, such as in the gut, lymph nodes or tonsils [1,2]. Latently infected cells have been identified in all of these sites. Other infected cells have been found in the brain, kidney, and testes, but it is sioned. Earlier estimates of half-lives were derived from unknown to what extent the virus in these other sites is patients in whom ongoing replication was originally replication competent, and capable of re-igniting wide- detected, and who were receiving what we now know spread infection. Any research on viral reservoirs faces the were suboptimal antiretroviral therapy. With the addition challenge of measuring the size of the reservoir with suffi- of new antiretrovirals targeting new stages of the viral life cient precision to determine whether any reservoir abla- cycle, estimated half-lives should decrease. tive strategy (RAS) has had an impact, i.e., decreased the size of the reservoir. THE DIFFERENT TECHNIQUES USED Initial research on HIV reservoirs focused on deter- TO MEASURE THE HALF-LIFE OF mining the time it took for a 50% reduction (the half-life of THE RESERVOIR the decrease in HIV infected cells). Much of this work was derived from mathematical models of decay that examined The life cycle of the HIV virus has multiple steps that early decay in the viral load in the plasma seen after the are required for both productive infection as well as latent initiation of HAART. A second phase of decay also was integration (see Figure 1, p. 6, “Targeting Viral Reservoirs”). seen, but again was based on viral load measures in blood. After the infection of cells by HIV, there are barriers to Thus, initial estimates for the reservoir running dry, leav- HIV’s ability to integrate into the host DNA. Following ing no HIV infected cells, were overly optimistic [3]. Later estimates of the half-life ranged from 6.4 to 44.2 months, attachment to susceptible cells, the virus enters the cell suggesting that antiretroviral medication alone would be and un-coats, releasing viral RNA into the cytoplasm. This unlikely to eliminate HIV infection, given the natural HIV initial virus RNA is labile and degraded rapidly if not quick- decay rate [4,5]. ly reverse transcribed by the enzyme reverse transcriptase More recently, as a result of more effective antiretro- that accompanies the RNA into the cell. Reverse transcrip- viral therapy, new estimates have been made suggesting tase copies the initial HIV RNA into double strands of that natural decay may be shorter than previously envi- DNA. At this stage, there is another barrier to the estab- BY STEPHEN J. BROWN, M.D. lishment of the reservoir. Much of the double stranded Medical Director, AIDS Research Alliance DNA never gets integrated into the cell’s DNA, and

12 WINTER 2007 | SEARCHLIGHT remains useless in the cytoplasm of the cell where it can • Detection of HIV-RNA and HIV DNA in GALT take several forms, including DNA circles that may remain • Detection of replication competent virus by co-cul- for a long time. Finally, some double stranded DNA is ture assays of a patient’s cells with those of a healthy imported into the nucleus and integrated into the host individual. This is done to activate the latent virus. DNA. Some cells continue to transcribe the DNA into Detection of replication competent virus should prob- viral RNA, resulting in productive infection. Other cells ably be the gold standard in interventional studies maintain the integrated DNA and return to a quiescent designed to perturb the reservoir, given the high rates of state. This is the dominant form of the latent HIV-1 virus. defective provirus and deficient viral replication, The integrated virus can lay dormant in long-lived, non- Unfortunately, with successful reservoir ablative strategies, activated memory CD4 T-cells, providing a source of viral the assays to determine competent virus become more rebound after ARV therapy is withdrawn. Elaborate labo- challenging with declining virus numbers, especially when ratory techniques can measure each of these forms of viral some studies report replication competent virus occurring genetic material in various cell populations. It is important at a frequency of between 2.5 and 15 infected cells per bil- to recognize that all forms measured are not equally lion resting CD4+T-cells [6]. Studies of GALT may mea- viable. Much of the integrated DNA is defective and not sure larger numbers of cells consistent with a larger com- replication competent. Estimates are that only about 1% of ponent of the reservoir, but co-culture methods from gut the integrated DNA can produce replication competent biopsies are difficult [2]. Proviral DNA may, therefore, be virus. easier to measure. The first step in measuring the viral reservoir is to Research in this area is complicated by multiple fac- select the cells to be studied. These can be easily collected tors. Many of the studies look at different measures of via blood draws, or may require biopsy (lymph nodes), virus, RNA, DNA, and replication competent virus. This colonoscopy or gastroscopy. Thus, there is little surprise makes it difficult to compare studies. The cohorts also may that most studies focus on blood-derived cells. Once isolat- differ in definition, with some treated earlier, or some on ed, the cells are sorted to enrich the sample so it is primari- more active therapy than others. These studies also conly comprised of resting CD4+ T-cells. This is done by sume a large amount of resources, time and personnel, not to mention patient tissue samples. For these reasons, many selectively depleting the samples of CD8+ cells, and cells of these studies involve small numbers of patients. This that have activation markers on them such as HLA-DR. affects the ability of some of these studies to detect small Then, analyses can be conducted on the remaining cells changes or differences. Additionally, with newer therapies that consist of pure resting CD4+ T-cells. being added to HAART, there will be newer combinations There is an exception to this sorting process when gut and strategies. Such strategies may deplete the reservoir associated lymph tissue (GALT) is isolated and sorted. Gut faster. Reliance on HAART alone may be insufficient to lymphoid tissue has an intrinsically high level of immune impact reservoirs, or may only work in some cells, but not activation, and there are few genuine resting memory others. Much of this effort relies on there not being other, CD4+ T-cells in these samples. Instead, the reservoir in as yet unidentified, significant reservoir sanctuary sites. GALT is comprised of activated CD4+memory T-cells (characterized as CD45+/RO+ cells). REFERENCES The reported measures of the reservoir include: 1 Belmonte La, Olmos Mc, Fanin Ac, Parodi Ca, Bare Pa, Concetti • Integrated Proviral DNA in resting T-cells in peripher- Hd, Perez Hb, de Bracco MMEa, Cahn Pb: The intestinal mucosa as al blood a reservoir of HIV-1 infection after successful HAART. AIDS 2007;21:2106-2108. • Integrated Proviral DNA in lymph nodes 2 Poles MAMDP, Boscardin WJP, Elliott JMS, Taing PBS, Fuerst • In situ hybridization (using labeled DNA probes for MMPMSRN, McGowan IMDP, Brown SMD, Anton PAMD: Lack the HIV derived genes gag and rev) in duodenal tissue of decay of HIV-1 in gut-associated lymphoid tissue reservoirs in maximally suppressed individuals. JAIDS Journal of Acquired (the first part of the small intestine) Immune Deficiency Syndromes 2006;43:65-68. continued on page 28

SEARCHLIGHT | WINTER 2007 13

CURRENT RESEARCH AND CLINICAL TRIALS AT ARA

STUDY & INDICATION DESCRIPTION STATUS

New Investigational Treatment for HIV-Associated This trial investigates the efficacy and safety of pregabalin Enrollment completed Neuropathic Pain (versus placebo) in the treatment of neuropathic pain in & Study ongoing Pregabalin A0081066 HIV positive volunteers. Pfizer

New Investigational Test To Measure Resistance This Phase I study investigates the efficacy of an in vitro to Anti-HIV Drugs Enrollment & diagnostic device, HIV SpectraPoint, in HIV positive volun- Study Ongoing HIV SpectraPoint teers with prior resistance to antiretroviral medications. SpectraDigital Corporation

Investigational HIV-1 This study investigates the safety and tolerability of the Therapeutic Vaccine Epimmune HIV-1 CTL epitope-based DNA vaccine in Enrollment completed HIV-1 infected individuals receiving potent combination & Study ongoing Pharmexa-Epimmune Inc. antiretroviral therapy (ART).

Observational Study to This single-visit study assesses behavioral features of anal Guide the Development of Enrollment & Rectal Microbicides intercourse that will affect microbicide utilization and Study Ongoing administration. US National Institutes of Health

Investigational This study investigates the efficacy and safety of NGX- HIV-Associated Enrollment completed Neuropathy Patch 4010 applied for 30 or 60 minutes for the treatment of & Study ongoing painful HIV- associated neuropathy (HIV-AN). NeurogesX Inc.

Investigational This study investigates the safety, tolerability and efficacy HIV-1 Vaccine Enrollment Closed & of an investigational HIV-1 vaccine in healthy volunteers at Study Ongoing Major Pharmaceutical Co. higher risk of HIV infection.

14 WINTER 2007 | SEARCHLIGHT

CURRENT RESEARCH AND CLINICAL TRIALS AT ARA

STUDY & INDICATION DESCRIPTION STATUS

This study compares the safety and activity of an investi- New Investigational gational integrase inhibitor in combination regimens with Anti-HIV drug optimized background treatment, compared to optimized Enrollment Completed Investigational Integrase Inhibitor background therapy alone in antiretroviral-experienced, & Study Ongoing Major Pharmaceutical Co. HIV-infected volunteers with documented resistance to one of the antiretroviral drugs in each class.

Investigational This study investigates the safety, tolerability and efficacy Enrollment Completed HIV-1 Vaccine of an investigational HIV-1 vaccine in healthy volunteers & Study Ongoing Major Pharmaceutical Co. at low risk of HIV infection.

Investigational Supplement for Quality of Life and Health of HIV This study measures the effects of two formulations of Enrollment & Positive Patients pomegranate juice on the indices of quality of life. Study Ongoing POM Wonderful

Investigational Treatment to Decrease Abdominal This study investigates the reduction in visceral adipose Fat Accumulation Enrollment Completed tissue (VAT) in HIV positive volunteers with an excess of & Study Ongoing TH9507 (Growth Hormone) abdominal fat accumulation. Theratechnologies, Inc.

Investigational Treatment This study investigates the efficacy and safety of an for Treatment of Enrollment & HIV-Associated Diarrhea investigational anti-diarrhea medication for treatment of Study Ongoing HIV-associated diarrhea. Napo Pharmaceuticals, Inc.

New Investigational Anti-HIV Drug This study investigates the drug's ability, in combination with Optimized Background Therapy, to decrease Enrollment & Investigational New the level of HIV virus (viral load) in the blood of study Study Ongoing CCR5 Receptor Blocker volunteers. Schering-Plough

New Investigational Enrollment Closed & Anti-HIV Supplement This study measures the effect of a nutritional supplement Study Ongoing on immunological status (e.g. T-cell count and viral load) (Enrollment to Reopen Numico Research B.V. Early 2008)

SEARCHLIGHT | WINTER 2007 15 BASIC SCIENCE

CAN ANIMALS HELP?

It has been a challenge to find toxin directed at the HIV protein or develop useful animal models gp120, plus IL-7 or prostratin and of HIV/AIDS in general and of deplete more than 50% of latently latency particularly [1]. Res- infected thymocytes [3]. However, earchers rely on animal models of because the latently infected CD4 human diseases to understand the cells in humans are memory T basic biology of the disease and to cells and not the naïve T cells in test potential treatments. Details this model, the relevance of these of the disease process can often be experiments is uncertain. Mice studied more thoroughly in ani- with mutations in two critical mals. These tests of potential new genes (Rag2 and γC) required for treatments in animals provide a roadmap to reducing risks the generation of immune system cells have also been and increasing the efficiency of human trials. HIV does not transplanted with human blood forming cells [4,5]. infect mice or rats or even small monkeys. Some chim- Evaluation of latency has not yet been reported in these panzees and certain apes are infected with very closely models. A novel immune deficient mouse model trans- related simian viruses. These simian viruses do not gener- planted with a human white cell line carrying latent HIV ally cause disease, and these animals are endangered and has been used to evaluate some small molecules as expensive to use. The study of methods to reduce reser- inhibitors of activation of latent virus [6]. voirs involves procedures such as activation of latent virus There are natural relatives of HIV called simian in those with no detectable virus in the blood, and the use immunodeficiency viruses (SIV) that infect monkeys. of potentially novel agents. Animal models would be valu- Using novel antiretroviral drugs, Siliciano and colleagues able for testing these procedures before human subjects have been able to mimic the effect of HAART on reduc- are put at risk. tion of plasma virus particles. In this model, latent virus To study HIV in animals, several different strains of was found in purified CD4 cells from blood, spleen and mice that have a genetic inability to develop an immune lymph nodes thus providing a model to test for strategies system have been transplanted with human blood cells or to deplete the latent reservoir [7]. This model has a limita- blood forming cells. These mice have been transplanted tion in that monkey SIV Reverse Transcriptase (RT) is dif- with either human white blood cells or pieces of human ferent from HIV RT and HAART RT inhibitors (particular- fetal liver and the thymus, a small organ that sits above the ly AZT, D4T, and Sustiva) will not work in this model. heart and generates T cells. These tissues contain blood Another SIV monkey model with the gene for HIV RT forming cells. Thus it is possible to create human immune inserted into SIV has subsequently been developed. This system in these murine models. model may well allow evaluation of latency strategies dur- The second mouse model allowed the development ing HAART [1,8,9]. of HIV-1 latently infected human thymocytes. Treatment Animal models will continue to provide insight into of the mice with the immune system signal protein the establishment of HIV latency and systems to test possi- Interleukin-7 caused expression of latent HIV [2]. ble strategies to overcome latency. Researchers also were able to treat the animals with a REFERENCES

BY BERNICE SCHACTER, Ph.D. 1 Ambrose Z, KewalRamani VN, Bieniasz PD, Hatziioannou T: HIV/AIDS: In search of an animal model. Trends in Biotechnology Bernice Zeldin Schacter, Ph.D., is a biotechnology consultant 2007;25:333-337. and freelance writer. continued on page 28

16 WINTER 2007 | SEARCHLIGHT BASIC SCIENCE

INTERVIEW WITH ROBERT SILICIANO, M.D., PH.D.

Johns Hopkins AIDS researcher DNA to RNA virus have been explored with mixed results. and immunologist, and Howard Evidence that an inhibitor of histone deacylation, valproic acid, Hughes Medical Institute (HHMI) activated latent virus was not corroborated and provided only investigator Robert F. Siliciano, incremental activation. Global activation of resting T cells is too M.D., Ph.D., focuses his research toxic. Sorting out the barriers to transcription of integrated virus on the latent form of HIV hidden seems the most promising. in the DNA in resting T cells. This reservoir presents a barrier to the Are there animal models, proof of concept complete clearance of HIV despite studies, that might add to your confidence? the advances with HAART. In the Latency clearance in a macaque/simian immunodeficiency Fall 2002 issue of Searchlight, Dr. Siliciano reviewed the chal- virus (SIV) model where latency in resting memory T cells has lenges the reservoir presents. Recently, Searchlight sat down with been demonstrated would be encouraging. Recently we have Dr. Siliciano and asked him about the progress and prospects for observed the co-culture of latently SIV infected macaque resting clearing the latent reservoir. T cells with human cell lines that caused contact dependent activation of the resting latently infected SIV macaque cells through The recent estimate by Tae-Wook Chun and Anthony the receptor CD2 and its binding protein, CD58. This process Fauci of 4.6 months for the latent reservoir half-life, does not involve the usual T cell receptor engagement and may thus reducing the time to clearance to 7.7 years in a provide an insight into pathways to target latent HIV-1. cohort of patients who began antiviral therapy early in infection, seems encouraging. Are the data suffi- What approaches are there for clearing tissue, gut ciently compelling to initiate studies that would begin associated lymphoid tissue, brain, bone marrow, and ART shortly after seroconversion? genital tract reservoirs? The problem is that few patients present early. Plus, the The best way to know about these tissue reservoirs, many reservoir is established early. Latently infected cells develop of which contain resting T cells latently infected, is to monitor early, even with early treatment. And we know the selection of the low level virus in the blood. Both low level replication of the the antiviral agent doesn’t seem to influence the establishment virus and release from the reservoir are likely contributing to the and maintenance of latency. low level viremia. What do you see as the main barriers to Is it time to talk about a cure for HIV? In other words, eradication? has there been significant progress in addressing the The generation and maintenance of the reservoir is com- latent reservoir for HIV-1? plex. It reflects the patient’s history of viral drug resistance, and It is too early to talk about a cure, but there is research incremental clearance will not suffice. The reservoir needs to be going on. depleted by a log scale. The processes of establishing latency are complex and the Untreated individuals have latent virus as unintegrated full- mechanisms maintaining latency of the virus, thus preventing it’s length DNA. This form of the virus in resting T cells is suscepti- expression as an RNA virus, are not completely understood. A ble to degradation. Latent virus becomes integrated into resting variety of genes and proteins involved in regulating transcription memory T cell DNA in a manner and at sites that prevent tran- in the resting memory T cell seem to interfere with the transcrip- scription, the copying of the viral DNA into a virus RNA particle tion of the latent, integrated virus. Incremental reduction of the that would be susceptible to antiviral drugs. latent reservoir is insufficient because it is clear that for a cure there must be complete elimination of the latent virus. Even for What strategy or strategies to eliminate the latent those on HAART, there is a low-level viremia and the viruses reservoir do you think should be pursued? reflect the history of drug resistance. Short of clearing the reser- We are at an early stage. For example, strategies that voir, lifelong control of viral replication is possible if suppression focused on stimulating transcription-copying of the integrated of viremia to below 50 copies/mL is maintained.

SEARCHLIGHT | WINTER 2007 17 COMMUNITY FORUM

HEALTH LITERACY: A TOOL FOR PEOPLE LIVING WITH HIV/AIDS

Have you ever: • Felt unsure of how much of which medicine to take how many times per day for how long? • Been unclear on why you were receiving treatment or undergoing a specific procedure? • Found patient education materials or forms to be full of medical terminology, hard to follow, or difficult to understand?

If you answered “yes” to any of these questions, you are not alone. About half of all American adults, approxi- mately 90 million people, have difficulty understanding and acting upon health information [1]. ings. Areas commonly associated with health literacy WHAT IS HEALTH LITERACY? include: • Patient-physician communication; Health literacy is the degree to which individuals can • Drug labeling; obtain, process, and understand the basic health informa- • Medical instructions and medical compliance; and tion and services they need in order to make appropriate • Informed consent. [1] health decisions. Similar to the traditional understanding of literacy, health literacy incorporates a range of abilities: WHAT IMPACT DOES LOW HEALTH • To read, comprehend, and analyze information; LITERACY HAVE ON HIV/AIDS? • To decode instructions, symbols, charts, and dia- grams; Health literacy has been proven to be an important • To weigh risks and benefits; and factor in the health and treatment of people living with • To make decisions and deal with medical challenges. [2] HIV/AIDS. Research has demonstrated that, compared to those with higher health literacy, HIV-infected people with Health literacy is not only about education, but rather lower health literacy: comes from a convergence of education, cultural and • Have lower CD4 cell counts, social factors, and health services [2]. While reading, writ- • Have higher viral loads, ing, and math skills make up the core of health literacy, • Were less likely to be taking antiretroviral many other skills and abilities are also important, including medications, speaking, listening, having adequate background informa- • Reported a greater number of hospitalizations, and tion, and being able to advocate for oneself in the health • Reported poorer health. [3] care system [2]. Not surprisingly, these are the very skills Moreover, poor health literacy creates barriers to fully that lead to longer life, improved quality of life, reduction understanding one’s health, illness, and available treat- of both chronic and health disparities, as well as cost sav- ments. Misperceptions about HIV treatment raise the risk BY AVA LENA WALDMAN, M.H.S. of transmitting treatment-resistant strains of the virus. Director of Community Education and Outreach These results have alarming implications for patient educa-

18 WINTER 2007 | SEARCHLIGHT

tion and treatment programs for people who have poor health-literacy skills and are living with HIV/AIDS [4]. In BOARD OF DIRECTORS other words, to improve upon current HIV health educa- CARY STEVENS tion efforts, there is a demonstrated need to improve Chair health literacy levels and skills among people living with Principal - Landa-Stevens Architects HIV/AIDS [1,4]. MARK ITKIN AIDS Research Alliance has adopted health as the key Secretary Partner - William Morris Agency component of our community education program. Educational materials and learning opportunities are avail- JOHN WONG Treasurer able in English and Spanish for communities threatened Assistant Vice President - Capital Group Companies with HIV/AIDS throughout Los Angeles County. The LOREEN ARBUS overall aim of the community education program is to President - Loreen Arbus Productions, Inc. develop health literacy skills for improved health-related KENNETH C. "CAM" DAVIS, JR. decision making and access to HIV/AIDS clinical trials. Vice President - Bernstein Investment Research & Management JAMES FROST THERE ARE WAYS TO IMPROVE Principal - Frost/Chaddock Developers, LLC YOUR HEALTH LITERACY DOUGLAS M. KINNEY Partner - Palmer Capital • Make a list of questions to bring with you to your medical appointment. This will help you remember ART McDERMOTT Director, Foundation Giving - Lambda Legal everything you want to discuss. KATHLEEN SCHEINFELD • Take notes at your medical appointment to help you Principal - Landmark Restorations remember what has been discussed. • Ask your medical provider to explain anything you do o not understand, including how, when, and how much INSTITUTIONAL REVIEW of your medication you should take. BOARD (IRB) • If you need to make a health-related decision, discuss SEYMOUR YOUNG, M.D. it with people whom you know and trust. Chair • Take time to think about a health-related decision. Neurologist - Desert Oasis Healthcare Rarely do you need to make any health-related deci- HERMINIO REYES, PH.D. sion right at the moment that the choice is presented. Vice-Chair Biomedical/Pharmaceutical Industry Consultant • Attend an AIDS Research Alliance community educa- Patient Advocate and Educator tion event to learn more about HIV/AIDS clinical trials. MARK ARNOLD, R.N. Staff Registered Nurse-Medical/Surgical For more information about our health literacy program, Cedars-Sinai Medical Center contact Ava Lena Waldman, MHS, Director of Community DAWN BREWER, ESQ. Education & Outreach at: [email protected]. Law Offices of Dawn Brewer JOSE CASTRO II, PHARMD REFERENCES Kaiser Permanente

1. National Institutes of Health www.nih.gov/icd/od/ocpl/resources/ JOHN DRATZ, JR. ESQ. improvinghealthliteracy.htm Law Offices of John Dratz, Jr. 2. Institute of Medicine. “Health Literacy: A Prescription to End MICHAEL D. GRAHN, ESQ. Confusion” Law Offices of Michael D. Grahn 3. Kalichman SC, Rompa D. “Functional health literacy is associated RICHARD LAPIN, M.D., M.P.H. with health status and health-related knowledge in people living Hospital Physician with HIV-AIDS.” J Acquir Immune Defic Syndr. 2000 Dec UCLA Center for Health Sciences 1;25(4):337-44. 4. Kalichman SC, Benotsch E, Suarez T, Catz S, Miller J, Riompa D. ANTHONY MILLS, MD “Health literacy and health-related knowledge among persons liv- Internal Medicine - Private Practice ing with HIV/AIDS.” Am J Prev Med. 2000 May;18(4):325-31.

SEARCHLIGHT | WINTER 2007 19 BOARD OF DIRECTORS UPDATE

AIDS RESEARCH ALLIANCE WELCOMES NEW MEMBERS TO THE BOARD OF DIRECTORS

LOREEN ARBUS ART MCDERMOTT

Loreen Arbus, president of Art McDermott serves as the Loreen Arbus Productions, Director of Foundation Inc., is the first woman in the Relations for the Lambda Legal United States to head program- Defense & Education Fund, ming for a national network, a Inc. (Lambda Legal). In 2006, feat she accomplished twice Art was responsible for raising (for both Showtime and Cable $1.8 million in foundation Health Network/Lifetime). grants to advance Lambda She possesses a distinguished Legal’s civil rights work on background in the entertain- behalf of the LGBT and HIV ment industry - with a solid track record as an executive in communities. Art first joined Lambda Legal’s develop- network television, pay and basic cable; and the print ment team in 1998, serving as the agency’s primary media; as a consultant to several established and new cable Development Officer in its Western Regional Office. Art networks; as a writer; and as a producer. was elevated to his current, national position in 2004. A high profile professional and pioneer in her field, Loreen is passionate about encouraging and mentoring HIV has been at the center of Art’s life for 25 years. women in film, television, and communications. For over Art was a professional dancer at the Kennedy Center for two decades, she has co-hosted a monthly luncheon for the Performing Arts when the AIDS crisis erupted in the high level women in communications. To date, over early 1980s. As president of the Gay Hotline in 15,000 women who represent various facets of the enter- Washington, DC, Art was one of the first organizing vol- tainment industry, as well as philanthropy, have participat- unteers of the Whitman-Walker Clinic’s AIDS Education ed in stimulating conversations about culture, industry Fund in 1982. By 1985, Art was the Deputy Director of the trends and issues that impact the daily lives of women. Sacramento AIDS Foundation. He spent the next 15 years Loreen is a tireless advocate for a variety of media- working full-time in HIV services. related and non-profit causes. In addition to joining the Over the years, Art worked for, or served as a consul- AIDS Research Alliance Board, she is committed to her tant to, many HIV organizations, including the San work with United Cerebral Palsy, founded by her parents, Francisco AIDS Foundation, the Haight-Ashbury Free Leonard and Isabelle Goldenson. She also serves on other Clinic, and the California Association of AIDS Agencies. boards, including the Paley Center for Media (formerly Art also served on the board of the AIDS Project of Contra The Museum of Television & Radio), The Academy of Costa for four years. In 1996, Art helped to establish the Television Arts & Sciences Foundation, Harvard Medical Ventura County AIDS Partnership, an affiliate of the School Committee for Campaign Resources, Harvard National AIDS Partnership, and under his leadership, the School of Public Health and The Brookings Institution. VCAP raised and granted over $300,000 annually to AIDS Her many honors include the “Heart of Giving service programs. Award” in 2001, presented by President Bill Clinton. In 2002, in Paris, France, she was named one of 40 Leading Women Entrepreneurs of the World. She is also a renowned Argentine tango dancer and VVV choreographer, having co-starred in and co-produced the first theatrical Argentine tango stage show to origi- nate in the United States, with which she has toured four continents.

20 WINTER 2007 | SEARCHLIGHT

EVENTS WRAP-UP

FRIENDS OF AIDS RESEARCH ALLIANCE STAY BUSY THIS FALL

AIDS RESEARCH ALLIANCE & the last decade, 3 million years of life have been saved in CRUNCH FITNESS SPIN FOR HIV the United States due to the advances in medical research”. MEDICAL RESEARCH With words of inspiration, and a clear mission in mind, the event began! Crunch Fitness provided eight of This summer, AIDS Research Alliance and Crunch Fitness their top Spin™ instructors, as well as guest celebrity hosted Revolutions 3, Spinning for a Cure. At 9:00 a.m., instructor Bob Harper from “The Biggest Loser”, to lead a with the August summer heat already baking the court- series of intense 30-minute work-out sessions. Sponsor and yard at 8000 Sunset, nearly fifty dedicated spinners excited- Crunch neighbor, Virgin Megastore, provided the terrific ly prepared for a three hour workout on their bikes, pro- sounds that kept instructors and spinners on beat, and vided by Star Trac, to show their dedication to the fight pushing harder yet. Universal Studios, Fox Studios, E! against AIDS. A smaller contingent mounted their bikes at Entertainment, and Paramount provided gift incentives Crunch Fitness in San Francisco. helping to draw participation among people of all spin skill Actor and advocate Wilson Cruz (Rent, My So-Called levels, and contributing to a successful, record breaking Life) opened the morning’s ceremony. AIDS Research Revolutions fundraising event! Alliance’s CEO Carolyn Carlburg quickly focused the You can view the photos from this event by checking enthusiastic crowd with the passionate assertion that “in out www.revolutions3.org.

Cindy Yang, a member of Team Instructor Bob Harper urges A needed water break. Capital Group, hitting her stride. on the riders.

SEARCHLIGHT | WINTER 2007 21

INTO THE ENCHANTED FOREST: A BEAUTIFUL CURE

In October, co-owners Jason Lara and David Abrams of luxelab salon & luxehaus transformed their Santa Monica stores into a bewitching space for Into the Enchanted Forest: A Beautiful Cure, a Westside fundraiser benefiting AIDS Research Alliance. The pampering began as twenty of luxelab’s stylists donated their time and tal- ents during an eight-hour couture Hair Cut-A-Thon. Guests enjoyed Barefoot Bubbly, delicious Sprinkles cup- Event Hosts and luxelab owners David Abrams (l) and Jason Lara (r) thank Carolyn Carlburg and Cary Stevens, ARA Board Chair. cakes, and artisan Valerie Chocolates, while being coifed to perfection. Later in the evening, 300 guests crowded the sleek Montana Avenue salon as it became a swank nightclub with a “Midsummer Night’s Eve” atmosphere. Held to raise research funds for AIDS Research Alliance, the event was produced by Marina del Ray, Calif.-based Aesthetica Events and Los Angeles-based Valentine Group. Aesthetica’s Shay Watson created the arboreal theme inspired by prostratin, a compound that may be effective in eradicating the HIV reservoirs when used in combination with antiretroviral therapy. Singer and actress Conchita Maria Alonso (l) joins “Enchanted” Guests entered the event beneath two trees overhang- Co-Chair and Emmy and Golden Globe Award-Winner, Marcia ing the entrance, even one springing from DJ Henry Cross of “Desperate Housewives.”

Guests enjoyed an enchanting evening raising funds for AIDS Research Alliance.

22 WINTER 2007 | SEARCHLIGHT

ENCHANTED FOREST EVENT PARTNERS Round Two Integrated Media Bobby Boroumand Fox Broadcasting Company Goldwell Planet Blue Rita Tuzon Red Dragon Karate Vance Walker (l) and “Enchanted” Co-Chair John Pardee, Executive Aesthetica Events Producer on the TV show Desperate Housewives, lend their support to the evening. Alta Tseng Design Blonde-Aid Hair Care Eshelman’s booth. As guests lined up for Absolut 100’s Tu Ciudad magazine pomegranate cocktails, artist Carlos Vera offered a live art Bumble and bumble demonstration in the salon’s front window. Mini Caprese Dermatologica sandwiches were provided by Iron Chef Kerry Simon of Deborah Page Gallery Simon LA restaurant; Caesar Parmesan tarts, and colossal Ferris & Ferris/Itilla shrimp cocktails were provided by The Palm restaurants; Jonathan Adler Kartell and chocolates crafted by Valerie Confections. Kérastase As luxelab stylists moved around the transformed Douglass Little salon, guests placed their bids in a silent auction that Madison Gallery helped to raise money for AIDS research. David Abrams Rosenthal Glassware and Jason Lara regularly give back to the community, and Sexy Hair are happy to report that the event raised $35,000 for AIDS Sunstyle Tanning Research Alliance.

Guests posing under the Philip Manzanares-designed "Tree of Hope." "Wood sprites" roamed under the trees during the evening's festivities.

SEARCHLIGHT | WINTER 2007 23

AFTERNOON OF HOPE: A GARDEN AFFAIR

In early September, Craig and Carolyn Watson opened their lovely South Pasadena home and garden for an AIDS Research Alliance benefit. It was a wonderful opportunity to introduce AIDS Research Alliance to new friends, and to thank our supporters in the San Gabriel Valley for their continued support. Carolyn H. Carlburg, Chief Executive Officer of ARA, explained that this event was called An Afternoon of Hope because, while great strides have been made in the treatment of HIV due to groundbreaking medical research, without a cure or vaccine to fight the virus that causes Carolyn and Craig Watson opened their beautiful home for AIDS, there is still more work to be done. An Afternoon of Hope. Enjoying a break in the region’s heat wave, more than 100 guests gathered in the Watson’s landscaped gardens, dining on gourmet hors d’oeuvres provided by Derek’s Bistro and wines supplied by Trader Joe’s. Charter Communications, Cable Positive, Arroyo Outdoor, and Partyline Rentals were the event sponsors.

Host Committee member, Chris Davidson (l), with Kathleen Guests gather in the garden for An Afternoon of Hope. Scheinfeld, Conger Gabel, and Adelaide Hixon.

AFTERNOON OF HOPE Deborah & Brian Smith Marilyn Johnson PATRONS & FRIENDS Sarah Smith Orr Lena Kennedy Carolyn & Craig Watson Dr. Michele Kipke & Dr. James Avedikian & Ken Evans Marjorie& Joe Wyatt Susan Turner-Lowe J.A. Bourknight, Jr. & Deborah Cara and Doug Yokomizo Dennis Mangers & Michael Sestak Harmon Bourknight Jan Michaels Claire and Bill Bogaard HOST COMMITTEE Assemblyman Anthony Portantino Dr. Katherine Gabel Stephen Ratliff Brenda & Bill Galloway Carolyn & Craig Watson Dr. Paulette Saddler & Adelaide Hixon Dr. James Avedikian & Ken Evans Dr. Oscar Streeter Gloria and Paul Kilian Faye & Bob Davidson Deborah & Brian Smith Dennis Mangers & Michael Sestak Chris Davidson Frank Stoltze Jan Michaels Dottie & Pete Ewing Steve Villano Wendy Munger & Dr. Katherine Gabel Beth Yale Leonard Gumport Brenda & Bill Galloway Dr. Elizabeth Smalley Dr. Michael Gottlieb

24 WINTER 2007 | SEARCHLIGHT

BASIC SCIENCE

AN EVENING WITH NOBEL LAUREATE DAVID BALTIMORE

On September 18, 2007, pharmaceutical giant Merck & Co. announced it was closing its study investigating the effectiveness of its HIV vaccine candidate, which used the adenovirus, a common cold virus, as a delivery vehicle to transport three synthetically produced HIV genes into the cells. Interim analysis of the Merck data found no evidence of a protective effect from the vaccine, and no dif- ference in the viral load of those people who became infected after receiving vaccine. Dr. Stephen J. Brown, AIDS Research Alliance Medical Director and one of the principal investigators of the study said, “The closing of the Merck vaccine study may impact the future of most Dr. David Baltimore (l), Carolyn Carlburg, Dr. Bob Winters, Clinical HIV vaccines candidates currently in clinical trials because, Physician, ARA and Dr. Marjan Hezareh, Scientific Director, ARA like the Merck vaccine, many are designed to similarly stimulate strong cell-mediated immune responses.” AIDS Research Alliance invited Dr. David Baltimore, viruses work by using surrogate or disabled viruses to stim- co-recipient of the 1975 Nobel Prize for Medicine, former ulate an antibody response to the virus. Efforts over the President of the California Institute of Technology, and years to develop an antibody based vaccine that would pre- current President of the American Association for the vent HIV have not succeeded; the virus has a sugar coating Advancement of Science, to discuss his stem cell strategy that blocks the ability of the antibody to bind and attack, for modifying the immune system to prevent HIV. At the plus HIV is genetically very changeable and can mutate to age of 37, while on the Massachusetts Institute of forms that elude the antibody. Technology faculty, he shared the Nobel Prize for the dis- An alternate approach would be a vaccine that could covery of reverse transcriptase. Reverse transcriptase is generate killer cell immunity - T cells able to recognize essential for the reproduction of retroviruses such as HIV, surface structures on HIV infected cells and kill those cells. and their discovery allowed the development of medica- There have been several vaccines that used engineered tions that interrupt the life cycle of the virus. Dr. Baltimore and CalTech have received $14 million over 5 years from the Bill and Melinda Gates Foundation to engineer immunity against HIV and other dangerous pathogens. Hosted in the lovely Hancock Park home of Robert and Ann Ronus, the event was sponsored by the Capital Group. An audience of AIDS Research Alliance's Circle of Hope donors, community and civic leaders, and researchers enjoyed an engaging dialogue with Dr. Baltimore about his work. Dr. Baltimore described the emergence of HIV from chimps nearly eighty years ago, and its slow spread to humans as a chronic and deadly disease, a disease that dev- Dr. Stephen J. Brown, Medical Director, ARA (l) and Robert Ronus in astates the immune system. Vaccines to prevent most the audience during Dr. Baltimore’s presentation. continued on next page

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Other killer cell vaccine trials are on hold while the Merck vaccine results are analyzed. Dr. Baltimore expanded on the idea that delivering a viral vaccine that inserts target DNA into cells to stimulate T cell immunity is a form of gene therapy, modifying the body's DNA to direct cells to make flags that will generate effective T cell immunity. The grant from the Bill and Melinda Gates Foundation is a challenge to bring the best ideas forward that will lead to immunity against HIV. One novel approach to be tried is the use of recently discovered forms Carrie Adrian (l), Dr. Herminio R. Reyes and Ann Ronus. of RNA called interfering RNA (iRNA) to deliver gene silencing signals to infected cells to overcome the ability to viruses to deliver the surface structures, the flags to stimu- escape immune attack. Synthetic versions of iRNA, short late killer T cells. This approach has not yet succeeded as hair-pin (shRNA), are on Dr. Baltimore's idea list. He evidenced by the report from Merck Pharmaceutical emphasized the need for new ideas, for entrepreneurial Company that their candidate vaccine, though active support and international cooperation. when tested in mice and monkeys, was ineffective in humans. More HIV infections were found in those who received the vaccine than in those who received a placebo. VVV

MESSAGE FROM THE CEO continued from page 2 tion [the three dimensional structure of the protein target] the viral reservoir. But our independent research program, about why it failed than there is now about the failure of particularly our work with prostratin, suggests how an the Merck vaccine.” The consensus among scientists was agent like prostratin might be used in conjunction with that VaxGen produced irrelevant antibodies. complementary strategies to achieve reservoir ablation. While scientists are unraveling the lessons to be That, we believe, will be the beginning of the end of AIDS. learned from the early termination of the Merck vaccine AIDS Research Alliance began as a scientific insur- study, non-vaccine strategies are being pursued. One of gency almost eighteen years ago. Today, we are consid- them focuses on the viral reservoir, areas of the human ered part of the mainstream of HIV/AIDS research. We body where the HIV is part of the DNA of infected cells conduct HIV/AIDS medical research for the leading phar- and is thus beyond the reach of antiretroviral therapy. This maceutical companies in the world, and we have grown is an area of great importance at AIDS Research Alliance, our own independent research program. But our mission which in licensed prostratin from NIH in 2001. If AIDS is the same in our sponsored work and our independent Research Alliance is successful in obtaining FDA approval work — a world without AIDS. for prostratin, it may become an effective tool in the eradi- As always, we appreciate the generosity of our con- cation of the viral reservoir, in combination with highly tributors, donors, volunteers, and community partners active antiretroviral therapy. who make our work possible. This issue of Searchlight includes an interview with prominent immunologist, Robert F. Silicano of Johns Hopkins University, who discusses the challenges of eliminating the viral reservoir, and the prospects for a cure. Dr. Silicano believes it is too early to speak of elimination of the viral reservoir as a possible cure for HIV, but acknowl- Carolyn H. Carlburg, J.D. edges that research is ongoing. Chief Executive Officer At AIDS Research Alliance, we are more hopeful. We share Dr. Silicano's views on the challenges of eradicating

26 WINTER 2007 | SEARCHLIGHT THE COMBINED FEDERAL CAMPAIGN (CFC)

I give my donations to AIDS research month- Partnerships with ly, and will not stop as long as I am able to work nonprofit organizations play a vital role in the and earn income. If I do not help my fellow man, CFC structure. In each then who will? We need to find a cure right now of the 320 CFC areas and WHEN we do, which I hope will be very throughout the country, soon, I want to say “I was part of that; I helped regional and national nonprofit organizations collaborate closely with commit- to make that happen!” tees of volunteer federal employees to design marketing This is very important to me because so many strategies for the campaign and to process the receipt and of the infected cannot afford the costly medicine distribution of federal employee contributions to the chari- that is required to prolong their lives and treat ties they choose. The CFC also involves participating nonprofit organi- this disease. We all need to stand up and show zation leaders in the design of new policies and programs our support to fight against this disease that has that are shaping the future of the Combined Federal claimed the lives of millions already. Campaign. These partnerships promote greater direct giving from employees to nonprofit organizations, while – Derrick, Fayetteville, NC helping the organizations use these contributions as lever- age for even greater financial resources from other The Combined Federal Campaign (CFC) is the largest sources. workplace giving campaign in the world, with over 20,000 CFC campaigns are delineated geographically along nonprofit charitable organizations participating. The chari- county lines. While the structure of the campaign estab- ties supported by federal workers through the CFC range lished in the early 1980’s remains essentially the same, a from nascent community groups to large, internationally- developing trend is toward greater collaboration among known charities. campaigns through the merging of local campaign opera- Now in its 10th year participating in the CFC, as well tions and other arrangements. Each campaign is managed as the Combined State Campaign (CSC), AIDS Research by a volunteer group of employees, who work with experi- Alliance receives donations from over 4,000 federal, state enced nonprofit executives in their communities to gener- and municipal employees. ate contributions and distribute them to eligible charities. We are extremely grateful to the individuals who make it possible for AIDS Research Alliance to conduct research that would not have been possible without the CFC and CSC. We salute each of you, and say thank you for helping make research work. If you work for the Federal Government, or for one of a number of state or municipal governments, you can join in the fight against AIDS by selecting AIDS RESEARCH ALLIANCE OF AMERICA, #12134, for your workplace contribution.

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MEASURING THE HIV RESERVOIR STAFF continued from page 13 CAROLYN H. CARLBURG, J.D. 3 Perelson AS, Paulina Essunger, Yunzhen Cao, Mika Vesanen, Arlene Chief Executive Officer Hurley, Kalle Saksela, Martin Markowitz & David D. Ho Decay characteristics of HIV-1-infected compartments during combination MEDICAL therapy Nature 1997;387:188-191. STEPHEN J. BROWN, M.D. 4 Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, Kovacs C, Gange SJ, Siliciano RF: Long-term follow-up studies Medical Director confirm the stability of the latent reservoir for HIV-1 in resting cd4+ ERIN BURKE t cells. Nat Med 2003;9:727-728. Research Administrator 5 Zhang L, Ramratnam B, Tenner-Racz K, He Y, Vesanen M, Lewin S, Talal A, Racz P, Perelson AS, Korber BT, Markowitz M, Ho DD, CORIE CASTRO Guo Y, Duran M, Hurley A, Tsay J, Huang Y-C, Wang C-C: Clinical Research Assistant Quantifying residual HIV-1 replication in patients receiving combi- EMERY CHANG, M.D. nation antiretroviral therapy. N Engl J Med 1999;340:1605-1613. 6 Chun TW, Justement JS, Moir S, Hallahan CW, Maenza J, Mullins Interim Associate Medical Director JI, Collier AC, Corey L, Fauci AS: Decay of the HIV reservoir in MARJAN HEZAREH, PH.D. patients receiving antiretroviral therapy for extended periods: Scientific Director Implications for eradication of virus. J Infect Dis 2007;195:1762-1764. MICHELE VERTUCCI, P.A.-C. Clinical Trials Manager ROBERT E. WINTERS, M.D. CAN ANIMALS HELP? Clinical Research Physician continued from page 16 ERICA YANG Clinical Research Assistant 2 Scripture-Adams DD, Brooks DG, Korin YD, Zack JA: Interleukin-7 induces expression of latent human immunodeficiency virus type 1 EDUCATION & OUTREACH with minimal effects on t-cell phenotype. J Virol 2002;76:13077- HABIBA ISMAIL 13082. 3 Brooks DG, Hamer DH, Arlen PA, Gao L, Bristol G, Kitchen CMR, Community Educator Berger EA, Zack JA: Molecular characterization, reactivation, and AVA LENA WALDMAN, M.H.S. depletion of latent HIV. Immunity 2003;19:413-423. 4 Zhang L, Kovalev GI, Su L: Hiv-1 infection and pathogenesis in a Director Community Education & Outreach novel humanized mouse model. Blood 2007;109:2978-2981. 5 Gorantla S, Sneller H, Walters L, Sharp JG, Pirruccello SJ, West JT, DEVELOPMENT Wood C, Dewhurst S, Gendelman HE, Poluektova L: Human VINCENT M. CUMMINGS immunodeficiency virus type 1 pathobiology studied in humanized Director of Development Balb/c-rag2-/-{gamma}c-/- mice. JVI 2007;81:2700-2712. 6 Stevens M, Pollicita M, Pannecouque C, Verbeken E, Tabarrini O, DONN MONTENEGRO Cecchetti V, Aquaro S, Perno CF, Fravolini A, De Clercq E, Schols IT Technician D, Balzarini J: Novel in vivo model for the study of human immunodeficiency virus type 1 transcription inhibitors: Evaluation of new MICHAEL SHELTON 6-desfluoroquinolone derivatives. AAC 2007;51:1407-1413. Development Associate 7 Shen A, Zink MC, Mankowski JL, Chadwick K, Margolick JB, Carruth LM, Li M, Clements JE, Siliciano RF: Resting CD4+ T lym- ADMINISTRATION phocytes but not thymocytes provide a latent viral reservoir in a simian immunodeficiency virus-macaca nemestrina model of TEAA BRADLEY human immunodeficiency virus type 1-infected patients on highly Office Manager active antiretroviral therapy. J Virol 2003;77:4938-4949. DONN MONTENEGRO 8 Hofman MJ, Higgins J, Matthews TB, Pedersen NC, Tan C, Schinazi RF, North TW: Efavirenz therapy in rhesus macaques infected with IT Technician a chimera of simian immunodeficiency virus containing reverse PETER SALVESON transcriptase from human immunodeficiency virus type 1. AAC Clinical/Technology Specialist 2004;48:3483-3490. 9 North TW, Van Rompay KKA, Higgins J, Matthews TB, Wadford LISA VASEY DA, Pedersen NC, Schinazi RF: Suppression of virus load by highly Chief Administrative Officer active antiretroviral therapy in rhesus macaques infected with a recombinant simian immunodeficiency virus containing reverse STU WALTER transcriptase from human immunodeficiency virus type 1. J Virol Controller 2005;79:7349-7354

28 WINTER 2007 | SEARCHLIGHT

DONORS

CIRCLE OF HOPE June – October 2007

LEADERS’ CIRCLE Larry Chrysler Arnold D. Kassoy, Esq. and $25,000 - $50,000 Groundspring Michael Stoltz Neighbor to Nation Richard N. Levine The Estate of Daphne Jergins The Estate of Matthew Rushton Phillip Manzanares Medical Research Charities The Maria and John Laffin Trust Maryland Charity Campaign The Estate of David Hope Michod Until There's A Cure Foundation Arthur J. McDermott and Jim White DIRECTORS’ CIRCLE Henry Meimen $10,000-$24,999 AMBASSADORS' Andrea Merryman CIRCLE $1,000-$4,999 Jean M. Morel Loreen Arbus Tibotec Therapuetics Tracy and Timothy Alderson Capital Group John Paul Tobias and Car Donation Program LLC Anonymous John Edward Sovella Focus on AIDS Foundation Gregg Britt Blossom Trustman William H. Hurt Margaret O. Baltimore John Wong Cromwell Foundation PARTNERS' CIRCLE Elliot Forte $5,000-$9,999 Fox Broadcasting Corporation Kenneth C. “Cam” Davis, Jr. and Fund for Better Health Grant Sam Randazzo Michael Karas

DONORS Jerryl Antee II Vincent M. Cummings Anna Hudson $500-$999 Jeet Asher Kevin W. Davis Henry Hurd AT&T Rick Davis Jim Itin James Avedikian and Ken Evans Andrew Ayala Richard M De Jesus Mark Allen Itkin and Bradley Bayou Nicholas Battaglio Jay Ayers and Matt Walket Beth Dickstein Enterprises Michael B. Jackson Deborah and Lon Bouknight Liz Ayoub Thomas J DiRenzo JoAnn D. Jacobsen Carolyn H. Carlburg, J.D. Daniel R Banchik Anna B. Dixon Jason and Kelly Jacoby Derrick Davis Anne Bartnett Amy M. Doidge Shirly Jahad Brenda and Bill Galloway Charles Beal George Drake Mark Katz, M.D. Jane and David Harris Yvonne C. Benson Kevin L. Durrance Alex Kaufman Adelaide F. Hixon Frederic J. Bergstein Dyce Inc Mona Kaufman Jeffrey Khteian Rob Bergstein Susan Essex Maryellen Kirchen Jan Michaels Samuel Bergstein Ivan Estrada Crystal Kung Wendy Munger and Amita Bhalla Carlo Ferro Marie L. Larkin Leonard L. Gumport Craig and Heidi Birker Frandzel, Robbins, Bloom, Csato Maria Lee Lisa and Alan Parsons Sandra Blasingame Katherine Gabel, Ph.D. Patrick Lee Rose Pilch Richard Bloch Brian Gamberg Vincent Lee Powhatan High School Todd M. Bloom Morton M. Gerson Kenneth W. Livingston Quayle Design William Bogaard Michael Giden Maria E. Lobato Jeffery Sakson Laurie Bradley Bert Goldberg Los Angeles United Way R. Bradley Sears Jay Brecker and Eileen Corwin Daniel Gonzales S Michael Marcy Deborah and Brian Smith Joyce A. Broersma Goodtree.com Lawrence H. Matt Mickey and Greg Smith Richard T. Capel Michael Gottlieb, M.D. David Mayhood South Asian Professional Network Tom Carpenter Allen Green Alan and Debbie McCurdy Mainstain Blattt Tanner Anthony Carvalho Lawrence Groseberg Conrad A. McGinnis United eWay Maria Casale Kristian Guidi Allen D. McMillan Lisa and Trevor Vasey Ellen Ceisler Richard Habic Larissa D. Mcshane DONORS Margaret Ann Champion Kathyrn Halley David E. Meckley $100 - $499 Christopher Street West Kenneth J. Halperin Nicole L. Meise Raul C. Cobian Eric I. Hammerlund Anthony Messina Kradija Abuyousif Michael H. Collins Ali Happy Mark W. Meyer Alberta Adams Thomas Collins Nancy C. Harris Kim Michalski Carrie Adrian Common Cents New York School Janice Hazeltine and William Harada Ron Morgan Joshua Michael Ahlberg Coronet Lance and Dr. Novellyn Heard Barbara W. Nathan Martin Alliare Countrywide Cares Betty Hefner Harley J. Neuman … And Company Joseph Courtney Ian Warren Hess Christopher Newman Erik Andreassen Michelle Covington Brian Hickman Mellissa Ngu Larry Angrisani Keith A. Cox Thomas P. Higgins John Nicholson

SEARCHLIGHT | WINTER 2007 29 Peter Nickolas Amy Agius Carlo Carmona Amy Garey David Oliveira/Falon Jade Alex Suzanne Carpenter Robert Gasdick/Houser, Jeff B. Ornstein Bruno P Allaire Rachel Cellinese Steven Gates Construction Richard Ortega Sebastian H. Allaire Emmy Chang Lillian W. Gephart Donna Pade Jason M. Allen Judy Chang Marla E. Gerstenblatt Joshua Parrish Kirk N. Allen Susan Chao Scott Gesele Jessica Patterson Stephanie Allen Jeffrey Chen Glacier Films Mathew E. Pausa Dana E. Alpert Kristina S. Chew, David Gold Steven R. Paxton Paul A. Alsdorf Ryan Chingcuangco Xiaobo Gong Southeastern Pennsylvania United Way Robert R. Amaya, Terence Chisholm David Gordon Robert and Betty Petrie Leonard Ambrosini Janet Choi Gayle A. Goss David A. Phillips Flavia Amon Robert Christ Peggy Gould Charles Pleshek Mark T. Anello Shawn Coakley Dane R. Grams Ron Powell Marc Anenberg Louise Collari Mary E. Gregory Angela Price Angeles, Josielyne Tyler Compton Michael Grizzi Debra Puebla P. Armagnac Cullen Conly Michelle A. Groman Rich Ratkelis and Drew Garber Associated Students Inc. Javier Contreras Maureen Grosberg Ian Reyes Roxanna M. Auer Jennifer A. Cook Denise B. Groseberg David A. Rios Richard Authier Mary Corrigan Miriann Guazzini Jullie J Roach Eric Avallone Lisa A. Corso Anthony Gucciardo Ronnie Roe Adan Avelar Patricia A. Coryell Heela Hadad Ralph Rust Jorge B. Ayala Christina Counselman Cidney Hamiton Barbara Salmanson Christina Ayoub Cara M. Crosetti Carrie Lynn Harney Sue Salveson Norma J. Ayoub Christopher S. Cruse Richard J. Harrison Kathleen Scheinfeld Moses Ayoubl Denise Cussano Wenhsiu F. Hassan Schwab Charitable Fund Christoph S. Babke Jessica P. Dabney The Heatherington Family Steven Schwid Greg Baker Ernand P. Dabuet Jan Heatherington Seymore Consulting Donata I. Barbour Jasper Dabuet Lee B. Heatherington and Craig Carter Charles Haver / Skolnick, Haver LLC Ken Barnett Brian W. Dailey Sean Heatherington Paula Sloan Craig Barnhart John Dale Kurt Heisler and Robert Ellington Elizabeth Smalley Laura Barrantes Sheila Darcey Mark Hemphill Geoffrey B. Smith Deborah Barrow Pierre David William Hemphill W. B. Smith Marco A. Barrueto Armando De La Rosa Jose Hernandez Tae Kyung Sohn Bay Area United Way Brianna B. Deane Rafael Herrera Melissa Spitzer Page S. Beacham Ray Deluca Lawrence Hershman Andrew Stancliffe Kate Benay Ayesha L. Denson Brock A. Hillman State Street Corporation Liliya Benderskaya Enric P. Devilla Evelyn Ho Frederic R. States Molly E. Beres Maria E. Diamantopoulos Lauren S. Hochberg Shelley Stephens and David Plenn Susan Berland Timothy A. Doherty Marlene Hoffman Lenny Steren Alexander O. Bernal Christin Donahue Lynda Hoke Gordon Stulberg Elise Warner and Robert Bernard Joseph Dondlinger Amy Holbrook Tina J. Stutzky Yashika N. Bethel Tara M. Donnelly Michelle Hooper Ryan Sullivan Jason A, Billick Scott M. Doyle Marci D. Y. Hopkins Tanner Sullivan Teryl Birkes Betty Dratz Marlene L. Horn Norma Tan Alison Blanchard Mark Dressner Jonathan Howe John Terlingo Richard Bloch Kenneth Dufford Howells Physical Therapy Virginia Torres Jerome Boroff Diana M. Duran Bryan Howland MH Tran Phearoth Bou Steven T. Dzibinski Grace J. Hsia Mai Darcy Vicki M. Bou Christopher Edwards Susy Yu Hsia Shaun C. Tucker Boyd E. Bowen Florence Edwards Tracy Huang Adrian Van Deudekom and Brewster B. Boyd Thomas E Edwards Amanda M. Huber Latham Jacoby Kimberly Ann Boyd-Bowman Brad D. Engel Ana Z. Hudson Vandenbroucke Winkreative Ltd. Teaa Bradley Robert Erickson Sarah Hudson Franscisco Vergas Holly D. Bruckner John F Estrada Stacey Hughes Stu Walter Michael Bryant Elizabeth Evans Barbara Humik Marsha Wang Ph.D. Marc Bunag TJ Falls Asher Hung Gary E. Wheeler Jonathan F. Burdios Fat Egg Eric W. Hunter Leah Wheeling Laurence Don Burgess Judy Feltman John Huntley Whitney Foundation Mary H. Burke Lisa Finnie Steven M. Hytry Cynthia Williams Austin M. Burko Roche M La Fleur Mandel Ilagan Adrian J. McMullan Wood Marissa N. Burton Todd D. Fonley Melchor O. Inciong Woodward J. Taylor Ruth Busenkell Benjamin D. Forde Central Indiana United Way Marjorie Wyatt Brad Butler Foresite Escrow Inc. Michael V. Ippolito Douglas and Cara Yokomizo Lawrence Cacciatore Cortlandt Franklin Diane and Ed Irvine Sy Young, M.D. Michael Calderon Levi J. Freeman Annie Irwin Andrea D. Calhoun Michael J Freeman Gregg Jachens DONORS Courtney M. Campbell Sinia M. Freeman Ina Jaffe $99 AND UNDER Michel D. Capua Sara Hope Fritz Tim Jahnke Alan Acosta Katy Cardenas Julio Fujihara Doug James Steve A. Addison Betsy J. Carignan Rich C. Fuller E.S. James Amy Adler Christy D. Carlton Elizabeth A. Galloway Hope L. Jay

30 WINTER 2007 | SEARCHLIGHT Andrew Johnson Laura Mavros Colleen Quinn Erin B. Stutelberg C. Johnson Sandra Maxwell Corine Ramsey Brian Sugden Ann Kalagian John F. McGowan James Ray Isabelle Sugimoto Charles R. Karsters Lucius O. McHerry Chris Reichert Tanya Sumholz Jeff Katz JG M. McIntire James Reid David Swinarski Jules B. Katz Kathryn M. McKenzie Ryan Rembaum Peter J. Szwez Dan Katzir Rozane T. McManus Sanny Rettig Mellissa B. Taddei Jeffrey Kaufman Kaushal Mehta Marty Rexinger Lisa A. Taneyhill Kristen Kaufman Bradley E. Mendelson Mary Richardson Dave S. Targan William D. Keane Jason Merrell Louise E. Risner Lisa A. Tauber Adam Keen Benjamin Meyer Darrell E. Rison Archie M. Tedoco Christopher Kelleher Lindsay M. Michaelson and Pedro A. Romanach Adam Teicholz Steve Kelly Brenden O. Mielke Gerard W. Rosco Temple Ahavat Shalom School Angela Kim Andrew Miller Lois W. Rosen Eldon Teper Christina N. Kim Arielle L. Miller Joel Rosenberg Breanna Tippits Christine H. Kim Ken W. Miller Sheryl and Billy Rosenberg Scott Tobin Colin I. Kim Josh Mintz Blake Ross Mutsuko Toshima Janaya Kizzie Mission Fish Lawrence A. Ross Dawn & Pat Tran Elizabeth A. Knapp Mary S. Moore Daniel Rossicone Serge Tran Naomi Kobayashi Robert M. Moore Linda A. Rossicone Sonya M.Tran Ilene Kobert Aaron and Harriet Moretzsky Marlene Rotblatt Cori Traub Michael T. Koshimizu Dave Morris Emily S. Rothstein Jonathan R. Tresch Donald Kreindler Thomas Mosley Daniel W La Roy Jonathan and Catherine Tuerk Donald Krochmal Carole S. Mujkogawa Steven M. Sager Emily J. Tufeld Richard Kuhn Andrew and Beth Mulbry Renee Saifer Christiane F. Turgel Rosa Pipitone Kurtz John Nagler Herbert Samuels Sheri Tuski Alexis A. Kuta Ryan Namdarkhan Jessica Samuel United Way Suntrust Kim D. Kuzma Michael H. Nathans Amy J. Samuels Uzoma Uwaezuoke Brian Lammers Ken W. Nather William R. Samuels Louis Vachon Melchior Lamy Natasha Navarro Robert Santana and Matthew Vafiadis Jeffrey Landers Patricia Nazario Mauricio A. Sanchez Tony E. Valenzuela Dwayne P. Landry Arash Nejad Costa Santos Karen L. Varley Wendy A. Lawrence Russell Nelson Annie Schapira Mala Vasan Jessica L. Lawson Network for Good Anonymous Christina Schiermann Jason A. Vasques T.F. Leary Dao M. Nguyen Jason R. Schramm Tim La Viano Jack Ledwith Mark Nguyen Jon Schuller John V. Villanueva Brandon Lee, Tram Nguyen Tony Scott Michelle L. Wahlen Sylvia Lee John F. Nicholson Heine M. Selzer Mary Anne B. Ware Vivian W. Lee Mindy A. Nyby Anissa Seymour David and Janet Waselefsky Mathew Leiker Keith G. O'Connell Brian M. Seymour Laurent Wassmer Samantha R. Leitzell Jim and Phyllis O'Connell Eiran Shaley Ralph C. Watkins Joyce Leong David K. O'Conner Ron Shapiro Robert F. Weaver Sonia Lesko Anita M. Offerman Solmaz Sharif Stephanie Wedryk Nichile J. Lesley Barbara S. Olson Briana Sharp Alessandro Weiss Evan Leventhal Russell Ormey Rachel Sheehy Gabriella Weiss Janet Levinson Denice Ornelas Steven Sherman Wellpoint Associate Giving David Levy A. Ostroz Erin Shilts Brain C. Wensel Marianne Libonati Pall Aeropower Corporation Scott Showalter Tracey Weston Sarah Lillard Joe A. Patrick Mathew Siedhoff Jason C. White Alexander Livingston Ryan Pears Beth Silvia Gayle L. Wilder Mike R. Livingston Gustavo Pena Eddy Skees Jeffrey L. Williams Dennis Lumpkin Maria Pennington Benjamin Skidmore R.E. Williams Michael Lynch Norma R. Petris Edwina Case Skyles Rita D. Wilson Martha Maas Michael Petronio Frank Smedley Daniel E. Wise Zino Macaluso Ant Pham Dennis and Marcy Smiler Deirde Wittman Paul MacDonald Gregory R. Knapp Phelan Sarah Smith Tommy Woelfel Gregg Mackell Thomas Phineas Zilpha Smith David R. Wood Cortney J. Mackin Rio Phior Ravel Smolyar Joe Woodhouse Laura F. Mackney Todd Pierce Cara Sommerfield Carl York Manohara Rao Maddinani Lloyd Pilch Barbara G. Sorensen Christopher Zahar Linda Renee Maddox Charlie Pinto Michael Sorum Sarah A. Zahar Lynn D Maize Frank P. Piontek Denise Spear Tom Zapata Lynda Malerstein Angela Plank Squidoo.com Nancy Zeidenberg Scott R. Manley Carol Polchow Peter Steinauer Jenna Zelman Darlene R, March Ester Pollack Jennifer A. Stentz Phillip L. Zimmerman Stephanie N. Marcy Michael Pollack Ermin Stepanian Claudia P. Zimmermann Juliana Mardones Michelle Pollack Cissie Stephenson Andrew Zorowitz Debra Margolius Katie Powell Joey Stoller Carole A. Zuber Mark Markline Serena F. Presley-Dickey Debi Struzan Katerina I. Martin Jim F. Pritchard Renee Studer Brent Martin and Cruz Velasco Jennifer L. Purcell Vanessa E. Stumpf

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