We propose to perform three small, focused clinical trials aimed at reversing HIV latency in long-term antiretroviral-treated adults. While our proposed studies seek to translate findings from the laboratory into the clinic, they are also designed to enable our laboratory-based scientists to further investigate the mechanisms that contribute to latency. We believe that this "reverse translation" is critical to advancing our knowledge about the biology of HIV persistence during therapy. In Specific Aim 1, we will perform a two-center, single arm, limited duration (two weeks) clinical study investigating the ability of disulfiram (an FDA-approved drug to treat alcoholism) to reverse HIV latency. This study is based on recent data from Dr. Siliciano and colleagues: using a primary cell assay for HIV latency developed by his laboratory to identify compounds that activate latent HIV, his group identified this drug as among the most promising agents. This study has received approval from the FDA and the Johns Hopkins IRB, and tentative approval from the UCSF IRB. In Specific Aim 2, we will perform a single-center, randomized, controlled study investigating the ability of maraviroc (a CCR5 inhibitor) to reverse latency. This study is based on emerging data from our group suggesting that this drug may directly affect latent HIV genomes independent of its effect on viral replication. We will work closely with Dr. Sharon Lewin (Project 5) to explore the potential mechanism for this effect. Our group has performed a similar study recently and expects to have no regulatory or logistical barriers to completing the study within one to two years. In Specific Aim 3, we will perform a limited center, dose-escalating phase I study of an anti-PD-1 antibody. This study is based on preliminary data outlined in Project 2 and 3, and will be performed within the ACTG using drug to be provided by Dr. Hazuda and her colleagues. This study has received ACTG approval for full protocol development. U19 funds will be used to support the intensive virology.

The optimal way to define the biology of HIV persistence in vivo is to perturb the steady state with a precisely-defined intervention. When performed carefully, these studies can advance our understanding of pathogenesis, while generating preliminary data necessary to support larger, more definitive clinical trials.