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. Ul9 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.
|Stevenson, Mario (2015) Role of myeloid cells in HIV-1-host interplay. J Neurovirol 21:242-8|
|Dunham, Richard M; Vujkovic-Cvijin, Ivan; Yukl, Steven A et al. (2014) Discordance between peripheral and colonic markers of inflammation during suppressive ART. J Acquir Immune Defic Syndr 65:133-41|
|Ribeiro, Susan P; Milush, Jeffrey M; Cunha-Neto, Edecio et al. (2014) The CD8? memory stem T cell (T(SCM)) subset is associated with improved prognosis in chronic HIV-1 infection. J Virol 88:13836-44|
|Stock, P G; Barin, B; Hatano, H et al. (2014) Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients. Am J Transplant 14:1136-41|
|Bullen, C Korin; Laird, Gregory M; Durand, Christine M et al. (2014) New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med 20:425-9|
|Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar et al. (2014) Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS 28:2251-8|
|Gray, Lachlan R; Roche, Michael; Flynn, Jacqueline K et al. (2014) Is the central nervous system a reservoir of HIV-1? Curr Opin HIV AIDS 9:552-8|
|Kim, Michelle; Hosmane, Nina N; Bullen, C Korin et al. (2014) A primary CD4(+) T cell model of HIV-1 latency established after activation through the T cell receptor and subsequent return to quiescence. Nat Protoc 9:2755-70|
|Cockerham, Leslie R; Jain, Vivek; Sinclair, Elizabeth et al. (2014) Programmed death-1 expression on CD4? and CD8? T cells in treated and untreated HIV disease. AIDS 28:1749-58|
|Anderson, Jenny L; Cheong, Karey; Lee, Amas K H et al. (2014) Entry of HIV in primary human resting CD4(+) T cells pretreated with the chemokine CCL19. AIDS Res Hum Retroviruses 30:207-8|
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