No one with HIV infection has been cured, regardless of the development of effective antiretroviral therapy (ART). Nevertheless, stable remission or cure of infection is the ultimate goal of HIV therapy. The difficulties of lifelong therapy make it imperative to understand the obstacles to eradication of HIV infection, and to attempt to overcome them. In addition to improved antivirals, agents that induce expression of latent HIV but do not enhance de novo infection are needed. First, recent studies suggest that HIV infection may persist in a spectrum of CD4 memory cell populations, perhaps related to the stage of disease reached when viremia is suppressed by ART. Therefore, we must specifically characterize the frequency of persistent infection in memory cell subpopulations (eg. naive, central, transitional, effector), and investigate the potential differences in responsiveness to agents that perturb latency. This will be important information if future anti-latency therapies are to be effective in all memory cell subsets, and in all patient populations. Second, across the Deianey Collaboratory investigators will develop new approaches and molecules to disrupt and deplete latent HIV infection across a wide variety of model systems, and will discover new mechanisms that establish or maintain latent HIV infection. However to move these advances toward clinical translation, this project will contribute to the advances ofthe Collaboratory via studies in the ultimate model system - - resting CD4+ T cells obtained from aviremic, ART-treated patients.
Specific Aim I : The frequency of resting CD4+ T cell infection in central and transitional, and effector memory cell will differ in patients treated during acute or chronic HiV infection.
Specific Aim 1 1: Novel molecules will be discovered that alone or in synergy with other reagents (eg. SAHA) disrupt latency in the resting CD4+ T cells of HIV-infected aviremic,ART-treated patients.
Specific Aim III : Targeting restrictions to expression in the resting CD4+ T cells of HIV+ patients will induce viral outgrowth.
Despite antiviral therapy, eradication of HIV infection is unachievable as the virus can establish latency in CD4+ cells. We seek to develop agents capable of inducing expression of quiescent HIV in these cells without enhancing new infection, so that persistent viral infection may be cleared. We will study novel compounds that can disrupt latent infection, to define their potency and efficacy, and seek new insight into the mechanisms of HIV latencv. and the cells that remain oersistentlv infected.
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|Marsden, Matthew D; Wu, Xiaomeng; Navab, Sara M et al. (2018) Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents. Virology 520:83-93|
|Beliakova-Bethell, Nadejda; Hezareh, Marjan; Wong, Joseph K et al. (2017) Relative efficacy of T cell stimuli as inducers of productive HIV-1 replication in latently infected CD4 lymphocytes from patients on suppressive cART. Virology 508:127-133|
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