Clearing Persistently HIV-Infected CD4+ T Lymphocytes

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DESCRIPTION (provided by applicant): No one with HIV infection has been cured, regardless of the development of effective antiretroviral therapy. 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. Both persistent infection of resting CD4 cells and residual viral replication despite highly active antiretroviral therapy (HAART) may prevent clearance of infection. In addition to novel antiviral drugs, agents that induce expression of latent HIV but do not enhance de novo infection are needed. Our studies suggest an approach that may augment HIV promoter and viral expression without global T cell activation. We have shown that the chromatin remodeling enzyme histone deacetylase 1 (HDAC1) plays a critical role in HIV latency. A clinically available HDAC inhibitor, valproic acid (VPA), induces outgrowth of latent HIV ex vivo without T cell activation or increased de novo HIV infection. Applying unique and established infrastructure, and with expert collaborators, our work will focus on a single specific aim. Specific Aim: Infected units per million (IUPM) resting CD4+ T cells will decline after VPA is added to suppressive HAART therapy IA: Quantitate replication-competent HIV recovered from resting CD4+ T cells in outgrowth assays: HAART plus VPA will deplete replication-competent HIV in resting CD4 cells. IB: Measure plasma HIV RNA by a supersensitive assay and quantitate replication-competent HIV in CDS-depleted PBMCs: HAART will prevent dissemination of viral infection following VPA 1C: Measure HIV-specific immunity at baseline on HAART, and after HAART plus VPA: Greater HIV-specific immune response will correlate with a steeper slope of decline of IUPM during VPA therapy. Proof-of-concept that depletion of the reservoir of HIV-infected resting CD4+ T cells is achievable could significantly alter the current approach to therapy for HIV infection.