Repression of HIV Transcription: from mechanism to anti-latency therapies

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Current antiretroviral therapy (HAART) can nearly eliminate viremia in patients with human mmunodeficiency (HIV) infection. Advances in the potency and improvements in the pharmacological oroperties of future antiviral therapies are likely. However, a subpopulation of HIV-infected ymphocytes avoids viral or immune cytolysis and returns to the resting state. New therapies to attack this quiescent or latent state of HIV infection are needed. We have demonstrated that histone deacetylase (HDAC) contributes to the maintenance of viral quiescence in T cells. We have shown that HDAC inhibitor valproic acid (VPA) perturbs latent infection in resting CD4+ cells obtained from aviremic HIV-infected donors, allowing recovery of replicationcompetent HIV from these cells. In a pilot clinical experiment, we found significant depletion of replication-competent HIV within the resting CD4+ T cell compartment in 3 of 4 volunteers given intensified HAART and VPA. Further translational study of this approach is ongoing. However, VPA may not prove to be the ideal HDAC inhibitor to target latent provirus, and alternatives to HDAC inhibitors may be needed to achieve a profound depletion of latent HIV infection. We will study the mechanisms that maintain proviral latency towards the goal of identifying and testing new and improved anti-latency therapies. We will test these hypotheses: Specific Aim I: To establish the role of HDACs in HIV LTR repression and proviral latency: HDAC1 plays a central role in chromatin remodeling and repression of HIV LTR expression Specific Aim II; To define novel regulators of LTR chromatin that contribute to latency: HDAC1 recruits other factors that inhibit LTR expression Specific Aim III: To validate the biological relevance of repression in cells from HIV+ patients: Novel and specific reagents that induce proviral expression in cell line models will allow recovery of replication-competent HIV from HIV-infected patients' cells Studies of down regulation of HIV gene expression and the role of host factors in the quiescent HIV infection gives insight into general mechanisms of transcriptional regulation, T cell and HIV biology, and may lead to rational therapies targeting persistent HIV infection within resting CD4+ T cells.