Mechanisms of chromatin regulation that drive HIV latency

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): The difficulties of lifelong therapy make it imperative to understand the obstacles to eradication of HIV infection, and to devise strategies overcome latent and persistent HIV. Chromatin modifying histone deacetylase enzymes play a critical role in the persistence of proviral latency, and HDAC inhibitors (HDACi) augment HIV promoter and viral expression without global T cell activation or increased de novo HIV infection. A more complete understanding of how HDACs contribute to proviral quiescence, both directly and through the recruitment of additional chromatin-modifying factors, and whether these influences are felt uniformly across memory cell subpopulations is needed to refine therapeutic approaches to disrupt persistent proviral infection. To achieve this we will comprehensively evaluate the following hypotheses using transformed and primary cell models of latency, and latently infected cells derived from patients: Specific Aim I: Novel and selective HDAC inhibitors (HDACi) induce the expression of quiescent proviral HIV: Inhibition of specific HDACs can induce proviral expression in cell line models, and allow recovery of replication-competent HIV from the resting CD4+ T cells of HIV-infected, ART-treated patients. Specific Aim II: Selected HDACs are specifically recruited to act at the HIV promoter: Unique cofactor complexes cooperatively recruit HDACs 1, 2, and 3 to act on the HIV LTR, where HDAC occupancy is convergently regulated Specific Aim III: Latent infection is established in different populations of memory CD4 cells as disease advances, altering the response of provirus to cellular signals or therapeutics: Quiescent infection predominates in central memory cells (TCM) in early infection, but in transitional memory cells (TTM) in more advanced disease. The response of provirus in these populations to HDACi is similar, but differs following IL7 exposure. Detailed studies of the repression of HIV expression and proviral quiescence will enhance our understanding of latency and focus potential therapeutic interventions. PUBLIC HEALTH RELEVANCE: Highly active antiretroviral therapy (ART) has lead to a significant decrease in the morbidity and mortality of HIV-infected individuals, but eradication of virus from HIV-infected individuals remains a distant prospect due largely to the ability of HIV to establish latency in resting CD4+ T-lymphocytes. To overcome HIV latency a more detailed understanding of the molecular mechanisms behind persistent infection is needed.