The in vivo effect of HDAC Inhibitors on HIV gene expression in resting CD4+ T Ce

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Lifelong antiretroviral therapy (ART) presents formidable problems. Therefore, among the many important goals for future HIV research is the development of temporally contained therapies capable of eradicating HIV infection. Although this goal is a distant one, research must begin towards it so that patients might someday benefit from therapies that can clear HIV infection. Despite ART, a small population long-lived CD4+ T cells remains persistently infected and unrecognized by the immune system, with minimal expression of HIV genes or proteins. The persistence of quiescent HIV infection is currently a major obstacle to eradication of HIV infection. We have defined a host cell molecular mechanism that maintains quiescence of HIV gene expression in infected resting CD4+ lymphocytes. Human transcription factors recruit histone deacetylase 1 (HDAC1) to the HIV long terminal repeat (LTR) promoter. HDAC1 mediates the formation of condensed heterochromatin, resulting in repression of LTR expression and viral production. We have demonstrated the ability of the potent inhibitor recently licensed for use in oncology, suberoylanilide hydroxamic acid (Vorinostat, VOR), selective for Class I HDACs, to induce HIV promoter expression in cell lines and virus production from the resting CD4+ T cells of antiretroviral-treated, aviremic HIV-infected patients. When the weak HDAC inhibitor valproic acid (VPA) was administered with intensified ART to aviremic, ART-treated HIV-infected individuals a depletion of resting cell infection (RCI) in three of four patients was measured. However, further studies by our group and others found infrequent and modest depletion of RCI in patients on standard ART treated with VPA. As these studies measured outcomes far downstream of the primary molecular mechanism of HDAC inhibitors, we propose to directly study the potential of potent HDAC inhibitors to induce the expression of persistent proviral HIV in vivo. We will compare the effect of the weak inhibitor VPA to the potent inhibitor VOR. The primary objectives are to measure HIV RNA expression within the resting CD4+ T cells of ART-treated, aviremic HIV-infected patients following a limited exposure to the HDAC inhibitors VPA or VOR and to assess safety and tolerability of a limited exposure to VPA or VOR. The secondary objectives are to measure peak and AUC plasma levels following a limited exposure to VPA or VOR and measure acetylated histones, and histone acetylation at the human p21 gene in the peripheral blood cells of ART-treated, aviremic HIV-infected patients following a limited exposure to VPA or VOR