Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells - PubMed (original) (raw)

. 2008 Apr 15;197(8):1162-70.

doi: 10.1086/529525.

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Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells

Shailesh K Choudhary et al. J Infect Dis. 2008.

Abstract

Background: Novel therapeutic approaches are needed to attack persistent proviral human immunodeficiency type 1 (HIV-1) infection. Hexamethylbisacetamide (HMBA), a hybrid bipolar compound, induces expression of the HIV-1 promoter in the long terminal repeat (LTR) region in a Tat-independent manner but mimics the effect of Tat, overcoming barriers to LTR expression and increasing the processivity of LTR transcription complexes.

Methods: We studied alterations in cellular factors and their LTR occupancy induced by HMBA in models of latent HIV-1 infection. We measured the induction of viral outgrowth by HMBA in resting CD4(+) T cells from aviremic HIV-1-infected donors.

Results: HMBA induced outgrowth of HIV-1 from resting CD4(+) T cells recovered from aviremic patients treated with antiretroviral therapy (ART). HMBA triggered cyclin-dependent kinase 9 (CDK9) recruitment to the LTR, a key factor in the induction of efficient HIV-1 expression, via an unexpected interaction with the transcription factor Sp1. The availability of Sp1 and Sp1 DNA binding sites were necessary for HMBA-induced CDK9 recruitment and LTR expression. HMBA signaling via both protein kinase C mu and phosphatidylinositol 3-kinase appeared to contribute to LTR induction.

Conclusions: The novel mechanism through which HMBA disrupts latent HIV-1 infection involves 2 cellular kinases that may be therapeutically exploited to induce expression of persistent proviral HIV-1.

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