Abstract
Hexamethylene bisacetamide (HMBA) is a potent inducer of cell differentiation and HIV production in chronically infected cells. However, its mechanism of action remains poorly defined. In this study, we demonstrate that HMBA activates transiently the PI3K/Akt pathway, which leads to the phosphorylation of HEXIM1 and the subsequent release of active positive transcription elongation factor b (P-TEFb) from its transcriptionally inactive complex with HEXIM1 and 7SK small nuclear RNA (snRNA). As a result, P-TEFb is recruited to the HIV promoter to stimulate transcription elongation and viral production. Despite the continuous presence of HMBA, the released P-TEFb reassembles rapidly with 7SK snRNA and HEXIM1. In contrast, a mutant HEXIM1 protein that cannot be phosphorylated and released from P-TEFb and 7SK snRNA via the PI3K/Akt pathway antagonizes this HMBA-mediated induction of viral production. Thus, our studies reveal how HIV transcription is induced by HMBA and suggest how modifications in the equilibrium between active and inactive P-TEFb could contribute to cell differentiation.
Highlights
Active antiretroviral therapy (HAART) has proven effective against progression to AIDS
The reservoir of HIV in infected people remains an insurmountable problem in the era of highly active antiretroviral therapy
Hexamethylene bisacetamide (HMBA) and related compounds lead to cellular differentiation and apoptosis
Summary
Active antiretroviral therapy (HAART) has proven effective against progression to AIDS. The inhibition of histone deacetylases (HDACs), whose recruitment to the HIV promoter has been associated with transcriptional repression [8], can activate viral transcription in peripheral blood mononuclear cells (PBMCs) from HAART-treated patients using valproic acid [9]. This compound is a weak HDAC inhibitor and despite encouraging results obtained in four patients [10], the latent reservoir was not reduced in patients receiving this drug chronically for neurological conditions [11]
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