HMBA Releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and Activates HIV Transcription

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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. The reservoir of HIV in infected people remains an insurmountable problem in the era of highly active antiretroviral therapy. Thus, the virus persists despite the best possible treatment. HIV hides in many cells and tissues, where its genome is not expressed. Thus, neither drugs nor the immune system can eradicate it from the body. One hope is to activate the production of HIV in these reservoirs in the presence of optimal treatment. Strategies aimed at activating hematopoetic cells and thus viral replication have been tried and failed. In this report, we targeted a specific host transcriptional complex that is essential for the transcription of HIV genome. Its activation should not lead to generalized stimulation of the immune system. Indeed, paradoxically, hexamethylene bisacetamide (HMBA) and related compounds lead to cellular differentiation and apoptosis. By studying properties of these differentiation agents, we discovered that they activate transiently transcription of HIV, be it in stable cell lines or in primary infected cells. Thus, compounds related to HMBA, some of which have now been approved for clinical use, could be tried to diminish or eliminate the reservoir of HIV in optimally treated infected individuals.