HIV-1 Tat commandeers nuclear export of Rev-viral RNA complex by controlling hnRNPA2-mediated splicing

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ABSTRACT Proliferation of HIV in astrocytes is limited when compared to CD4+ T lymphocytes, but the molecular mechanisms behind the disparity in cell-specific HIV propagations are unclear. In this study, we show that HIV-1 Tat determined nuclear export of Rev-viral RNA complex in CD4+ T lymphocytes by downregulating heterogenous nuclear ribonucleoprotein A2 (hnRNPA2)-mediated HIV-1 RNA splicing that increased the levels of unspliced/partially spliced viral RNA, thereby increasing virion production. Notably, hnRNPA2 was not downregulated in astrocytes due to limited Tat nuclear import. Providing alternate nuclear localization signal that rescued Tat localization to the nucleus or knocking out hnRNPA2 in astrocytes reversed the viral restrictive phenotype of astrocytes to productive phenotype. Mutant analyses identified the RNA recognition motif-1 and the disordered region of hnRNPA2 as key determinants in regulating alternate splicing. The study shows the mechanism of Tat-mediated maintenance of splice variants of viral RNA that dictates nucleocytoplasmic trafficking of Rev-RNA complex and virion production during infection. IMPORTANCE HIV-infected host cells impose varied degrees of regulation on viral replication, from very high to abortive. Proliferation of HIV in astrocytes is limited when compared to immune cells, such as CD4+ T lymphocytes. Understanding such differential regulation is one of the key questions in the field as these cells permit HIV persistence and rebound viremia, challenging HIV treatment and clinical cure. This study focuses on understanding the molecular mechanism behind such cell-specific disparities. We show that one of the key mechanisms is the regulation of heterogenous nuclear ribonucleoprotein A2, a host factor involved in alternative splicing and RNA processing, by HIV-1 Tat in CD4+ T lymphocytes, not observed in astrocytes. This regulation causes an increase in the levels of unspliced/partially spliced viral RNA and nuclear export of Rev-RNA complexes which results in high viral propagation in CD4+ T lymphocytes. The study reveals a new mechanism imposed by HIV on host cells that determines the fate of infection.

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