Mechanisms of Reactivation of Latent HIV by HDAC Inhibitors

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DESCRIPTION: Although combinations of anti-HIV drugs can effectively suppress virus replication, infected individuals possess a reservoir of latent HIV-1. Upon cessation of drugs, viruses in this reservoir reactivate and re-kindle infection, thereby preventing a cure of infectio. To purge the viral reservoir, a strategy termed "shock-and-kill" has been described. This strategy proposes to develop small molecules that reactivate latent HIV without inducing global T cell activation. A recent study has shown that a histone deacetylase inhibitor (HDACi) known as vorinostat (also named SAHA) can reactivate latent HIV in some patients, providing evidence that the shock-and-kill strategy may be feasible. In addition to its ability to derepress the chromatin state of the integrated HIV provirus, our recent results demonstrate that vorinostat can stimulate P-TEFb in resting primary CD4+ T cells through activation of CDK9 Thr186 (T-loop) phosphorylation. P-TEFb is a cellular cofactor whose core is composed of CDK9 and Cyclin T1 and it mediates HIV Tat activation of the integrated provirus. Phosphorylation of the CDK9 T-loop is essential for its kinase function and is therefore also essential for Tat function. In resting CD4+ T cells, however, CDK9 T-loop phosphorylation is repressed. Therefore, activation of CDK9 T-loop phosphorylation by vorinostat likely contributes to its ability to reactivate latent virus in patients. We propose to investigate mechanisms by which vorinostat and other HDACis activate CDK9 T-loop phosphorylation in resting CD4+ T cells. Given that vorinostat is currently being evaluated in human trials for the ability to reactivate latent HIV, i is important to understand its mechanisms of action. The proposed research can aid in the development of more potent reactivating molecules, as well as inform clinical protocols that utilize the shock-and-kill strategy. The research proposed in this application has the potential fo a high impact on strategies to cure HIV infection.