Mechanisms of Reactivation of Latent HIV by HDAC Inhibitors

描述：尽管联合使用抗hiv药物可以有效地抑制病毒复制，但被感染的个体拥有潜伏的HIV-1储存库。停药后，这个病毒库中的病毒重新激活并重新点燃感染，从而阻止了感染的治愈。为了清除病毒储存库，已经描述了一种称为“冲击-杀死”的策略。这一策略建议开发小分子，在不诱导全局T细胞激活的情况下重新激活潜伏的HIV。最近的一项研究表明，一种被称为伏立诺他（也被称为SAHA）的组蛋白去乙酰化酶抑制剂（HDACi）可以在一些患者中重新激活潜伏的HIV，这为休克和杀伤策略可能是可行的提供了证据。除了能够抑制整合HIV病毒的染色质状态外，我们最近的研究结果表明，伏立诺他可以通过激活CDK9 Thr186 （T-loop）磷酸化来刺激静息原发CD4+ T细胞中的P-TEFb。P-TEFb是一种核心由CDK9和Cyclin T1组成的细胞辅助因子，它介导整合前病毒的HIV Tat激活。CDK9 t环的磷酸化是其激酶功能的必要条件，因此也是Tat功能的必要条件。然而，在静止的CD4+ T细胞中，CDK9 T环磷酸化被抑制。因此，伏立诺他激活CDK9 t环磷酸化可能有助于其在患者中重新激活潜伏病毒的能力。我们建议研究伏立诺他和其他hdac在静息CD4+ T细胞中激活CDK9 T环磷酸化的机制。鉴于伏立诺他目前正在人体试验中评估重新激活潜伏HIV的能力，了解其作用机制非常重要。拟议的研究可以帮助开发更有效的再激活分子，并为利用休克和杀伤策略的临床方案提供信息。本应用程序中提出的研究有可能对治愈艾滋病毒感染的策略产生重大影响。

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.