Mechanisms of Reactivation of Latent HIV by HDAC Inhibitors

描述：尽管抗HIV药物的组合可以有效地抑制病毒复制，但感染者拥有潜伏的HIV-1储藏库。一旦停药，这个蓄水池中的病毒就会重新激活并重新引发感染，从而阻止感染的治愈。为了清除病毒库，已经描述了一种名为“电击并杀死”的策略。这一战略建议开发小分子，在不诱导全球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，一种组蛋白去乙酰酶抑制剂(HDACi)，也被称为voinostat(也称为SAHA)，可以在一些患者中重新激活潜伏的HIV，这提供了证据，表明休克和杀死策略可能是可行的。除了降低整合的HIV前病毒染色质状态的能力外，我们最近的研究结果表明，voinostat可以通过激活CDK9 Thr186(T-loop)磷酸化来刺激静止的原代CD4+T细胞中的P-TEFb。P-TEFb是一种以CDK9和Cyclin T1为核心的细胞辅因子，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所必需的，因此也是TAT功能所必需的。然而，在静息的CD4+T细胞中，CDK9 T环的磷酸化被抑制。因此，旋转器激活CDK9T环磷酸化可能有助于其在患者体内重新激活潜伏病毒的能力。我们建议研究伏立诺和其他HDAC激活静息的CD4+T细胞中CDK9 T环磷酸化的机制。鉴于目前正在人体试验中对涡旋剂重新激活潜伏的艾滋病毒的能力进行评估，我认为了解其作用机制非常重要。这项拟议的研究可以帮助开发更有效的再激活分子，并为利用休克和杀死策略的临床方案提供信息。这项申请中提出的研究有可能对治愈艾滋病毒感染的策略产生很大影响。

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.