Interaction of HIV-1 Vpr with the Host Cell Cycle

说明(申请人提供)：组合介绍 抗逆转录病毒治疗在很大程度上导致了艾滋病的下降 最近几年的定义诊断。然而，很明显，虽然目前 联合逆转录病毒疗法抑制艾滋病毒复制，病毒库 在被感染的宿主中持续存在，当治疗时病毒会卷土重来 被打断了。延长目前抗HIV逆转药物的治疗时间 不幸的是，转录酶和蛋白酶与并发症有关。 副作用和发病率，而这些药物的使用 受到抗药性发展的限制。作为HIV治疗学的代言人 正在改变，我们将需要新的目标，除了逆转录酶和 抗艾滋病病毒的蛋白酶。人们越来越认识到，配饰 HIV基因(vif、vpr、vPU和nef)在病毒的调控中起着重要作用。 体内致病机制。因为它们与宿主细胞途径相互作用 最大化病毒复制和/或逃避宿主免疫反应，解体 他们的机制可能提出了干扰复制的新方法 宿主体内的艾滋病毒循环。VPR已被证明可以延迟G2中的细胞 细胞周期的阶段。对寄主细胞周期的操纵是一种高度 研究的所有灵长类慢病毒VPR等位基因的保守性 日期，这表明这一定为病毒复制提供了优势 在主机内循环。这项建议旨在进一步了解 VPR与正常控制的宿主细胞因子相互作用的机制 宿主细胞周期的进展，并探索靶向于 这些细胞因子的作用类似地改变VPR功能。

DESCRIPTION (Provided by the applicant): The introduction of combination antiretroviral therapy has been largely responsible for the decline of AIDS defining diagnosis in recent years. However, it is clear that while current combination retroviral therapy suppresses HIV replication, viral reservoirs persist in the infected host and virus resurgence will occur when treatment is interrupted. Prolonged treatment with current drugs against HIV reverse transcriptase and protease has unfortunately been associated with complication from adverse side effects and morbidity and the use of these medications has been limited by the development of resistance. As the face of HIV therapeutics is changing, we will need new targets besides reverse transcriptase and protease against HIV. It is increasingly being recognized that the accessory genes of HIV (vif, vpr, vpu and nef) play important roles in modulating viral pathogenesis in vivo. Because they interact with host cellular pathways to maximize viral replication and/or evade the host immune response, unraveling their mechanism may suggest novel ways of interfering with the replication cycles of HIV within the host. Vpr has been shown to delay cells in the G2 phase of the cell cycle. Manipulation of the host's cell cycle is a highly conserved property of Vpr alleles from all primate lentiviruses studied to date, suggesting that this must confer an advantage to the viral replication cycle within the host. This proposal aims at further understanding the mechanism of how Vpr interacts with host cellular factors that normally control progression of the host's cell cycle and explores if drugs that target the function of these cellular factors similarly modify Vpr functions.