Interaction of HIV-1 Vpr with the Host Cell Cycle

描述（申请人提供）：组合介绍 抗逆转录病毒疗法是艾滋病下降的主要原因 近年来的诊断。然而，很明显，虽然目前 联合逆转录病毒治疗抑制HIV复制，病毒库 在受感染的宿主中持续存在，当治疗 打断用现有药物长期治疗艾滋病毒逆转 不幸的是，转录酶和蛋白酶与 不良副作用和发病率，这些药物的使用 受到耐药性发展的限制。作为艾滋病治疗的代言人 正在发生变化，我们将需要新的目标，除了逆转录酶， 抗HIV蛋白酶。人们越来越认识到， HIV基因（vif、vpr、vpu和nef）在调节病毒感染中起重要作用， 体内发病机制。因为它们与宿主细胞通路相互作用， 最大化病毒复制和/或逃避宿主免疫应答， 它们的机制可能提示了干扰复制的新方法 艾滋病病毒在宿主体内的循环。Vpr已被证明可以延迟G2中的细胞 细胞周期的阶段。操纵宿主细胞周期是一种高度 所有灵长类慢病毒Vpr等位基因的保守性， 日期，这表明这必须赋予病毒复制的优势 在主机内循环。本建议旨在进一步了解 Vpr如何与宿主细胞因子相互作用的机制， 宿主细胞周期的进展，并探讨是否药物靶向 这些细胞因子的功能类似地改变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.