In vivo Consequences of VIf anatgonism

在这一应用中，我们建议开发HIV Vif蛋白的小分子抑制剂。 虽然Vif已被认为是病毒感染性的重要基因，但其细胞机制 造成这种影响的原因直到最近才被阐明。VIF的功能是灭活细胞 防御蛋白APOBEC 3G，否则会导致病毒DNA脱氨基，使其 非传染性的。我们之前在疫苗开发方面的工作已经证明了体内至关重要的 Vif对恒河猴病毒复制的意义并支持该药物的相关性 目标。马萨诸塞大学医学院(UMMS)建立了一种高通量药物 筛选设施，以确定具有抗艾滋病毒/SIV VIF活性的先导化合物。作为这项工作的一部分 一家大型化学库已经使用基于细胞的抑制剂对抗Vif化合物进行了筛选 Screen和许多先导化合物已被确定为具有靶向外周的潜力 和中枢神经系统的HIV-1复制和持久性的储备库。拟议的工作将有助于进一步 这些VIF抑制剂的开发。该应用程序将一个协作团队聚集在一起， 在药物化学、分子病毒学和体内系统方面的不同专业知识，以检查临床 这类抑制剂的潜力。 我们的目标是利用在啮齿动物物种中的药代动力学和疗效研究 优化方法将非人类灵长类动物的主体证明研究保留到最有希望的 毒品候选人。长期疗效研究将使我们能够检查Vif抑制剂对血浆的影响 病毒载量和免疫缺陷标志物以及药物治疗对SIV的影响 脑炎，一种慢病毒特有的疾病过程。为了实现这些目标，我们提出了以下建议 具体目标： 具体目标1：确定新型Vif抑制剂在啮齿动物体内的药代动力学和安全性 还有恒河猴。 特定目的2：检测Vif抑制剂对病毒复制和病毒复制的短期体内影响 啮齿动物和恒河猴HIV感染模型中的细胞储存库。 具体目标3：检测Vif抑制剂对中枢神经系统炎症和炎症生物标志物的疗效 神经艾滋病SIV-猕猴模型中中枢神经系统病理的形态证据。

In this application we propose the development of small molecule inhibitors of the HIV Vif protein. While Vif has been recognized as an important gene for viral infectivity, the cellular mechanism responsible for this effect has only recently been elucidated. Vif functions to inactivate the cellular defense protein APOBEC 3G which otherwise induces deamination of viral DNA rendering it noninfectious. Our previous work in vaccine development has demonstrated the crucial in vivo significance of Vif to viral replication in the rhesus macaque and supports the relevance of this drug target. The University of Massachusetts Medical School (UMMS) established a high throughput drug screening facility in order to identify lead compounds with activity against HIV/SIV Vif. As part of this venture, a large chemical library has been screened for anti-Vif compounds using a cell-based inhibitor screen and a number of lead compounds have been identified that have the potential to target peripheral and CNS reservoirs of HIV-1 replication and persistence. The proposed work will facilitate the further development of these Vif inhibiting agents. The application brings together a collaborative team with diverse expertise in medicinal chemistry, molecular virology, and in vivo systems to examine the clinical potential of such inhibitors. Our objective is to utilize pharmacokinetic and efficacy studies in rodent species in a lead optimization approach reserving proof-of-principal studies in nonhuman primates to the most promising drug candidates. Long term efficacy studies will allow us to examine the effect of Vif inhibitors on plasma viral load and markers of immunodeficiency as well as to evaluate the effect of drug treatment on SIV encephalitis, a lentiviral specific disease process. To accomplish these goals we propose the following specific aims: Specific aim 1: To define the pharmacokinetic and safety profile of novel Vif inhibitors in rodents and rhesus macaques. Specific aim 2: To examine the short term in vivo effect of Vif inhibitors on viral replication and cellular reservoirs in rodent and rhesus macaque models of HIV infection. Specific aim 3: To examine the efficacy of Vif inhibitors on biomarkers of CNS inflammation and morphologic evidence of CNS pathology in an SIV-macaque model of neuroAIDS.