Role of Cul5 E3 ubiquitin ligasae in HIV Vif function

描述（由申请人提供）：全球有超过4000万人感染HIV-1，这是艾滋病的病原。迄今为止，对艾滋病毒感染最有效的治疗包括抑制两种基本病毒编码酶——逆转录酶和蛋白酶——作用的药物组合。然而，与药物失败、耐药变异的出现和治疗相关的不良后果相关的重大问题仍然存在。因此，在缺乏有效的艾滋病疫苗的情况下，需要扩大抗艾滋病毒药物的范围。人类细胞编码的蛋白质可以自然地抑制病毒感染。其中一种蛋白质，APOBEC3G，已经被发现表现出抗hiv -1的活性，这种活性被病毒编码的蛋白质Vif所中和。APOBEC3，G是一种胞苷脱氨酶，在新合成的负链病毒DNA中诱导胞嘧啶修饰尿嘧啶，在缺乏Vif的情况下导致无功能病毒。我们最近发现了一系列复杂的蛋白质，包括Cu15、长链蛋白B、长链蛋白C和Rbx1，它们使HIV能够绕过人类细胞的自然防御并进行复制。发现这些作为E3泛素连接酶的蛋白质是理解HIV-1 Vif如何克服宿主防御的关键。在这项应用中，我们提出(1)进一步表征Cul5-Elongin B-Elongin C E3泛素连接酶复合物在HIV-1 Vif功能中的作用；(2)研究Cul5-Elongin B-Elongin C E3泛素连接复合物组分与HIV-1 Vif的分子相互作用；(3)探讨Cul5-Elongin B-Elongin C E3泛素连接酶复合物在其他慢病毒Vifs功能中的作用。本研究利用一个独特的模型系统来研究病毒和细胞因子的协同作用。这项研究应该为病毒和宿主因素之间复杂的相互作用提供关键的见解，并可能为我们设计有效的艾滋病毒干预策略提供关键信息。

DESCRIPTION (provided by applicant): More than 40 million people worldwide are infected with HIV-1, the etiologic agent for AIDS. To date, the most effective treatments for HIV infection include combinations of drugs that inhibit the action of two essential virus-encoded enzymes, reverse transcriptase and protease. However, significant problems related to drug failure, emergence of drug-resistant variants, and treatment-related adverse consequences persist. Therefore, in the absence of effective AIDS vaccines, the range of anti-HIV drugs needs to be expanded. Human cells encode proteins that naturally suppress virus infection. One of these proteins, APOBEC3G, has been found to exhibit anti-HIV-1 activity that is neutralized by the virally encoded protein Vif. APOBEC3,G is a cytidine deaminase that induces modification or cytosines to uracil in newly synthesized minus-strand viral DNA, resulting in non-functional viruses in the absence of Vif. We have recently identified a complex series of proteins, including Cu15, Elongin B, Elongin C, and Rbx1, that enable HIV to bypass the natural defenses of human cells and replicate. Discovery of these proteins that function as an E3 ubiquitin ligase is the key to understanding how HIV-1 Vif overcomes host defenses. In this application, we propose (1) To further characterize the role of Cul5-Elongin B-Elongin C E3 ubiquitin ligase complex in HIV-1 Vif function; (2) To study the molecular interaction between components of the Cul5-Elongin B-Elongin C E3 ubiquitin ligasae complex and HIV-1 Vif; (3) To examine the role of the Cul5-Elongin B-Elongin C E3 ubiquitin ligase complex in the functions of other lentiviral Vifs. The proposed research utilizes a unique model system to study the concerted action of viral as well as cellular factors. This study should provide critical insight into the complex interplay between viral and host factors and may provide us with critical information regarding the design of effective intervention strategies for HIV.