Role of Cul5 E3 ubiquitin ligase in HIV Vif function

描述(申请人提供)：全球有4000多万人感染艾滋病毒-1，这是艾滋病的病原体。到目前为止，对艾滋病毒感染最有效的治疗方法包括联合用药来抑制两种基本的病毒编码酶--逆转录酶和蛋白酶的作用。然而，与药物失效、耐药变种的出现以及与治疗相关的不良后果相关的重大问题依然存在。因此，在缺乏有效的艾滋病疫苗的情况下，抗艾滋病毒药物的范围需要扩大。人类细胞编码的蛋白质可以自然抑制病毒感染。其中一种蛋白质APOBEC3G已被发现具有抗HIV-1活性，但可被病毒编码的蛋白质Vif中和。APOBEC3，G是一种胞苷脱氨酶，在新合成的负链病毒DNA中诱导尿嘧啶的修饰或胞嘧啶，导致在没有Vif的情况下产生无功能病毒。我们最近发现了一系列复杂的蛋白质，包括Cu15、Elongin B、Elongin C和Rbx1，它们使HIV能够绕过人类细胞的天然防御进行复制。这些作为E3泛素连接酶功能的蛋白质的发现，是理解HIV-1 Vif如何克服宿主防御的关键。在这一应用中，我们建议(1)进一步鉴定Cul5-Elongin B-Elongin C E3泛素连接酶复合体在HIV-1 Vif功能中的作用；(2)研究Cul5-Elongin B-Elongin C E3泛素连接酶复合体的组成与HIV-1 Vif的分子相互作用；(3)研究Cul5-Elongin B-Elongin C E3泛素连接酶复合体在其他慢病毒Vif功能中的作用。这项拟议的研究利用一种独特的模型系统来研究病毒和细胞因素的协同作用。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洞察力，并可能为我们提供关于设计有效的艾滋病毒干预策略的关键信息。

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.