Structural Studies of HIV Vif and Its Cellular Binding Partners

描述（由申请方提供）：人抗病毒蛋白APOBEC3G诱导广泛突变并防止HIV DNA积累，使病毒无感染性。为了逃避这种宿主防御机制，HIV表达病毒体感染因子（Vif）。Vif模拟多组分细胞泛素连接酶中的底物受体，并募集连接酶以聚泛素化APOBEC3G用于蛋白酶体介导的降解。通过与APOBEC3G和泛素连接酶组分ElonginB/ElonginC和Cullin 5的直接相互作用，Vif使HIV能够逃避先天免疫反应的关键因素。我们的总体目标是建立HIV Vif隔离APOBEC3G的结构原理，并提供Vif与宿主细胞蛋白之间相互作用的结构细节。我们将确定HIV Vif与其各种细胞结合伴侣的复合物以及Vif/APOBEC3G/泛素连接酶的完整复合物的晶体结构。具体而言，我们将检查含有i）Vif-ElonginB/ElonginC、ii）Vif-Cullin 5和iii）Vif-APOBEC 3G相互作用的复合物的结构。从这些研究中获得的结构信息将提供对HIV Vif劫持宿主泛素连接酶以规避APOBEC3G的先天免疫应答的机制的深入理解。此外，这些结构细节将使Vif抑制剂的合理设计成为可能，从而为HIV感染提供新的治疗干预措施。 公共卫生相关性：该研究旨在建立HIV蛋白质病毒体感染因子（Vif）劫持细胞蛋白质降解途径以逃避人类抗病毒蛋白APOBEC3G的先天免疫反应的结构原理。获得的结构细节将为HIV的发病机制提供新的见解，并可能提供新的治疗靶点。

DESCRIPTION (provided by applicant): Human antiviral protein APOBEC3G induces extensive mutations and prevents the accumulation of HIV DNA rendering the virus non-infectious. To evade this host defense mechanism, HIV expresses the virion infectivity factor (Vif). Vif mimics the substrate receptor in a multi-component cellular ubiquitin ligase and recruits the ligase to polyubiquitinate APOBEC3G for proteasome-mediated degradation. Through direct interactions with APOBEC3G and the ubiquitin ligase components ElonginB/ElonginC and Cullin5, Vif enables HIV to escape a key element of the innate immune response. Our overall goal is to establish the structural principles by which HIV Vif sequesters APOBEC3G and to provide structural details of the interactions between Vif and host cellular proteins. We will determine the crystal structures of HIV Vif in complex with its various cellular binding partners as well as a complete complex of Vif/APOBEC3G/ubiquitin ligase. Specifically, we will examine the structures of complexes that contain i) the Vif-ElonginB/ElonginC, ii) the Vif-Cullin5, and iii) the Vif- APOBEC3G interactions. Structural information gained from these studies will provide an in-depth understanding of the mechanism by which HIV Vif hijacks the host ubiquitin ligase to circumvent the innate immune response from APOBEC3G. Further, the structural details will enable the rational design of Vif inhibitors that might lead to new therapeutic interventions for HIV infection. PUBLIC HEALTH RELEVANCE: The proposed research aims to establish the structural principles by which the HIV protein, virion infectivity factor (Vif) hijacks a cellular protein degradation pathway to evade the innate immune response from a human antiviral protein, APOBEC3G. The structural details obtained will provide new insights to the pathogenesis of HIV and may provide new therapeutic targets.