HIV Vif克服宿主天然限制因子的新调节机制

HIV-1 Vif是病毒复制的必要蛋白。本项目申请人历经多年努力，发现和鉴定了Vif通过募集宿主细胞内的EloB/C、Cul5、CBFβ、Rbx等宿主蛋白，诱导形成E3泛素化连接酶复合物，克服宿主内天然限制因子APOBEC3（A3)的作用机制。细胞内是否存在Vif负调节因子属于本领域的国际空白。我们新近鉴定出一个Vif的负调节因子VIFBP。前期研究表明，VIFBP广泛分布于多种细胞内并抑制Vif诱导的A3G的降解。本项目将通过外源蛋白真核表达、定位突变、基因敲除等技术鉴定Vif-VIFBP的结合方式；探讨VIFBP对Vif 蛋白多种已知功能的影响：包括Vif诱导E3复合物形成的能力、Vif诱导细胞抗病毒因子的降解、Vif诱导细胞周期改变的能力等。本课题将通过以上研究详细、深入地探讨VIFBP的作用机制。研究成果将对研发新的抗HIV-1药物提供全新的机制和靶点。

HIV-1 Vif is essential for viral replication. The applicant of this project discovered the mechanism of Vif recruiting host EloB/C, Cul5, Rbx proteins to form E3 ubiquitin ligase complex and to overcome host restriction factors APOBEC3(A3) factors. However, it is not clear whether there is negative regulator of Vif function. Our recent results identified a novel Vif negative regulator VIFBP. Preliminary data indicate that VIFBP is widely distributed in various cell types. VIFBP inhibits Vif induced A3G degradation. In this application, we will use overexpression, mutation, gene silencing etc technique to study Vif-VIFBP interaction, VIFBP influence on various known Vif function including Vif formation of E3 ligase, Vif-induced A3 degradation, Vif-triggered cell cycle alteration. The research performed in this application will enhance our knowledge about the mechanism of VIFBP function and offer potential new targets for the development of anti-HIV-1 strategies.