宿主蛋白A3G的超频突变诱导能力和抗病毒活力、以及其受到HIV-1编码的Vif蛋白介导的降解，十多年来一直是HIV-1分子机理的研究重点。尽管去泛素化蛋白在天然抗病毒的作用逐步受到关注，但其是否参与A3G的降解目前尚无报道。在前期研究中，申请人通过siRNA文库筛选发现，去泛素化蛋白USP41能够直接结合A3G蛋白，显著增强其稳定，并能抑制HIV-1复制。本项目拟在此基础上进一步展开：①明确USP41与A3G的相互结合位点及分子作用机制；②寻找调控USP41的宿主和病毒蛋白，解析其抗病毒的分子调控网络；③开展临床关联实验，分析USP41的表达与A3G蛋白含量，以及与HIV-1临床病理进程以及病毒储藏库组分的相关性。期望通过本项目的研究，阐明去泛素化蛋白稳定A3G的分子机制，深入了解HIV-1与宿主细胞相互作用的分子机理，为研发控制HIV-1感染和清除病毒储藏库的新方法提供新的理论依据。

The hypermutation capability and antiviral activity of the host antiviral factor apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, A3G), as well as its degradation mediated by HIV-1 Vif protein, have been an important research area of HIV-1 molecular biology for more than a decade. Although more and more attention has been paid to the role of deubiquitination (DUB) in innate antiviral activities, it has not been reported whether deubiquitinated proteins participate in the degradation of host A3G protein. Through screening with an siRNA mini library and several confirmations, our previous studies have found that the deubiquitinated protein USP41 was able to interact with A3G protein and significantly enhanced the expression of A3G protein, consequently inhibiting the replication of HIV-1. Based upon these findings, we will: ①clarify the interaction sites between USP41 and A3G and the molecular mechanisms for USP41 to stabilize A3G; ② search for the host and viral proteins which regulate the USP41, and further analyze the regulatory network for its antiviral activity; ③through clinical study, analyze the correlation between USP41 expression and A3G protein expression, as well as HIV-1 disease progression and the components of viral reservoir. It is expected that through this study, we will further demonstrate the molecular mechanism for deubiquitinated protein to stabilize A3G, and the interaction between HIV-1 and host cells. As a result, our work will open a new avenue for the development of new methods to control HIV-1 infection and eradicate viral reservoir.