HIV-1非结构蛋白Vpu选择性拮抗cGAS-STING介导的天然免疫的机制研究

天然免疫是宿主限制病毒复制的主要屏障，所有病毒都进化出拮抗天然免疫的机制来促进病毒复制。但HIV拮抗天然免疫促进病毒复制的研究还比较薄弱。申请人发表文章证明HIV-2/SIV特有的Vpx蛋白能够拮抗天然免疫反应促进病毒复制。HIV-1比HIV-2病毒感染性和致病能力更强。前期研究证明HIV-1特有的Vpu蛋白能特异性拮抗cGAS-STING介导的NF-кB免疫通路激活。重要的是比Vpx功能更加高效，Vpu与STING结合并劫获宿主泛素化复合物降解未知靶蛋白来拮抗免疫反应。本项目拟通过基因芯片，蛋白质谱，免疫共沉淀等方法发现并鉴定Vpu降解的关键靶蛋白，揭示其拮抗免疫反应促进病毒复制的具体分子机制，阐明Vpu/Vpx蛋白具有趋同性进化的观点。Vpu协助病毒逃避DNA天然免疫概念提出是HIV-1非结构蛋白拮抗宿主天然免疫反应新方向的突破,而其机制的揭示为抗艾滋病的治疗提供全新的策略。

Innate immunity is the host main barrier to restrict viral replication. Almost all viruses have evolved to antagonize innate immunity, thereby promoting viral replication. However, the study of HIV antagonizing natural immunity promoting virus replication is still weakness. The proposer has published paper to demonstrate HIV-2/SIV accessory protein Vpx selectively represses innate immune responses to promote viral replication. Compared with HIV-2, HIV-1 has stronger infectivity and pathogenesis. Previous study identified HIV-1 Vpu antagonized cGAS-STING-mediated NF-κB pathway activation, has no impact on IRF3 signaling. Importantly, Vpu degrades unknown target via E3 ubiquitin ligase. We will apply microarray, mass spectrum and co-IP etc. approaches to identify the unknown target and reveal the mechanism of Vpu antagonizing innate immune responses. The concept is a breakthrough on HIV-1 accessory protein evading innate immune sensing, providing new targets for the development of anti-viral strategy against HIV.