研究HIV-1高暴露不易感(HESN)人群是发现HIV免疫耐受机制的有效策略。我们前期发现HESN人群SHP-1表达异常升高，同时SHP-1过表达可抑制HIV-1复制，并伴随IFN-Ⅰ水平升高，提示SHP-1可能通过正调控IFN-I通路影响HIV-1感染。生信分析证明IRF3/7是IFN-Ⅰ调控的核心因子，可能被SHP-1正调控。据此提出假说“SHP-1可能通过去磷酸化调控IRF3/7活化，上调IFN-Ⅰ水平，继而抑制HIV-1感染”。为了验证这一假说，本项目首先分析SHP-1-IRF3/7-IFN-Ⅰ信号轴相关因子的表达，明确SHP-1抑制HIV-1感染的途径，然后分析IRF3/7负磷酸化位点，确证SHP-1的靶蛋白、底物作用位点和酶活中心，阐明其抑制HIV-1感染的机制。本研究首次从磷酸化/去磷酸化的角度解释HESN人群不易感机制，可为抗病毒天然免疫提供新认识。

The mechanism of anti-HIV-1 infection in highly exposed seronegative (HESN) populations is largely unknown, and the research is an effective strategy to discover the mechanism of HIV immune tolerance. Our preliminary results on HESN populations indicated that expression of SHP-1 is significantly higher than the healthy control. We also found that HIV-1 infection was suppressed, where as, interferons alpha/beta, critical factors in antiviral natural immunity, may be regulated by SHP-1, were higher, with SHP-1 overexpressing. Thus, in this application, a scientific hypothesis is proposed that SHP-1 could increase the production of IFN-Ⅰby inhibiting the activation of IRF3/7, the core factor of IFN -Ⅰ regulation, directly or indirectly, and then in turn to inhibit the infection of HIV-1. This funtion may be dependent on its phosphatase activity, which acts on the phosphorylation inactivating site of IRF3/7 or its kinase upstream with negative regulation, by dephosphorylation at the post-translational modification level. In this project, the IFN-Ⅰ pathway, by which SHP-1 inhibit HIV-1 infection, would be confirmed, via the expression analysis of key cytokines in IRF3/ 7- IFN-Ⅰ signal axis. Then the target protein and substrate active site of SHP-1 would be ascertaind, on the basis of negative phosphorylation site analysis on IRF3/ 7. Besides, whether SHP-1could promote the activation of IFN relying on its phosphatase activity was confirmed, and as well as its phosphatase domain and active site which exercise the regulating function, so as to elucidate the regulating mechanism on HIV-1 infection. It is the first attempt to explain the mechanism of insensitivity of HESN population via phosphorylation/ dephosphorylation modification, which will provide a theoretical basis for the research of antiviral innate immune response.