SAMHD1是新近发现的HIV-1宿主限制因子。早期研究提示SAMHD1有可能通过其dNTPase活性降低胞内dNTP水平，抑制病毒cDNA合成，但该酶活性与抗病毒活性并不完全相关，表明其抗病毒机制仍有待阐明。我们的前期工作首次发现SAMHD1可以特异性抑制HCV的复制。由于HCV生活周期中不涉及DNA的合成，我们提出了“SAMHD1具有dNTPase非依赖抗病毒机制”假说。前期机制研究表明SAMHD1靶向HCV RNA复制，并可以显著抑制胞内脂质合成，但二者的关联及其具体机制尚不清楚。针对上述科学问题，本课题将深入研究参与SAMHD1抗HCV活性的关键结构域、抑制病毒RNA复制的关键环节和分子事件、脂代谢在SAMHD1抗HCV活性中的功能，并鉴定SAMHD1的结合蛋白，开展相关功能研究。以期深入解析SAMHD1抑制HCV病毒复制的分子机制，阐明其dNTPase非依赖的新抗病毒机制。

SAMHD1 is a newly discovered HIV-1 host restriction factor, which can reduce the level of intracellular dNTP by the activity of its dNTPase activity and thereby inhibiting viral cDNA synthesis. Our preliminary work for the first time found that SAMHD1 can specifically inhibit the replication of HCV and play an important role in the interferon mediated host innate immunityagainst HCV. Because the HCV life cycle does not involve the synthesis of DNA, the results suggest that SAMHD1 has anew dNTPase-independent antiviral mechanism. Preliminary mechanism study showed that SAMHD1 targets HCV RNAreplication, and significantly inhibits the intracellular lipid synthesis, but the association between the two activities and the detail mechanism underlying are not clear. To answer these questions, the proposed work aims to investigate the key motifs in SAMHD1 required its anti-HCV activity, the target step in the HCV RNA replication and the role of lipid metabolism in the its anti HCV activity. In addition, we will identify SAMHD1-binding proteins and investigate their function in the anti-HCV activity of SAMHD1. The objectives of the project are to shed light in the anti-HCV mechanisms of SAMHD1anddNTPase-independent antiviral mechanism, explore the role of lipid metabolism in the host antiviral innate immunity, which will led toward identificicaion of new target for anti HCV drug and development of new control means forHCV infection.