利用基因敲除小鼠研究宿主抗病毒因子ZAP在病毒感染中的作用及其作用机理

锌指抗病毒蛋白(ZAP)是本实验室长期研究的宿主抗病毒因子，特异抑制某些重要疾病相关病毒的复制，如HIV、埃博拉病毒和包括辛德毕斯病毒（SINV）在内的多种甲病毒，其抗病毒机制已被我们深入揭示。但上述实验都在培养细胞中进行，ZAP的体内抗病毒功能仍有待明确。前期工作中，我们构建了ZAP敲除小鼠，其原代细胞在体外比正常细胞更有效地支持病毒复制，确证了ZAP的抗病毒活性；但超乎预期的是，SINV感染后ZAP敲除小鼠的存活率反而高于野生小鼠。根据已有实验结果我们提出假说，在野生小鼠中SINV利用ZAP对其在细胞中的抑制作用从而逃逸免疫监控和攻击。本项目将利用ZAP敲除小鼠验证上述假说，重点研究ZAP在体内对SINV复制的影响，并揭示ZAP对病理进程影响的机制；我们还将分析ZAP在体内对逆转录病毒感染的影响，更全面了解ZAP在体内病毒感染过程中的作用。上述研究有望揭示一些病毒与宿主博弈的新规律。

Zinc finger antiviral protein(ZAP) is a host antiviral protein identified by our lab. ZAP specifically inhbits the replication of certain disease related viruses,including HIV-1,Ebola virus and sevral alphavirues(such as sindbis virus),and the detailed mechanism for ZAP has been uncovered by us.But all the data are got from cultured cells, and in vivo evidence for ZAP's antiviral activity has been lacking. In previous work, we constructed ZAP knockout mice, and viruses replicated more efficiently in ZAP-/- primary cells than in WT ones,indicating mZAP is active to inhibit viral replication. Howerver,ZAP KO mice displayed much higher survival rate after SINV infection. Based on the above data, we hypothesize that SINV exploits ZAP's inhibition to virus replication in cells for escaping from immune surveillance and attack.In this project we will verify the hypothesis using ZAP knock out miec,with emphasis on ZAP's influence on SINV replication in vivo and the underlying mechanisms of ZAP in modulation of pathology. We will also study ZAP's influence on retroviruses replication in vivo for a comprehensive understanding of ZAP's function in viral infection. Our studies may uncover some new rules involved in the battle betweeen host and viruses.