宿主蛋白SP100抑制人类单纯疱疹病毒I型建立复制中心的分子机制的研究

人类单纯疱疹病毒I型（HSV-1）是疱疹病毒家族中研究最为广泛和深入的模式病毒之一，终身潜伏于人体宿主并伺机复发。HSV-1在全球的感染率达67%(2012年)，除引起口唇疱疹外，还能引起脑膜炎、致盲性结膜炎等。目前抗疱疹药物主要为核苷（酸）类似物，临床耐药株在免疫抑制病人中频繁出现。本项目在"PML小体主要成分蛋白SP100能抑制HSV-1在核内建立病毒DNA复制中心"的前期工作基础上，希望通过1.在人源SP100-/-单克隆细胞系中稳定表达SP100各剪接异构体、蛋白修饰位点突变体及SIM Motif突变体等，并分析HSV-1在这些细胞系中的复制情况；2.研究过表达SP100蛋白的重组病毒在动物体内中的感染情况；探索SP100抑制HSV-1建立病毒复制中心的分子机制，寻找以HSV-1为代表的疱疹病毒在核内组织DNA复制中心的分子基础，开发抗病毒复制新靶点，为新药研发提供崭新平台.

Human simplex virus type 1 (HSV-1) is among the most studied viruses in Herpesviridae. It infects human hosts and causes a lifelong disease. The global serum positivity estimated for HSV-1 is around 67% as in 2012. HSV-1 does not only cause fever blisters around the mouth and lips, but also causes severe diseases such as herpes simplex virus encephalitis (HSE) and herpes simplex keratitis (HSK), which may result in blindness. The common anti-herpesvirus drugs in use are nucleoside or nucleotide analogues, with frequent incidence of leading to drug-resistant virus strains during clinical administrations, especially in immunosuppressed or immunocompromised patients. Based on the previous finding that "SP100, a major component of PML body, suppresses replication and the assembly of HSV-1 replication compartments", our group is proposing to investigate the molecular mechanisms of SP100's inhibition on the assembly of HSV-1 replication compartments through 1. establish permanent expression cell lines of different SP100 isoforms, various SP100 protein modification site mutants and SP100 SIM motif mutant on the background of the previously constructed human SP100-/- cells and compare replication and the assembly efficiency of HSV-1 replication compartments in those cell lines; 2. compare the replication of a recombinant HSV-1 over expressing SP100 to wild type HSV-1 in mice. These findings may further shed lights on the general controlling mechanism of host cells on viral/foreign DNA replication and provide new targeting sites for development of anti-herpesvirus drugs.