丙型肝炎病毒（HCV）嗜肝性感染常导致慢性肝炎，部分患者进展为肝硬化和肝癌。我国HCV感染者和丙型肝炎发病者人数均居世界首位。尽管抗病毒药物治疗的持久应答率已相当乐观，但其高昂费用、易诱生耐药株、无法阻碍肝癌发生等缺陷，仍对根治丙肝提出挑战。阐明HCV持续感染的致病机制对根治慢性丙肝至关重要。丙肝研究受限于缺乏合适的小型动物模型，对肝脏局部免疫细胞与病毒互作规律，HCV持续感染和慢性化肝炎进展的规律尚不清楚。本申请前期工作获得了世界首个、准确反映HCV感染自然史和持续感染病理进程的小鼠模型。本申请将利用该迄今为止最先进、最优越的小型动物模型，重点研究（1）肝脏原位DC和NK细胞免疫失衡/受损，（2）T细胞耐受和/或功能耗竭等在HCV建立持续感染中的基本规律，勾画慢性丙肝的复杂免疫病理过程，加深对免疫逃逸和免疫耐受基础理论的认识，并为丙肝临床诊治和治疗药物创制提供关键线索。

To better understand the pathogenesis of virus-induced liver disease and hepatocellular carcinoma (HCC), a small animal model permissive for HCV infection and modeling liver disease biology is needed. HCV infection is limited to humans and chimpanzees, predominantly due to distinct host-dependency factors and innate antiviral immune responses precluding cross-infection of other species. Efforts over the past 15 years or so have not been successful by focusing on humanizing mice permissive to HCV persistent infection. The breakthrough by this application manage to establish that HCV can persistently infect the immune-competent mouse with hepatically expression of two HCV entry receptors-CD81 and Occludin. This application is aimed to use this mouse model to further characterize the immune response to HCV infection, and the dysregulated immunity associated with the HCV persistent infection. This applicaion has two approaches, (1) to study the mechanisms of how HCV impairs the innate immunity (DCs and NK cells) during the acute phase of infection, and (2) to study the mechanism of how HCV persistent infection induce tolerance of CD8+ T cells response. These sutdies are timely and stategically critical soon after the mouse model of HCV natural infection has been available. The outcome of this application would provide the first glimpse of the dynamics of immune response to HCV infection in vivo.