HCV NS2-5B/GBV-B嵌合病毒对小型灵长类动物狨猴感染性研究

丙型肝炎病毒（HCV）可以感染黑猩猩和基因修饰小鼠，但仍缺少小型灵长类实验动物感染模型，严重阻碍了丙型肝炎新药和疫苗研发。前期我们利用HCV完整结构蛋白（CE1E2p7）基因，建立了HCV-CE1E2p7/GBV-B嵌合病毒感染狨猴模型，呈现出典型的病毒性肝炎特征（Li T et al. Hepatology 2014）。基于HCV非结构蛋白在病毒感染与免疫中的重要作用，本课题拟构建HCV完整非结构蛋白与GBV-B的嵌合病毒（HCV NS2-5B/GBV-B），进而感染狨猴模拟HCV在灵长类动物体内的复制活动。同时，详细分析HCV NS2-5B嵌合病毒感染狨猴的病毒学、病理学和免疫学特性，研究病毒和狨猴宿主细胞的相互作用以及感染与免疫机制，为临床前评价HCV蛋白酶、解旋酶、RNA聚合酶抑制剂类新型抗病毒药物效果，或评价HCV非结构蛋白抗原候选疫苗免疫效果，提供理想的小型灵长类动物模型。

The development of vaccination and novel therapy for hepatitis C virus (HCV) has been hampered by the lack of suitable small primate animals. Recently, we reported common marmosets infected with HCV-CE1E2p7/GBV-B chimeras containing HCV structural genes coding for whole core and envelope proteins (CE1E2p7) substituted for the counterpart elements of GBV-B. Naïve animals intra-hepatically injected with chimeric RNA transcripts or intravenously injected with sera from primary infected animals produced high levels of circulating infectious chimeric viruses and developed a typical viral hepatitis of chronic infection (T Li et al.Hepatology 2014,IF 12.003). Based on the important function of HCV nonstructural proteins in HCV infection and immunity, and in the development of vaccine and antiviral drugs, we propose to establish HCV NS2-5B/GBV-B infecting marmoset model for the best mimicking of HCV infection in small primates. Virological, pathological and immunological characteristics of the HCV chimera infected marmosets will be furtherly analyzed to explore the interaction between the chimeric virus and the host cells,the mechanisms underlying HCV infection and immunity.It might provide a technical platform of small primate suitable for evaluating the effects of antiviral drugs, such as HCV protease, helicase and RNA polymerase inhibitors, or for protective evaluation of vaccine candidates with nonstructural antigens of HCV.