title: Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice.
abstract: The majority of hepatitis C virus (HCV) infection develops chronic infection, which causes steatosis, cirrhosis and hepatocellular carcinoma. However, understanding HCV chronicity and pathogenesis is hampered by its narrow host range, mostly restricted to human and chimpanzee. Recent endeavour to infect a variety of humanized mice has not been able to achieve persistent HCV infection unless the essential innate immune responsive genes are knocked out. Nevertheless, such immune-compromised humanized mice still lacked HCV infection-induced hepatopathogenesis. Here we report that transgenic mice in ICR background harboring both human CD81 and occludin genes (C/O(Tg)) are permissive to HCV infection at a chronicity rate comparable to humans. In this mouse model, HCV accomplishes its replication cycle, leading to sustained viremia and infectivity for more than 12 months post infection with expected fibrotic and cirrhotic progression. Host factors favorable for HCV replication, and inadequate innate immune-response may contribute to the persistence. Lastly, NS3/4 protease inhibitor telaprevir can effectively inhibit de novo RNA synthesis and acute HCV infection of C/O(Tg) mice. Thus, chronic HCV infection with complete replication cycle and hepatopathologic manifestations is recapitulated, for the first time, in immune-competent mice. This model will open a new venue to study the mechanisms of chronic hepatitis C and develop better treatments.
authors.affiliation: State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors.forename: Jizheng
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hairong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Chi
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: The Institute of Biotechnology, Shanxi University, Taiyuan, Shanxi 030006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors.forename: Honghe
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Pei
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 210093, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
authors.forename: Junqi
authors.initials: J
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: 1] State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China [2] Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
mesh_terms: D000818:Animals; D005260:Female; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D007121:Immunocompetence; D007372:Interferons / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D008297:Male; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic
chemical_list: D007372:Interferons