Volume 24, No 9, Sep 2014

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 24 Issue 9, September 2014: 1050-1066   |  Open Access

ORIGINAL ARTICLES

Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice

Jizheng Chen^1,*, Yang Zhao^2,*, Chao Zhang^2,*, Hairong Chen^2,*, Jin Feng², Xiumei Chi³, Yu Pan³, Jun Du⁴, Min Guo¹, Huang Cao¹, Honghe Chen¹, Zilong Wang¹, Rongjuan Pei¹, Qian Wang⁵, Lei Pan², Junqi Niu³, Xinwen Chen¹ and Hong Tang^1,2

¹State Key Laboratory of Virology and the Center for Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China
²Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
³Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
⁴The Institute of Biotechnology, Shanxi University, Taiyuan, Shanxi 030006, China
⁵Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 210093, China Correspondence: Hong Tang, Tel: +86-10-64888438; Fax: +86-10-64848357 E-mail: tanghong@moon.ibp.ac.cn; Xinwen Chen, Tel: +86-10-64888438; Fax: +86-10-64848357(chenxw@wh.iov.cn)

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/OTg) 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/OTg 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.

10.1038/cr.2014.116

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