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

作　　者：Jizheng Chen Yang Zhao Chao Zhang Hairong Chen Jin Feng Xiumei Chi Yu Pan Jun Du Min Guo Huang Cao Honghe Chen Zilong Wang Rongjuan Pei Qian Wang Lei Pan Junqi Niu Xinwen Chen Hong Tang 

机构地区：[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 lmmunity, Institute of Biophysics, Chinese Academy of Sciences,Beijing 100101, China [3]Department of Hepatology, The First Hospital of Jilin University, Changehun, Jilin 130021, China [4]TheInstitute of Bioteehnology, Shanxi University, Taiyuan, Shanxi 030006, China [5]Key Laboratory of Human Functional Genomics ofJiangsu Province, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 210093, China

出　　处：《Cell Research》2014年第9期1050-1066,共17页细胞研究（英文版）

基　　金：Acknowledgments We are grateful to Drs T Wakita （National Institute of Infec- tious Diseases, Japan） for pJFH-1 clone, F Chisari （The Scripps Research Institute） for Huh7.5.1 cell line, L Su （University of North Carolina） for cDNA clones of human CD81 and Occludin, and C Rice （The Rockefeller University） for NS5A antibody. We thank Drs Y Tian and S Meng for making a series of transgenic mice; C-X Wei for the genotyping of transgenic mice. We thank Drs L Su, Y-X Fu （The University of Chicago）, R Sun （University of California, Los Angeles） and P Hertzog （Monash University, Australia） for their critical reading and comments on the manuscript. This work was supported by grants from the National Basic Research Program of China （2009CB522506 and 2011CB946104 to HT, 2009CBl18903 to XC, and 2010CB530100 to LP）, the National Natural Science Foundation of China （31200135 to XC and 31030031 to HT）, Knowledge Innovation Program Projects of Chinese Academy of Science （2010-Biols-CAS-0201to HT, and KSCXI-YW-10 to XC and HT）.

摘　　要：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.

关 键 词：HCV animal model humanized mice immune-competent 

分 类 号：Q78[生物学—分子生物学] S858.28[农业科学—临床兽医学]