Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice

1 Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan 2 Liver Research Project Center, Hiroshima University, Hiroshima, Japan 3 Research Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan 4 Laboratory for Liver Disease, SNP Research Center, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan 5 Hirosimakinen-Hospital, Internal Medicine, Hiroshima, Japan 6 Developmental Biology Laboratory, Department of Biological Science, Graduate School of Science, Hiroshima University, Higashihiroshima, Japan 7 Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Japan 8 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan Correspondence Kazuaki Chayama chayama{at}hiroshima-u.ac.jp The establishment of clonal infection of hepatitis C virus (HCV) in a small-animal model is important for the analysis of HCV virology. A previous study developed models of molecularly cloned genotype 1a and 2a HCV infection using human hepatocyte-transplanted chimeric mice. This study developed a new model of molecularly cloned genotype 1b HCV infection. A full-length genotype 1b HCV genome, HCV-KT9, was cloned from a serum sample from a patient with severe acute hepatitis. The chimeric mice were inoculated intrahepatically with in vitro -transcribed HCV-KT9 RNA. Inoculated mice developed viraemia at 2 weeks post-infection, and this persisted for more than 6 weeks. Passage experiments indicated that the sera of these mice contained infectious HCV. Interestingly, a similar clone, HCV-KT1, in which the poly(U/UC) tract was 29 nt shorter than in HCV-KT9, showed poorer in vivo infectivity and replication ability. An in vitro study showed that no virus was produced in the culture medium from HCV-KT9-transfected cells. In conclusion, this study developed a genetically engineered genotype 1b HCV-infected mouse. This mouse model will be useful for the study of HCV virology, particularly the mechanism underlying the variable resistance of HCV genotypes to interferon therapy. The GenBank/EMBL/DDBJ accession numbers for the sequences of HCV-KT9 and HCV-KT1 determined in this work are AB435162 and AB426117, respectively.