Establishment of laboratory transgenic mouse strains for hepatitis C virus infection

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The hepatitis C virus (HCV) is the major causative agent of non-A/non-B hepatitis. A major characteristic of HCV infection is the extremely high (up to 80%) risk of chronicity; in addition, chronic infection of HCV can frequently leads to liver cirrhosis and hepatocellular carcinoma. An important issue regarding the pathogenesis of HCV-associated liver lesions is to determine whether HCV proteins might have a direct effect on cellular phenotype. however, little was known about this respect. To address this question, we tried to establish animal model for HCV. Introducing an efficient Cre/loxP conditional transgenesis, we created several lines of transgenic mice with HCVcDNA (nucleotides 294-3435). After administration of adenovirus that expresses Cre recombinase, the HCV genome introduced as a transgene can express several HCV-specific core proteins in most hepatocytes of the transgenic mice. Moreover, pathological changes and elevated level of serum alanine animotransferase suggested that liver injury occurred in the transgenic mice that express the HCV transgene. A CD4 and CD8 positive cells depletion assay normalized both the serum alanine aminotransferase increases and the pathological changes in the liver. These results suggested that HCV proteins are not directly cytopathic and that the host immune response plays a pivotal role in HCV infection. Thus, this HCV cDNA transgenic mouse provides a powerful tool with which to investigate the immune responses and pathogenesis of HCV infection.