Construction and analysis of viral hepatocarcinogenesis model using HCV transgenic mouse model

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Missing of proper culture system and animal model has hampered fine analysis of viral life cycle and pathogenesis of HCV infection, especially hepatocarcinogenesis. We established hepatitis C virus (HCV) transgenic mice mediated by Cre/loxP system using HCV cDNA including core, E1, E2 and NS2 gene. Intravenous infection of a recombinant adenovirus which expresses Cre DNA recombinase (AxCANCre) induced HCV structural protein expression in the liver of the transgenic mouse. HCV core protein production and transgene recombination in the mouse liver were serially evaluated after AxCANCre infusion. Core protein was efficiently expressed and transgene was almost totally recombinated in mouse liver after 3 days, then the levels of both core protein production and transgene recombination continuously decreased for 28 days. However, 30.6% of trasgene recombination remained at 28 days and only 2.7% of core production remained at 28 days after infection. Compared with non-transgenic controls, serum alanine aminotransferase levels of transgenic mice were significantly higher 10, 14 and 21 days after adenovirus infection. Histological scoring also indicated severe pathological changes in the liver of transgenic mice after adenovirus injection. AxCANCre infusion increased CD8^+ lymphocyte infiltration into the liver of transgenic mice compared with that of non-transgenic controls. Furthermore, cytotoxic T lymphocytes (CTLs) isolated from transgenic mice during liver injury were specific for the HCV proteins, E1, E2 and NS2 but not for core protein. These results suggest that HCV structural proteins expressed in the liver of transgenic mouse enhanced liver injury. The function of HCV-specific CTLs may be to enhance hepatitis. This transgenic mouse model system allows us to analyze the functions of viral products and host immune system in HCV infection and hepatocellular carcinogenesis of HCV.