Establishment of a non-transgenic mouse model for chronic hepatitisB virus infection

Abstract

OBJECTIVES: Chronic hepatitisB virus (HBV) infection is a severe worldwide public health problem. Although HBV transgenic mice have been developed to mimic the immune tolerant state of chronic HBV infection, lack of a non-transgenic mouse model make it difficult, to address what happen in the early phase of infection and how the outcome of viral infection (to be eliminated or persistent) is determined. This study aimed to develop a chronic HBV infection mouse model using a humanized mouse strain with HLA-transgenic H-2 knockout background (MHC-TgKO mouse). METHODS: 20 ug of pAAV/HBV1.2, a plasmid encoding 1.2-fold of HBV genome, was delivered into mouse tail rein by hydrodynamic injection. HBsAg, HBeAg and HBV DNA were monitored in one-week intervals during a period of over 6 months. Early immune responses to HBV antigens were also determined. RESULTS: The results showed that, over 60% of injected MHC-TgKO mice persistently produced HBsAg and HBV DNA for over 6 months, which met the criteria of chronic HBV infection in humans. HBV replicative intermediates and transcripts were exclusively detected in the liver carrier mice, but not in other organs. Similar to that in human, injected female mice had lower HBsAg persistent rate, HBsAg concentration and HBV DNA levels than the male. A significant lower immune response to HBcAg was detected in MHC-TgKO mice than that in C57BL/6 by ELISPOT assay, which may explain the high persistent rate in MHC-TgKO mice. CONCLUSION: This study has established a mouse model for chronic HBV infection, and further investigations are on going to characterize the virological and immunological properties in carrier mice.