| Summary: | 博士 === 國立臺灣大學 === 微生物學研究所 === 100 === The mechanism underlying the chronicity of hepatitis B virus (HBV) infection has long eluded researchers. The mechanism has remained unclear largely due to the lack of an animal model that can support persistent HBV replication and allow for the investigation of the relevant immune responses. In this study, we used hydrodynamic injection to introduce HBV replicon DNA into the livers of three different mouse strains, BALB/c, C57BL/6, and FVB/N. Interestingly, we found that an HBV clone persistently replicated in the livers of FVB/N mice for up to 50 weeks but was rapidly cleared from the livers of BALB/c and C57BL/6 mice. Flow cytometric analysis and quantitative reverse transcription PCR analysis of the mouse livers indicated that after DNA injection, FVB/N mice had few intrahepatic activated cytotoxic T lymphocytes (CTLs) and produced low levels of alanine aminotransferase, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and the CXCL9 and CXCL10 chemokines. These responses were in sharp contrast to those observed in BALB/c and C57BL/6 mice, reflecting a strong correlation between the degree of liver inflammation and viral clearance. Mutational analysis further demonstrated that a change from Asn-214 to Ser-214 in the HBV surface antigen permitted the clearance of the persistent HBV clone in FVB/N mice, and the response was accompanied by increased levels of activated CTLs and upregulated liver expression of IFN-γ, CXCL9, and CXCL10. The model was demonstrated to be useful for the in vivo evaluation of the efficacies of various anti-HBV drugs. Supplementary expression of CXCL9, CXCL10 and C5a in the carrier mice enhanced the clearance of the chronic infection. These results indicate that the heterogeneity of the host factors and viral sequences may influence the immune responses against HBV. An inadequate activation of immune or inflammatory responses can lead to persistent HBV replication in vivo.
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