title: Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes.
abstract: Hepatitis B virus (HBV) core promoter mutations have been implicated in the pathogenesis of fulminant hepatitis B. Due to the limited availability of primary human hepatocytes, the functional characterization of HBV mutants has been performed predominantly in transformed cells, which may not represent ideal model systems for studying virus-cell interactions. We and others have shown that primary hepatocytes of the tree shrew Tupaia belangeri support HBV infection and replication. In this study, we used primary Tupaia hepatocytes to analyze the phenotype of two HBV core promoter mutations that have been associated with a clinical outbreak of fatal fulminant hepatitis. Similar to previous findings in human hepatoma cells, the HBV core promoter mutations resulted in enhanced viral replication and core expression. Surprisingly, however, the presence of the mutations had a marked effect on hepatocyte viability not previously observed in hepatoma cells. Reduced cell viability was found to be due to the induction of apoptosis, as evidenced by caspase-3 activation and nuclear fragmentation. In conclusion, HBV mutants exhibit a novel phenotype in primary hepatocytes distinctly different from previous findings in hepatoma cell lines. This phenotype may have important implications for the understanding of the fulminant clinical course associated with HBV mutations.
authors.affiliation: Department of Medicine II, University of Freiburg, Freiburg, Germany. Thomas.Baumert@uniklinik-freiburg.de <Thomas.Baumert@uniklinik-freiburg.de>
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Peter
authors.initials: P
authors.lastname: Schürmann
authors.forename: Josef
authors.initials: J
authors.lastname: Köck
authors.forename: Christian
authors.initials: C
authors.lastname: Ziegler
authors.forename: Carsten
authors.initials: C
authors.lastname: Grüllich
authors.forename: Michael
authors.initials: M
authors.lastname: Nassal
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Fritz
authors.initials: F
authors.lastname: von Weizsäcker
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D006509:Hepatitis B / Q000503:physiopathology* / Q000821:virology*; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology*; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D014161:Transduction, Genetic; D014417:Tupaia / Q000821:virology*
chemical_list: D006514:Hepatitis B Surface Antigens