Viral Hepatitis

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Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes†

  1. Thomas F. Baumert1,‡,*,
  2. Chun Yang1,
  3. Peter Schürmann1,
  4. Josef Köck1,
  5. Christian Ziegler2,
  6. Carsten Grüllich2,
  7. Michael Nassal1,
  8. T. Jake Liang3,
  9. Hubert E. Blum1,
  10. Fritz von Weizsäcker1

Article first published online: 19 JAN 2005

DOI: 10.1002/hep.20553

Issue

Hepatology

Hepatology

Volume 41, Issue 2, pages 247–256, February 2005

Additional Information

How to Cite

Baumert, T. F., Yang, C., Schürmann, P., Köck, J., Ziegler, C., Grüllich, C., Nassal, M., Liang, T. J., Blum, H. E. and von Weizsäcker, F. (2005), Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes. Hepatology, 41: 247–256. doi: 10.1002/hep.20553

Author Information

  1. 1

    Departments of Medicine II, University of Freiburg, Freiburg, Germany

  2. 2

    Medicine I, University of Freiburg, Freiburg, Germany

  3. 3

    Liver Diseases Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD

  1. ‡

    fax: (49) 761-270-3610

*Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany

  1. †

    Conflict of interest: Nothing to report.

  2. ‡

    fax: (49) 761-270-3610

Publication History

  1. Issue published online: 19 JAN 2005
  2. Article first published online: 19 JAN 2005
  3. Manuscript Accepted: 8 NOV 2004
  4. Manuscript Received: 13 JUN 2004

Funded by

  • German Research Council, Bonn, Germany. Grant Number: Ba1417/5-2
  • Bundesministerium für Bildung und Forschung, Bonn, Germany. Grant Number: 01KI9951
  • China Program of the Department of Medicine II, University of Freiburg, Freiburg, Germany

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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. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2005.)41:247–256

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