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Journal of Virology, January 2007, p. 159-165, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01292-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of Alpha Interferon Signaling by Hepatitis B Virus{triangledown}

Verena Christen,1 Francois Duong,1 Christine Bernsmeier,1 Dianxing Sun,2 Michael Nassal,2 and Markus H. Heim1*

Department of Research, University Hospital Basel, CH-4031 Basel, Switzerland,1 Department of Medicine II, University Hospital Freiburg, D-79106 Freiburg, Germany2

Received 20 June 2006/ Accepted 13 October 2006

Alpha interferon (IFN-{alpha}) and pegylated IFN-{alpha} (pegIFN-{alpha}) are used for the treatment of chronic hepatitis B (CHB). Unfortunately, only a minority of patients can be cured. The mechanisms responsible for hepatitis B virus (HBV) resistance to pegIFN-{alpha} treatment are not known. pegIFN-{alpha} is also used to treat patients with chronic hepatitis C (CHC). As with chronic hepatitis B, many patients with chronic hepatitis C cannot be cured. In CHC, IFN-{alpha} signaling has been found to be inhibited by an upregulation of protein phosphatase 2A (PP2A). PP2A inhibits protein arginine methyltransferase 1 (PRMT1), the enzyme that catalyzes the methylation of the important IFN-{alpha} signal transducer STAT1. Hypomethylated STAT1 is less active because it is bound by its inhibitor, PIAS1. In the present work, we investigated whether similar molecular mechanisms are also responsible for the IFN-{alpha} resistance found in many patients with chronic hepatitis B. We analyzed the expression of PP2A, the enzymatic activity of PRMT1 (methylation assays), the phosphorylation and methylation of STAT1, the association of STAT1 with PIAS1 (via coimmunoprecipitation assays), the binding of activated STAT1 to interferon-stimulated response elements (via electrophoretic mobility shift assays), and the induction of interferon target genes (via real-time RT-PCR) in human hepatoma cells expressing HBV proteins as well as in liver biopsies from patients with chronic hepatitis B and from controls. We found an increased expression of PP2A and an inhibition of IFN-{alpha} signaling in cells expressing HBV proteins and in liver biopsies of patients with CHB. The molecular mechanisms involved are similar to those found in chronic hepatitis C.

* Corresponding author. Mailing address: Department of Research, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Phone: 41 61 265 25 25. Fax: 41 61 265 53 52. E-mail: markus.heim{at}unibas.ch.

{triangledown} Published ahead of print on 25 October 2006.

Journal of Virology, January 2007, p. 159-165, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01292-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Randall, R. E., Goodbourn, S. (2008). Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 89: 1-47 [Abstract] [Full Text]  
  • Wu, M., Xu, Y., Lin, S., Zhang, X., Xiang, L., Yuan, Z. (2007). Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Stat1. J. Gen. Virol. 88: 3260-3269 [Abstract] [Full Text]  


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