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Journal of Virology, September 2006, p. 8541-8553, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00830-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Inhibition by Woodchuck Hepatitis Virus of Class I Major Histocompatibility Complex Presentation on Hepatocytes Is Mediated by Virus Envelope Pre-S2 Protein and Can Be Reversed by Treatment with Gamma Interferon

Jinguo Wang1 and Tomasz I. Michalak1,2*

Molecular Virology and Hepatology Research, Division of Basic Medical Science,1 Discipline of Laboratory Medicine, Faculty of Medicine, Health Science Centre, Memorial University, St. John's, Newfoundland, Canada2

Received 21 April 2006/ Accepted 19 June 2006

Presentation of class I major histocompatibility complex (MHC) is severely down-regulated on hepatocytes in chronic hepatitis caused by woodchuck hepatitis virus (WHV). To determine which of the viral proteins mediates class I MHC antigen suppression, cultured normal woodchuck hepatocytes were transfected with the complete WHV genome, sequences encoding individual virus proteins, or whole virus genomes in which transcription of selected proteins was disabled by site-specific mutagenesis. It was found that hepatocyte presentation of class I MHC antigen was significantly inhibited following transfection with complete WHV genome or with viral subgenomic fragments encoding envelope pre-S2 protein or pre-S1 protein, which naturally encompasses pre-S2 amino acid sequence. In contrast, hepatocytes transfected with WHV X gene alone demonstrated a profound enhancement in the class I antigen display, whereas those expressing virus major S protein or nucleocapsid (core) protein were not different from control hepatocytes. Analysis of the mutated WHV sequences confirmed that the envelope pre-S2 protein was responsible for inhibition of the class I MHC antigen display. Interestingly, treatment with recombinant woodchuck gamma interferon (rwIFN-{gamma}) restored the inhibited presentation of the class I antigen. Moreover, the class I antigen suppression was not associated with down-regulation of hepatocyte genes for class I MHC heavy chain, ß2-microglobulin, transporters associated with antigen processing, and proteasome subunits. These findings indicate that the defective presentation of class I MHC antigen on hepatocytes transcribing WHV is a consequence of posttranscriptional suppression exerted by virus pre-S2 protein and that this hindrance can be fully reversed by IFN-{gamma}.

* Corresponding author. Mailing address: Molecular Virology and Hepatology Research, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, Canada A1B 3V6. Phone: (709) 777-7301. Fax: (709) 777-8279. E-mail: timich{at}mun.ca.

Journal of Virology, September 2006, p. 8541-8553, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00830-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dougherty, A. M., Guo, H., Westby, G., Liu, Y., Simsek, E., Guo, J.-T., Mehta, A., Norton, P., Gu, B., Block, T., Cuconati, A. (2007). A Substituted Tetrahydro-Tetrazolo-Pyrimidine Is a Specific and Novel Inhibitor of Hepatitis B Virus Surface Antigen Secretion. Antimicrob. Agents Chemother. 51: 4427-4437 [Abstract] [Full Text]  
  • Wang, J., Gujar, S. A., Cova, L., Michalak, T. I. (2007). Bicistronic Woodchuck Hepatitis Virus Core and Gamma Interferon DNA Vaccine Can Protect from Hepatitis but Does Not Elicit Sterilizing Antiviral Immunity. J. Virol. 81: 903-916 [Abstract] [Full Text]  


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