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Journal of Virology, September 2008, p. 8579-8591, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.01022-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Intrahepatic Expression of Genes Affiliated with Innate and Adaptive Immune Responses Immediately after Invasion and during Acute Infection with Woodchuck Hepadnavirus{triangledown}

Clifford S. Guy,1 Patricia M. Mulrooney-Cousins,1 Norma D. Churchill,1 and Tomasz I. Michalak1,2*

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

Received 15 May 2008/ Accepted 23 June 2008

The importance of effective immune responses in recovery from acute hepadnaviral hepatitis has been demonstrated. However, there is no conclusive delineation of virological and immunological events occurring in the liver immediately after hepadnavirus invasion and during the preacute phase of infection. These very early events might be of primary importance in determining the recovery or progression to chronic hepatitis and the intrinsic hepadnaviral propensity to persist. In this study, applying the woodchuck model of acute hepatitis B, the hepatic kinetics of hepadnavirus replication and activation of genes encoding cytokines, cytotoxicity effectors, and immune cell markers were quantified in sequential liver biopsies collected from 1 h postinoculation onward by sensitive real-time cDNA amplification assays. The results revealed that hepadnavirus replication is established in the liver as early as 1 hour after infection. In 3 to 6 h, significantly augmented intrahepatic transcription of gamma interferon and interleukin-12 were evident, suggesting activation of antigen-presenting cells. In 48 to 72 h, NK and NKT cells were activated and virus replication was transiently but significantly reduced, implying that this early innate response is at least partially successful in limiting virus propagation. Nonetheless, T cells were activated 4 to 5 weeks later when hepatitis became histologically evident. Collectively, our data demonstrate that virus replication is initiated and the innate response activated in the liver soon after exposure to a liver-pathogenic dose of hepadnavirus. Nevertheless, this response is unable to prompt a timely adaptive T-cell response, in contrast to infections caused by other viral pathogens.

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

{triangledown} Published ahead of print on 2 July 2008.

Journal of Virology, September 2008, p. 8579-8591, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.01022-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Gujar, S. A., Michalak, T. I. (2009). Primary Occult Hepadnavirus Infection Induces Virus-Specific T-Cell and Aberrant Cytokine Responses in the Absence of Antiviral Antibody Reactivity in the Woodchuck Model of Hepatitis B Virus Infection. J. Virol. 83: 3861-3876 [Abstract] [Full Text]  


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