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Journal of Virology, April 2009, p. 3861-3876, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02521-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Shashi A. Gujar1 and Tomasz I. Michalak1,2*

Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences,1 Discipline of Laboratory Medicine, Faculty of Medicine, Health Sciences Centre, Memorial University, St. John's, Newfoundland A1B 3V6, Canada2

Received 8 December 2008/ Accepted 27 January 2009

Although the virological features of serologically silent hepadnaviral primary occult infection (POI) have been relatively well recognized in the woodchuck model of hepatitis B virus infection, the characteristics of accompanying immune responses remain unknown. In this study, the kinetics of woodchuck hepatitis virus (WHV)-specific and generalized (mitogen-induced) T-cell proliferative responses and cytokine expression profiles in circulating lymphoid cells and the liver, along with WHV-specific antibody responses, were investigated during experimentally induced POI and subsequent challenge with a liver-pathogenic dose (>103 virions) or liver-nonpathogenic dose (50 virions) of the same virus. The data revealed that POI, which does not prompt WHV surface antigenemia, antiviral antibody response, and hepatitis or protect from challenge with a liver-pathogenic virus dose, was accompanied by the appearance of a strong WHV-specific T-cell response directed against multiple viral epitopes that intermittently persisted at low levels for up to 10-months during follow-up. Furthermore, immediately after exposure to a liver-nonpathogenic dose of WHV, lymphocytes acquired a heightened capacity to proliferate in response to mitogenic stimuli and displayed augmented expression of alpha interferon, interleukin-12 (IL-12), and IL-2, but not tumor necrosis factor alpha. Overall, the kinetics of WHV-specific and mitogen-induced T-cell proliferative and cytokine responses in POI were closely comparable to those seen in infection induced by liver-pathogenic viral doses. The data demonstrated that virus-specific T-cell proliferative reactivity is a very sensitive indicator of exposure to hepadnavirus, even to small amounts inducing serologically mute infection. They also showed that hepadnaviral POI is not only a molecularly but also an immunologically identifiable and distinctive entity.

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

{triangledown} Published ahead of print on 4 February 2009.

Journal of Virology, April 2009, p. 3861-3876, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02521-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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