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.
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 (>10(3) 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.
Gujar
Shashi A
SA
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.
Michalak
Tomasz I
TI
D000818:Animals; D001769:Blood / Q000382:microbiology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005500:Follow-Up Studies; D006509:Hepatitis B / Q000276:immunology*; D006510:Hepatitis B Antibodies / Q000276:immunology*; D017919:Hepatitis B Virus, Woodchuck / Q000276:immunology; D008099:Liver / Q000276:immunology; D008392:Marmota; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006510:Hepatitis B Antibodies