| Summary: | Thesis (Ph.D.)--Memorial University of Newfoundland, 2009. Medicine Includes bibliographical references (leaves 296-325) Hepatitis B virus (HBV) causes acute liver inflammation that apparently resolves completely or advances to chronic hepatitis, cirrhosis and hepatocellular carcinoma. These differential outcomes of HBV infection are orchestrated to a large extent by the virus-specific T cell responses, which characteristically appear late after exposure to hepadnavirus. In this context, the objective of this study was to delineate the kinetics and understand inter-relationships between virus-specific and non-specific T cell proliferative, humoral as well as innate cytokine responses, along with serological and molecular markers of hepadnaviral infection induced after exposure and re-exposure to liver pathogenic or nonpathogenic doses of woodchuck hepatitis virus (WHV). Our results revealed that infection of woodchucks with either a liver pathogenic (>103 virions) or nonpathogenic (<103 virions) dose of WHV induced strong, but delayed, virus-specific T cell responses with comparable kinetics. Interestingly, immediately after exposure to virus, the non-specific proliferative capacity of lymphocytes in response to mitogenic stimulation was heightened and then subsided preceding the appearance of WHV-specific T cell response. This augmented non-specific proliferative reactivity was accompanied by the increased expression of interferon-alpha (IFN-α), interleukin-12 (IL-12) and IL-2 in circulating lymphoid cells; while its decline was associated with activation-induced cell death of lymphocytes. Importantly, the postponement of virus-specific T cell response coincided with the absence of TNF-α expression, while its rise was marked by synchronously elevated expression of TNF-α, IFN-α, IFN-γ, IL-2, IL-12, and IL-10 in lymphoid cells. Nonetheless, the virus-specific T cell responses induced during low-dose (occult) infection, in contrast to infection caused by liver pathogenic dose, did not provide protection against viral hepatitis. -- We conclude that hepadnavirus infections induce delayed virus-specific T cell proliferative responses irrespective of the dose of invading virus and symptomatic or asymptomatic outcome of the infection. This postponement of anti-viral T cell responses is preceded by the aberrant activation of lymphocyte and innate cytokine responses. Such an impaired activation of immune responses following hepadnavirus infection represents a possible mechanism that allows evasion of initial clearance and subsequent elimination of virus, permits its dissemination, and contributes to the establishment of persistence.
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