Role of lymphatic system in the persistence and pathogenesis of woodchuck hepatitis virus infection

Gujar, Shashi Ashok (2008) Role of lymphatic system in the persistence and pathogenesis of woodchuck hepatitis virus infection. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

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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