Suri, Deepak; (2003) Non-cytolytic control of hepatitis B virus replication and the role of interleukin-12 (IL-12). Doctoral thesis (M.D), UCL (University College London).

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Abstract

Hepatitis B is a non-cytopathic virus that causes major morbidity worldwide. Data from animal models suggest that T lymphocytes can control hepatitis B virus (HBV) replication without killing infected hepatocytes through interferon-γ (IFN-γ). Furthermore, IFN-γ production is regulated by interleukin-12 (IL-12), which not only has a direct anti-viral effect but also promotes T helper-1 type cell- mediated immune responses, which are important in the control of HBV. The aim of this thesis was to investigate non-cytolytic control of HBV in human infection, and the role of virus-specific CD4+ T-cells in the resolution of chronic HBV infection. Furthermore, the role of IL-12 in human HBV infection and the potential of combining anti-viral and immunomodulatory drugs for the treatment of chronic HBV infection was investigated. Activated peripheral blood mononuclear cells (PBMC) from chronically infected HBV carriers reduced cytoplasmic HBV DNA in a liver cell line by releasing IFN-γ, and without killing hepatocytes. Furthermore, recombinant IFN-γ reduced the levels of HBV DNA in naturally infected hepatocytes by between 0.3 to 3 log10 and the level of HBV transcription by up to 71% non-cytolytically. Adoptive transfer of HBcAg-reactive CD4+T cells in bone marrow transplant recipients resulted in an ALT flare and the subsequent resolution of chronic HBV infection through the development of anti-HBs. IL-12 receptor (IL-12R) expression was reduced in chronic HBV infection as measured by flow cytometry. This may be a cause of the Th2 immune responses seen in chronic HBV infection. IL-12R expression could be increased to normal levels by recombinant human IL-12 (rhIL-12) resulting in Th1 effector functions. Combination therapy of lamivudine and IL-12 in chronically infected HBV patients has an enhanced anti-viral effect, which is associated with induction of HBcAg-specific CD4 T-cell reactivity and increased frequency of HBcAg- specific CD4+ T-cells, which produce IFN-γ.

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