Hepatitis B virus (HBV) remains as one the most common pathogens afflicting the human population despite the existence of an efficacious vaccine for the past 20 years. It is estimated that 350 million people worldwide are presently burdened with a persistent HBV infection and its associated sequelae, which include cirrohsis and hepatocellular carcinoma. Thus, there is an ever-growing need to develop curative strategies that relieve infected individuals of this unwieldy burden. At the heart of such intentions lies the need to more completely understand the successful array of biological defenses employed by the host during an acute HBV infection that does not result in persistence. HBV infection of the common chimpanzee has proved useful in evaluating this scenario, as it is the only species other than humans known to be infected by HBV. Depletion studies in infected chimpanzees have revealed that CD8+ T cells are an essential component of a successful HBV-specific immune response and also participate in immunopathogenesis. However, no study to date has visualized the HBV-specific component of the total CD8 population residing in the liver during viral clearance and the development of pathology. The proposed study will temporally quantify the frequency, topography, and interactions (i.e., immunologic synapses) of intrahepatic HBV-specific cytotoxic lymphocytes (CTL) using a novel methodology developed in a murine model system to analyze antigen-specific T cells in situ. The proposed study will also determine the impact of viral load on the quality and frequency of intrahepatic CTL interactions. The main objective of this research is to more precisely define the contribution of HBV-specific CTL to viral clearance and pathogenesis by providing the first comprehensive analysis of these cells in situ.
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| Brooks, David G; Trifilo, Matthew J; Edelmann, Kurt H et al. (2006) Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12:1301-9 |
