The hepatitis B virus (HBV) is a noncytopathic, hepatotropic DMAvirus that causes acute and chronic hepatitis and kills a million people each year from cirrhosis of the liver and hepatocellular carcinoma. Delineation of the mechanisms responsible for viral persistence and disease pathogenesis during HBV infection and the use of that information to develop strategies to terminate chronic HBV infection are the long term objectives of this application. Building on our prior studies showing that the course and severity of acute HBV infection are related to the kinetics, magnitude, and quality of the intrahepatic T cell response, we recently developed a model of persistent HBV infection in young adult chimpanzees. Preliminary evidence suggests that viral persistence in these animals reflects the failure to prime the T cell response at the outset of infection, thus compromising the kinetics, magnitude and quality of the downstream effector functions required to terminate the infection. The establishment of this model is a practical as well as a conceptual breakthrough because, for the first time, it creates the opportunity to study the host-virus interactions responsible for the establishment, maintenance, and termination of chronic HBV infection under controlled experimental conditions in healthy immunocompetent adults. The main objectives of the current application, therefore, are to define the early immunological and molecular events that precede the onset of persistent HBV infection and that evolve during its progression, to apply that knowledge to establish a cohort of persistently infected animals, and to use those animals to examine the therapeutic potential of novel immunomodulatory strategies to eliminate the virus and, hopefully, cure this deadly disease.
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