Transient and chronic infections by a hepatitis B virus involve every hepatocyte in the liver and trigger an immune response that leads to inflammation. A difference between transient and chronic disease is that the former suddenly ceases, often without overt symptoms, whereas the alter may persist for life. A major question thus concerns the nature of the host responses that play a role in recovery. Using woodchuck hepatitis virus infection of woodchucks as a model for HBV, we have found that the immune system is able to rapidly eliminate virus from the liver by mechanisms that involve both cell killing and cell curing. The long term objective of our research is now to determine how the immune response (endogenous immune response) achieved this outcome and how an immunotherapy might be designed, based on this formation, for the treatment of chronic infections. Towards this objective, we will i) clone woodchuck T-cell markers and cytokines known to act as mediators in antiviral immune responses; ii) characterize the endogenous immune response during chronic infections and during the course of a transient infection and, in particular, during the critical clearance phase and iii) examine the possibility of curing chronic infections through the temporal expression of specific cytokine sin the liver, including woodchuck interferon gamma and TNF alpha. Accordingly, experiments have been designed to obtain a comprehensive picture of the critical recovery phase of a transient infection, in reference to viral infection within individual hepatocytes, hepatocyte turnover and the endogenous immune response. It is anticipated that the results from these studies will reveal how changes in cytokine expression and T-cell responses in transient infections lead to the start of virus clearance, as well as providing clues as to why chronic infections fail to clear. Information gained from our results will be exploited for the development of anti-viral strategies using recombinant adenovirus vectors that permit expression of immunological mediators in livers in chronically infected animals.
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| Balsara, B R; Pei, J; De Rienzo, A et al. (2001) Human hepatocellular carcinoma is characterized by a highly consistent pattern of genomic imbalances, including frequent loss of 16q23.1-24.1. Genes Chromosomes Cancer 30:245-53 |
