Murine Model for Hepatitis Antiviral/Anticancer Testing

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DESCRIPTION (provided by applicant): Persistent infection with hepatitis viruses, hepatitis B virus (HBV) and hepatitis C virus, (HCV) constitute a worldwide health problem that is growing in prevalence in the United States. Persistent infections are increasing the occurrence of primary hepatocellular carcinoma, (HCC), a cancer for which there is no effective therapy. Therefore, there is an urgent need for experimental systems that can model the process of persistent hepatitis infection and hepatocarcinogenesis. The woodchuck hepatitis virus (WHV) animal model has been integral in the testing and licensing of antiviral drugs for HBV. The aim of this application is to validate a novel murine-based model for large scale antiviral and anticancer testing. The model extends the usefulness of the WHV model by duplicating the persistent infection phase and modeling the hepatocarcinogenesis phase in mice in a much shorter time frame and potentially at a lower cost. The new model involves the transplantation of woodchuck or tupaia hepatocytes into immunocompromised "universal recipient" transgenic mice that contain a urokinase plasminogen activator, uPA transgene. This gene creates a mouse liver that readily accepts and allows growth of transplanted xenogenic hepatocytes. Recently, a dipeptidyl peptidase IV knockout allele (DPPIV-/-) has been added to the genotype of the recipient mice and this allows direct detection and quantitation of transplanted hepatocytes in a rapid and simple manner. This advance will simplify quantitative hepatocarcinogenesis assays and expand the use of the model into anticancer applications. Recent demonstration of transplantation of tupaia hepatocytes and their HBV infection in the model will be exploited to directly study antiviral and anticancer treatments for HBV. The experiments outlined are those needed to validate the woodchuck, and tupaia transplantation systems ("woodmice and tupaiamice" respectively) for large scale antiviral and anticancer testing. These studies also will position the tupaiamouse system for HCV research if the model is shown to be suitable for HCV infection in future studies.