Hepatocellular carcinoma (HCC) is now a firmly established and largely incurable complication of chronic HCV, and its prevalence in this country will continue to grow as a large cohort of patients infected decades ago comes to clinical attention. While most cases appear to arise in the setting of chroinic inflammation, cirrhosis, and regeneration, the pathogenesis of HCV-related HCC remains unknown. Transgenic mouse models permit the opportunity to examine the effects of selective expression of viral proteins. A recent report has suggested that transgenic mice expressing the HCV core protein alone develop HCC. We have created a transgenic mouse model that successfully expresses HCV core as well as the two envelope glycoproteins (core-E1-E2); however, these animals do not develop liver disease. The basis for these observed differences is unknown.
We are exploring the contributions of three major arms to HCV-related HCC: (1) viral protein expression; (2) host genetic predisposition; and (3) the host immune response. To accomplish this, we wil use novel transgenic mouse models to explore the direct contribution of both HCV structural and nonstructural proteins to transformation. We have also crossed our transgenic HCV structural protein mice with NF2 +/- heterozygotes that spontaneously develop HCC in a large portion of aging animals. This cross will allow us to "read out" the contribution of viral protein expression to HCC development (by increased frequency or acceleration of HCC formation), as well as to determine whether HCV-induced HCC requires a host genetic predisposition. We are also creating a novel, inducible transgenic model that expresses the full length HCV polyprotein (and which replicates HCV RNA in transfection studies) to explore the contribution of activation of the host immune system to HCV-related hepatocarcinogenesis. Finally, we are using the core mouse to examine the longitudinal events in gene expression to determine which host genes contribute to disease progression in this model. Together, these models will help dissect the factors responsible for this devastating complication of chronic HCV infection.