Creation of a transgenic pig model permissive to HBV infection

The lack of a convenient animal model that is susceptible to hepatitis B virus (HBV) infection has prevented the development of curative therapies for a disease chronically infecting over 300 million people worldwide. To address the need for a universally applicable large animal model that can be used to advance understanding of HBV biology and test curative strategies for chronic infection, the long-term goal is to establish an immunocompetent pig model susceptible to HBV infection. Prior studies have shown that the introduction of the HBV entry receptor, human sodium taurocholate cotransporting polypeptide (hNTCP), into pig hepatocytes in vitro was sufficient to mediate HBV infection and covalently closed circular DNA (cccDNA) genome formation. The central hypothesis is that pigs expressing hNTCP will be capable of replicating HBV at high levels and subsequently will establish chronic HBV infection in the liver with similar features to human patients. The innovation of the proposed research lies both in the (i) methods for interrogation of the most suitable DNA construct to accomplish the overall objective and (ii) the final deliverable – a transgenic animal that is susceptible to HBV infection, which is currently not available to the HBV field. The significance lies in providing a convenient, immunocompetent pig model capable of authentic HBV to test novel HBV therapeutic strategies. Thus, the proposed research benefits all, facilitating testing therapies stimulating HBV immunity toward the development of a cure for chronic HBV infection.