CHARACTERIZING THE MECHANISM OF HEPATITIS B AND DELTA VIRUS HOST TROPISM IN MICE

Abstract

Worldwide, at least 296 million people are persistently infected with hepatitis B virus (HBV), which can lead to a broad spectrum of disease outcomes, including cirrhosis and/or hepatocellular carcinoma (HCC). Approximately 15-20 million chronic HBV carriers are co-infected with hepatitis delta virus (HDV), a small satellite virus reliant on HBV surface proteins (HBsAg) to form infectious virions. Co-infected patients experience a faster progression of liver disease and have the highest mortality rate (20%) of any of the viral hepatitis. It is widely believed that the outcome of these viral infections and the pathogenesis of the associated liver diseases are determined by host-virus interactions mediated by the immune response. Studies of the mechanisms of viral persistence, pathogenesis, and development of effective therapies for chronic hepatitis B and delta have been hampered by the scarcity of experimentally tractable animal models. Notably, HBV and HDV have a narrow host tropism, only infecting humans and chimpanzees. Due to ethical concerns, the use of chimpanzees in biomedical research has virtually ended creating an urgent need for small animal models supporting HBV and HDV infections. While mouse models transgenically expressing the human orthologue of the cellular receptor for HBV and HDV – sodium taurocholate co-transporting peptide (hNTCP) - and HBsAgs support HDV infection, HBV replication is still obstructed. Directly introducing the HBV genome into nuclei of mouse hepatocytes in vitro and in vivo facilitates assembly and release of infectious HBV virions, indicating that HBV is blocked at the step of nuclear import and/or capsid disassembly. This dissertation delves into the utility of current mouse models for characterizing early HDV kinetics and elucidates the mechanism of the HBV restriction barrier in mice. Research described in this thesis further identifies human nuclear import proteins, known as karyopherins, that can overcome this block when expressed in mouse hepatoma cells and lead to HBV replication. Results from this dissertation highlight a path for generating a mouse model with inherent susceptibility and permissiveness to HBV to further study HBV pathogenesis and therapeutics in vivo.