Project 466785

Hepatitis B virus (HBV) has established chronic infections in more than 296 million individuals worldwide and is associated with liver cancer and cirrhosis. Lifelong regiments of nucleos(t)ide analogs suppress viral replication, but fail to achieve a virological cure due to the stable covalently closed circular DNA (cccDNA) established in infected cells. The woodchuck hepatitis virus (WHV) naturally infects eastern North American woodchucks and also belongs to the Hepadnaviridae family, resulting in an animal model that is pathogenically compatible to HBV infections in humans. The woodchuck-WHV model shares many characteristics with the human-HBV model, such as genome size, disease progression patterns and age-dependent risk of chronicity. We aim to investigate the importance of resident macrophages known as Kupffer cells (KCs) in influencing the outcome of acute WHV infections by selectively depleting them in a subset of woodchucks using chlodronate liposomes (CLL). We predict that weakened KC function leads to viral persistence in susceptible hosts. By optimizing WHV-specific assays to assess both intrahepatic and systemic responses to acute WHV infections, we aim to monitor protein markers using Enzyme Linked Immunosorbent Assays (ELISAs) and nucleic acid markers of infection using qualitative PCR (qPCR).We also seek to develop a productive cell line for the standardization of the described assays and generation of purified WHV stocks. Woodchucks treated with CLLs will be compared to control woodchucks using systemic and intrahepatic serological markers as well as the optimized assays. The application of these findings to human HBV infections will navigate our understanding of virus-host interactions in the liver and viral disease outcomes.