Identification of an intrahepatic transcriptional signature associated with self‐limiting infection in the woodchuck model of hepatitis B

Approximately 350 million individuals live with chronic hepatitis B (CHB), and over half a million people are estimated to die each year due to HBV-associated liver diseases, such as cirrhosis and hepatocellular carcinoma (HCC) (1). Defining the immune determinants of viral clearance during acute hepatitis B (AHB) and during successful treatment of CHB will likely support the development of improved therapeutic strategies to treat HBV infection. However, since the current therapies for CHB rarely lead to cure (2), and identification of patients in the early preclinical phase of AHB is challenging, animal models have been used to characterize the immune requirements of viral control. Studies of acute HBV infection in chimpanzees have identified the central role of CD8+ T cells in the resolution of viral infection (3, 4), and studies in transgenic (5, 6) and hydrodynamic (7) mouse models have also identified potentially important determinants of HBV clearance. Since ethical and cost issues limit the use of chimpanzees for biomedical research and there is no small animal model of natural HBV infection, further dissection of the host-virus interactions during self-limiting infection would greatly benefit from the availability of an alternative, well characterized, immunocompetent animal model of AHB. The Eastern woodchuck (Marmota monax) is naturally infected with WHV, a hepadnavirus closely related to human HBV. After experimental infection of neonatal woodchucks with WHV, 25-40% of animals resolve the infection, while the remainder become persistently infected and subsequently develop HCC (8). Therefore, the woodchuck has been used in a number of studies to characterize the immune correlates of viral control (9-12), but the lack of sequence information has previously precluded global transcriptional analysis. To address this major limitation of the model, we recently described the sequencing, assembly and annotation of the woodchuck transcriptome, together with the generation of custom woodchuck microarrays (13). Using this new platform, we initially characterized the intrahepatic transcriptional profiles of persistent WHV infection, and identified important parallels between the immune response to WHV in woodchucks and HBV in man (13). Since this first study established the translational value of the woodchuck model, we have now utilized the woodchuck microarray to characterize the immune determinants of WHV clearance during self-limiting infection.