Transcriptomic analysis of the woodchuck model of chronic hepatitis B

Approximately 350 million individuals live with CHB, and over 500,000 people die each year due to HBV-associated liver diseases, such as cirrhosis and HCC (1). Pegylated interferon-α (IFN-α) and various nucleos(t)ides are currently licensed for the treatment of CHB, but while these therapies reduce viremia and improve long-term outcome, they rarely lead to cure (2). There is, therefore, an urgent need to develop novel antiviral therapies to achieve this goal. Due to the difficulty in obtaining liver biopsy specimens from chronically infected patients, much of what has been learned about human HBV has been determined in animal models. Studies of acute infection in transgenic (3, 4) and hydrodynamic (5) mouse models and also in chimpanzees (6) have provided useful insights into immunological mechanisms that may contribute to the outcome of HBV infection. However, the immune correlates of cure of chronic HBV infection, and the role of host-virus interactions in persistent infection, are still ill defined. Characterization of these complex immunological phenomena has been hampered by the lack of a well characterized, immunocompetent small animal model of CHB. This therefore remains an important goal, since identification of the mechanism(s) by which HBV escapes or circumvents the host immune response will likely contribute to the identification of novel targets with potential to lead to new antiviral therapies. The Eastern woodchuck (Marmota monax) is naturally infected with WHV, a hepadnavirus which is genetically closely related to human HBV, and has a disease course similar to that in HBV-infected persons (7). As such, the woodchuck has been used to study viral pathogenesis, and to evaluate antiviral and anticancer therapeutics (7). However, a notable limitation of this model is that transcriptional analysis of the woodchuck is restricted to a few hundred sequenced gene segments. To address this shortcoming, we report here the sequencing, assembly and annotation of the woodchuck transcriptome, together with the generation of woodchuck microarrays. By using this new platform, we describe the first global transcriptional analysis of persistent WHV infection and WHV-induced HCC.