Grant: Project Grant

Hepatitis B virus (HBV) belongs to the most deadly human microbes. It causes life-threatening liver diseases, such as chronic hepatitis B, cirrhosis and liver cancer called hepatocellular carcinoma (HCC). More than 2 billion people (~1/3 of global population) show evidence of HBV infection, while 240-370 million have symptomatic chronic hepatitis B of which up to one million die annually. In Canada, ~270,000 individuals have chronic hepatitis B. We discovered that, in addition to symptomatic infection, HBV in humans and woodchuck hepatitis virus (WHV) in woodchucks cause asymptomatic (occult) chronic infection that can also culminate in development of HCC. This occult infection under certain conditions, like immunosuppression or anti-cancer therapy, can reactivate and cause sever hepatitis, liver failure and death. The mechanisms of this reactivation are unknown. Because HBV infects only humans and higher primates and the caused liver disease cannot be studied in cultured cells, the use of an appropriate animal model is essential. We developed a unique research facility at Memorial University in which woodchucks susceptible to WHV infection are studied. We also devised models of occult HBV infection in woodchucks. In this study, we want to reactivate occult infection in woodchucks by commonly used drugs, such as dexamethasone (corticosteroid) and a drug against rheumatoid arthritis and B cell lymphoma. We want to identify factors that predispose to development of severe hepatitis in occult infection and molecular mechanisms involved. By doing so, we can learn how to predict if reactivation may occur and what to do to prevent it. Also, the preclinical model for testing of new drugs for their HBV reactivation abilities will be established. In addition, we will learn about mechanisms of reactivation of other silent (latent) viral infections which complicate current treatments.