Professor John Murray

School of Mathematics and Statistics

University of New South Wales

hepatitis B virus modelling

Globally 350 million people are chronically infected with hepatitis B virus (HBV), and it is responsible for 10% of liver transplants in Australia. Antiviral treatment of HBV infection is of limited success due to persistence of the template of HBV replication, the covalently closed circular DNA (cccDNA), present in the nucleus of infected hepatocytes. In contrast, immune-mediated clearance of HBV at acute infection is highly efficient. The processes that differentiate these outcomes are of considerable interest.

The half-life of HBV virions

The half-life of HBV virions has been ascertained from the dynamics of HBV DNA in sera of patients chronically HBV-infected and commencing antiviral therapy. Previously it was believed that the dynamics of HBV decay implied HBV virions had a half-life of approximately 1 day. In collaboration with groups in the US and Germany we used a more complete description of the HBV infection cycle, plus data from animal and human studies to show that virions are cleared much more quickly (Murray et al., Hepatology 2006), and clearance can increase with lower viral levels (Dandri et al., Hepatology 2008).

Clearance of cccDNA

Little is known about the molecular events occurring in the early phases of HBV infection and the mechanisms regulating formation and amplification of the intrahepatic cccDNA pool in vivo. It is also difficult to assess the exact contribution to cccDNA loss during cellular proliferation at acute infection given the difficulty of finding individuals in this stage of the disease, and the confounding effects of the adaptive immune response. It is also uncertain whether this same process operates as extensively and efficiently for individuals who are chronically infected. A greater understanding of cccDNA regulation and loss may lead to more efficient therapies, which are currently severely hampered by the long-term maintenance of these templates of infection. In collaboration with researchers in Germany, we are investigating cccDNA dynamics during cellular proliferation in a "humanized mouse" model (Lutgehetmann et al., Hepatology 2010).