Transplantation of Human Hepatocytes in Immunodeficient UPA Mice: A Model for the Study of Hepatitis B Virus

Persistent infection with hepatitis B virus (HBV) is a major worldwide health problem, and chronically infected individuals are at high risk for developing liver cirrhosis and hepatocellular carcinoma (1 ,2 ). Despite the availability of an HBV vaccine, there are still more than 350 million chronically infected people worldwide, and the few antiviral treatments currently available have a limited rate of efficacy. As for other infectious diseases in humans, advances in the study of viral hepatitis have been critically dependent on the development of suitable experimental systems. Replication of HBV can be successfully achieved by transfecting hepatoma cell lines with cloned HBV DNA genomes. However, the lack of culture systems permissive for hepadnavirus infection and the narrow host range of HBV have hampered the understanding of some crucial events of the hepadnavirus life cycle, as well as the development of more effective antiviral drugs aimed at eradicating the virus from chronic carriers. Although HBV has been grown successfully in cultures of human hepatocytes, primary human hepatocytes are difficult to maintain in culture and become nonpermissive for HBV very soon after plating. In addition, they normally differ in function and gene expression from hepatocytes integrated in the liver architecture. Therefore, any technique that would allow keeping human hepatocytes in an environment that supports both cell growth and liver-specific differentiation would offer unique opportunities to study human hepatotropic viral infections and to evaluate the efficacy of novel antiviral drugs in a system closely mimicking the in vivo situation.