Sustained survival of human hepatocytes in mice: A model for in vivo infection with human hepatitis B and hepatitis delta viruses

Persistence of hepatocytes transplanted into the same or related species ha s been established(1-8). The long-term engraftment of human hepatocytes int o rodents would be useful for the study of human viral hepatitis, where it might allow the species, technical and size limitations of the current anim al models to be overcome. Although transgenic mice expressing the hepatitis B virus (HBV) genome produce infectious virus in their serum, the viral li fe cycle is not complete, in that the early stages of viral binding and ent ry into hepatocytes and production of an episomal transcriptional DNA templ ate do not occur(9,10). As for hepatitis delta virus (HDV), another cause o f liver disease(11,12), no effective therapy exists to eradicate infection, and it remains resistant even to recent regimens that have considerably ch anged the treatment of HBV (ref. 13). Here, we demonstrate long-term engraf tment of primary human hepatocytes transplanted in a matrix under the kidne y capsule of mice with administration of an agonistic antibody against c-Me t. These mice were susceptible to HBV infection and completion of the viral life cycle. In addition, we demonstrate super-infection of the HBV-infecte d mice with HDV. Our results describe a new xenotransplant model that allow s study of multiple aspects of human hepatitis viral infections, and may en hance studies of human liver diseases.