Nature Medicine
6, 327 - 331 (2000)
doi:10.1038/73187
Sustained survival of human hepatocytes in mice: A model for in vivo infection with human hepatitis B and hepatitis delta virusesKazuo Ohashi1, Patricia L. Marion2, Hiroyuki Nakai1, Leonard Meuse1, John M. Cullen3, Bruno B. Bordier4, Ralph Schwall5, Harry B. Greenberg4, Jeffrey S. Glenn4
& Mark A. Kay11
Program in Human Gene Therapy, Department of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
2
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
3
College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA
4
Division of Gastroenterology, Stanford University School of Medicine, and Veterans Administration Medical Center, Palo Alto, California 94305, USA
5
Department of Molecular Oncology, Genentech, South San Francisco, California 94080, USA
Correspondence should be addressed to Mark A. Kay markay@stanford.eduPersistence of hepatocytes transplanted into the same or related species has been established1,
2,
3,
4,
5,
6,
7,
8. The long-term engraftment of human hepatocytes into rodents would be useful for the study of human viral hepatitis, where it might allow the species, technical and size limitations of the current animal models to be overcome. Although transgenic mice expressing the hepatitis B virus (HBV) genome produce infectious virus in their serum, the viral life cycle is not complete, in that the early stages of viral binding and entry into hepatocytes and production of an episomal transcriptional DNA template do not occur9,
10. As for hepatitis delta virus (HDV), another cause of liver disease11,
12, no effective therapy exists to eradicate infection, and it remains resistant even to recent regimens that have considerably changed the treatment of HBV (ref. 13). Here, we demonstrate long-term engraftment of primary human hepatocytes transplanted in a matrix under the kidney capsule of mice with administration of an agonistic antibody against c-Met. These mice were susceptible to HBV infection and completion of the viral life cycle. In addition, we demonstrate super-infection of the HBV-infected mice with HDV. Our results describe a new xenotransplant model that allows study of multiple aspects of human hepatitis viral infections, and may enhance studies of human liver diseases.
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