The Hepatitis B Virus-Trimera Mouse: A Model for Human Hbv Infection and Evaluation of Anti–Hbv Therapeutic Agents

Abstract

Previous studies have demonstrated the feasibility of implantation of human blood cells or tissues in lethally irradiated mice or rats, radioprotected with SCID mouse bone marrow cells: The Trimera system. In the present study, we describe the development of a mouse Trimera model for human hepatitis B virus (HBV) infection. In this model, viremia is induced by transplantation of ex vivo HBV-infected human liver fragments. Engraftment of the human liver fragments, evaluated by hematoxylin-eosin staining and human serum albumin mRNA expression, was observed in 85% of the transplanted animals 1 month postimplantation. Viremia levels were determined in these mice by measuring serum HBV DNA using polymerase chain reaction (PCR), followed by dot-blot hybridization. HBV DNA is first detected 8 days after liver transplantation. Viremia attains a peak between days 18 and 25 when HBV infection is observed in 85% of the transplanted animals. Hepatitis B virus (HBV) infection is a major public health problem affecting millions of people worldwide. 1 Following acute HBV infection, 5% to 10% of the adult patients will develop persistent infection that may lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. 2-4 Whereas considerable progress has been achieved regarding the identification and characterization of the virus, the development of new, effective therapies has been impeded because of the lack of a practical small HBV animal model. Attempts to establish animal models to study HBV infection in rats, 5 nude mice, 6 and transgenic mice 7-9 have been described. Other animal models, based on HBV-related hepadnaviruses that infect nonprimates, were developed and successfully used for assessment of antiviral drugs. These models, however, involve relatively large animals that are difficult to handle in most laboratories. In addition, testing of antiviral agents such as nucleoside analogs could produce aberrant results as a consequence of virus-specific differential susceptibility of the viral polymerase. 10 Chimpanzees provide a good HBV animal model in which effects of vaccines and therapeutic agents can be evaluated. 11 Nonetheless, the limited availability and the high cost of these primates severely restrict their use for such purposes.Recently, we have developed a human-mouse radiation chimera in which normal mice, preconditioned by lethal total body irradiation and radioprotected with SCID mouse bone marrow cells, are permissive for engraftment of human hematopoietic cells and tissues. [12][13][14][15][16] This resulting humanmouse model that comprises three genetically disparate sources of tissue is therefore termed ''Trimera.'' The Trimera mouse, engrafted with human peripheral blood lymphocytes, has been adapted successfully to generate human monoclonal antibodies. 17 Likewise, transplantation of Trimera mice with hepatitis C virus-infected human liver tissue was used for the development of an hepatitis C virus infection model. 14 In the present study, we describe in detail the development of an HBV ani...

Repopulation of Mouse Liver With Human Hepatocytes And In Vivo Infection With Hepatitis B Virus

“…Clearly, our system will offer the possibility to test antivirals that interfere not only with viral replication, but also with viral spread. In 2 other recently reported xenotransplantation models, cell engraftment was achieved by implanting human liver slices 42 or hepatocyte suspensions 43 extrahepatically, under the kidney capsule of immunodeficient mice. Although production of HBV was demonstrated, both these systems allowed survival, but not growth, of human hepatocytes in mice.…”

Infection of Human Hepatocyte Chimeric Mouse With Genetically Engineered Hepatitis B Virus *

“…The HBVtrimera mouse is another useful mouse model. 13 In this model, ex vivo HBV-infected human liver fragments are implanted into lethally irradiated mice after SCID mouse bone marrow transplantation. Approximately 80% of the mice develop viremia 2 to 3 weeks after infection.…”

Of mice and men: A small animal model of hepatitis C virus replication

“…Implantation of human hepatocytes or liver slices under the kidney capsule of immunodeficient mice allowed their infection with HBV and the delta agent. 9,10 Moreover, Petersen et al successfully reconstituted the liver of Alb-uPA/RAG2 mice with woodchuck and human hepatocytes, allowing productive infection with woodchuck hepatitis virus and HBV, respectively. 11,12 The report by Mercer et al represents a logical extension of these studies and a significant breakthrough in the development of small animal models of HCV infection.…”