The hepatitis B virus-trimera mouse: A model for human HBV infection and evaluation of Anti-HBV therapeutic agents

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 stud y, we describe the development of a mouse Trimera model for human hepatitis B virus (HBV) infection. In this model, viremia is induced by transplantat ion of ex vivo HBV-infected human liver fragments. Engraftment of the human liver fragments, evaluated by hematoxylin-eosin staining and human serum a lbumin mRNA expression, was observed in 85% of the transplanted animals 1 m onth postimplantation. Viremia levels were determined in these mice by meas uring serum HBV DNA using polymerase chain reaction (PCR), followed by dot- blot hybridization, HBV DNA is first detected 8 days after liver transplant ation. Viremia attains a peak between days 18 and 25 when HBV infection is observed in 85% of the transplanted animals. The HBV-Trimera model was used to evaluate the therapeutic effects of human polyclonal anti-HBs antibodie s (Hepatect) and of two reverse-transcriptase inhibitors, lamivudine (3TC) and beta-L-S-fluoro-2',3'-dideoxycytidine (beta-L-5FddC). Treatment of HBV- Trimera mice with these drugs effectively reduced both the percentage of in fected animals and the viral load in their sera. Treatment cessation result ed in rebound of viral load, indicating HBV replication upon drug withdrawa l. These results show that the HBV-Trimera model represents a novel experim ental tool for simulating human HBV infection and evaluating potential anti -HBV therapeutic agents.