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The human liver chimeric mouse is a milestone animal model for hepatitis B virus (HBV) infection. Such mice with primary human hepatocyte (PHH) transplantation are adequate to support chronic HBV infection for several weeks and to evaluate antiviral drugs. However, the drawbacks of PHHs include lack of available donors, poor expansion in vitro and ethical issues that limit the application of human liver chimeric mice, necessitating the search for alternatives. Here, we transplanted primary tupaia hepatocytes (PTHs) into the livers of immunodeficient mice and achieved high liver chimerism within six weeks. These tupaia liver chimeric mice are adequate to support chronic infection of the four common HBV genotypes A, B, C and D for 36 weeks, as well as evaluate of antiviral drugs, including hepatitis B immune globulin (HBIG), monoclonal antibody and nucleoside analogues (NAs), for preventative therapy and treatment post infection. In conclusion, the tupaia liver chimeric mouse model provides a convenient, efficient and stable animal model for chronic HBV infection and long-term drug evaluation.

Background & Aims Human liver chimeric mice are useful models of human hepatitis virus infection, including hepatitis B and C virus infections. Independently, immunodeficient mice reconstituted with CD34 + hematopoietic stem cells (HSC) derived from fetal liver reliably develop human T and B lymphocytes. Combining these systems has long been hampered by inefficient liver reconstitution of human fetal hepatoblasts. Our study aimed to enhance hepatoblast engraftment in order to create a mouse model with syngeneic human liver and immune cells. Methods The effects of human oncostatin-M administration on fetal hepatoblast engraftment into immunodeficient fah −/− mice was tested. Mice were then transplanted with syngeneic human hepatoblasts and HSC after which human leukocyte chimerism and functionality were analyzed by flow cytometry, and mice were challenged with HBV. Results Addition of human oncostatin-M enhanced human hepatoblast engraftment in immunodeficient fah −/− mice by 5–100 fold. In contrast to mice singly engrafted with HSC, which predominantly developed human T and B lymphocytes, mice co-transplanted with syngeneic hepatoblasts also contained physiological levels of human monocytes and natural killer cells. Upon infection with HBV, these mice displayed rapid and sustained viremia. Conclusions Our study provides a new mouse model with improved human fetal hepatoblast engraftment and an expanded human immune cell repertoire. With further improvements, this model may become useful for studying human immunity against viral hepatitis. Lay summary Important human pathogens such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus only infect human cells which complicates the development of mouse models for the study of these pathogens. One way to make mice permissive for human pathogens is the transplantation of human cells into immune-compromised mice. For instance, the transplantation of human liver cells will allow the infection of these so-called "liver chimeric mice" with hepatitis B virus and hepatitis C virus. The co-transplantation of human immune cells into liver chimeric mice will further allow the study of human immune responses to hepatitis B virus or hepatitis C virus. However, for immunological studies it will be crucial that the transplanted human liver and immune cells are derived from the same human donor. In our study we describe the efficient engraftment of human fetal liver cells and immune cells derived from the same donor into mice. We show that liver co-engraftment resulted in an expanded human immune cell repertoire, including monocytes and natural killer cells in the liver. We further demonstrate that these mice could be infected with hepatitis B virus, which lead to an expansion of natural killer cells. In conclusion we have developed a new mouse model that could be useful to study human immune responses to human liver pathogens.