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Hepatitis C virus replication in mice with chimeric human livers

Nature Medicine volume 7, pages 927–933 (2001)Cite this article

Abstract

Lack of a small animal model of the human hepatitis C virus (HCV) has impeded development of antiviral therapies against this epidemic infection. By transplanting normal human hepatocytes into SCID mice carrying a plasminogen activator transgene (Alb-uPA), we generated mice with chimeric human livers. Homozygosity of Alb-uPA was associated with significantly higher levels of human hepatocyte engraftment, and these mice developed prolonged HCV infections with high viral titers after inoculation with infected human serum. Initial increases in total viral load were up to 1950-fold, with replication confirmed by detection of negative-strand viral RNA in transplanted livers. HCV viral proteins were localized to human hepatocyte nodules, and infection was serially passaged through three generations of mice confirming both synthesis and release of infectious viral particles. These chimeric mice represent the first murine model suitable for studying the human hepatitis C virus in vivo.

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Figure 1: Detection of human albumin (HA) produced from human hepatocytes in chimeric livers (samples represent individual mice).
Figure 2: Histochemical analysis of human chimerism in mouse livers.
Figure 3: Mice homozygous for the Alb-uPA transgene support quantitatively higher levels of human hepatocyte engraftment than hemizygotes.
Figure 4: Detection of positive- (+) and negative- (−)strand HCV RNA in liver samples taken from infected homozygous chimeric mice.
Figure 5: Immunohistochemical detection of HCV proteins within human hepatocytes in transplanted homozygous Alb-uPA mice.

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Acknowledgements

We thank C.A. Compston for invaluable assistance with the RPA assay; T. Cavanagh for providing enzymes; M. Craig for assistance with western-blot analysis; and P. Dickie for assistance with genotyping offspring.

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Authors and Affiliations

  1. Department of Surgery, Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada

    David F. Mercer, Daniel E. Schiller, Donna N. Douglas, Thomas A. Churchill, Jonathan R.T. Lakey & Norman M. Kneteman

  2. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada

    John F. Elliott, William R. Addison, Karl P. Fischer & David L.J. Tyrrell

  3. Department of Pathology, University of Alberta, Edmonton, Alberta, Canada

    Chunhai Hao

  4. Centre de Recherche du CHUM, Hôpital Saint-Luc, Montréal, Québec, Canada

    Aline Rinfret

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  1. David F. Mercer
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  2. Daniel E. Schiller
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Correspondence to Norman M. Kneteman.

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Mercer, D., Schiller, D., Elliott, J. et al. Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7, 927–933 (2001). https://doi.org/10.1038/90968

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