Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment
Karl-Dimiter Bissig, … , Francis V. Chisari, Inder M. Verma
Karl-Dimiter Bissig, … , Francis V. Chisari, Inder M. Verma
Published February 22, 2010
Citation Information: J Clin Invest. 2010;120(3):924-930. https://doi.org/10.1172/JCI40094.
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Technical Advance

Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment

Abstract

A paucity of versatile small animal models of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has been an impediment to both furthering understanding of virus biology and testing antiviral therapies. We recently described a regulatable system for repopulating the liver of immunodeficient mice (specifically mice lacking fumaryl acetoacetate hydrolase [Fah], recombination activating gene 2 [Rag2], and the γ-chain of the receptor for IL-2 [Il-2rγ]) with human hepatocytes. Here we have shown that a high transplantation dose (3 × 106 to 5 × 106 human hepatocytes/mouse) generates a higher rate of liver chimerism than was previously obtained in these mice, up to 95% human hepatocyte chimerism. Mice with a high level of human liver chimerism propagated both HBV and HCV, and the HCV-infected mice were responsive to antiviral treatment. This human liver chimeric mouse model will expand the experimental possibilities for studying HBV and HCV infection, and possibly other human hepatotropic pathogens, and prove useful for antiviral drug testing.

Authors

Karl-Dimiter Bissig, Stefan F. Wieland, Phu Tran, Masanori Isogawa, Tam T. Le, Francis V. Chisari, Inder M. Verma

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Figure 3

HCV infection of mice with high human chimerism.

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HBV-infected mouse with high human chimerism. (A) Immuno­staining for FA...
HCV RNA in mouse serum after inoculation with HCV genotype 2a (A) or clinical isolate of HCV genotype 1a or chimeric HCV genotypes (1a/2a and 1b/2a) (B). (C) HCV RNA intermediates detected in chimeric livers and human albumin levels in the murine serum of HCV-infected mice. HCV RNA was normalized to human GAPDH levels and expressed as GE per μg total RNA. (D) Antiviral treatment with peg-IFN alone, peg-IFN and ribavirin, and peg-IFN and Debio 025 for 2 weeks. Results are shown as normalized mean ± SD. (E–G) Fluorescent costaining of an HCV-infected chimeric liver for FAH (green) and HCV NS5a (red); nuclear counterstaining with DAPI (blue). (E) FAH and nuclear staining. (F) NS5a and nuclear staining. (G) Merge of E and F showing colocalization of HCV and human hepatocytes in yellow. (H) Control mouse liver repopulated with human hepatocytes but not inoculated with HCV. Costaining for FAH (green) and HCV NS5a (red); nuclear counterstaining with DAPI (blue). Scale bars: 50 μm.