Hepatitis C: Humanized Mouse Model to Study Immune Response, and Liver Disease

Article in Press

A Humanized Mouse Model to Study Hepatitis C Virus Infection, Immune Response, and Liver Disease


Abstract
Background & Aims:
Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C pathogenesis and treatment.

Methods
To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2-/- γC-null mice. Co-transplantation of human CD34+ human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leukocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases.

Results
HCV-infected livers of AFC8-hu HSC/Hep mice generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes.

Conclusions
AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease, because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection.


Michael L. Washburn
Affiliations
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,
Moses T. Bility
Affiliations
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,
Liguo Zhang
Affiliations
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China,
Grigoriy I. Kovalev
Affiliations
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,
Adam Buntzman
Affiliations
Departments of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,
Jeffery A. Frelinger
Affiliations
Departments of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,
Walter Barry
Affiliations
Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, 10065 USA,
Alexander Ploss
Affiliations
Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, 10065 USA,
Charles M. Rice
Affiliations
Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, 10065 USA,
Lishan Su
Affiliations
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Departments of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

Correspondence should be addressed to L.S., telephone: 919-966-6654; fax: 919-966-8212.
Received 12 September 2010; received in revised form 21 December 2010; accepted 10 January 2011. published online 14 January 2011. Accepted Manuscript