TY - JOUR
T1 - A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease
AU - Washburn, Michael L.
AU - Bility, Moses T.
AU - Zhang, Liguo
AU - Kovalev, Grigoriy I.
AU - Buntzman, Adam
AU - Frelinger, Jeffery A.
AU - Barry, Walter
AU - Ploss, Alexander
AU - Rice, Charles M.
AU - Su, Lishan
N1 - Funding Information:
Funding Supported in part by a UNC UCRF innovation grant; grants from NIH ( AI076142 , AA018009 , AI077454 and AA018372 to L.S.), an immunology training grant ( T32 AI007273 to M.L.W.) and UNC Lineberger Comprehensive Cancer Center Postdoctoral Training Grant (M.T.B.); and a grant from LCRF (to J.A.F.); from the UNC University Cancer Research Fund innovation grants (to L.S. and J.A.F.); from Ministry of Science and Technology ( 2009CB522507 , 2006CB910901 & KSCX20YW-R-150 to L.Z.); from Ministry of Health ( 2009ZX10604 to L.Z. and 2008ZX10002-011 to L.Z., L.S.); from the Greenberg Medical Research Institute , the Ellison Medical Foundation , the Starr Foundation , the Ronald A. Shellow Memorial Fund , the Richard Salomon Family Foundation , and by a grant from the Foundation NIH through the Grand Challenges in Global Health initiative (to C.M.R. and A.P.); and a grant from the Center for Clinical and Translational Research ( RR024143 to A.P.).
PY - 2011/4
Y1 - 2011/4
N2 - 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 virus 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. Cotransplantation 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: AFC8-hu HSC/Hep mice supported HCV infection in the liver and 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.
AB - 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 virus 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. Cotransplantation 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: AFC8-hu HSC/Hep mice supported HCV infection in the liver and 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.
KW - Animal Model of Hepatitis
KW - Fibrosis
KW - Human Immunology
KW - Virology
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UR - http://www.scopus.com/inward/citedby.url?scp=79953196869&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2011.01.001
DO - 10.1053/j.gastro.2011.01.001
M3 - Article
C2 - 21237170
AN - SCOPUS:79953196869
SN - 0016-5085
VL - 140
SP - 1334
EP - 1344
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -