title: A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Washburn
authors.forename: Moses T
authors.initials: MT
authors.lastname: Bility
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
authors.forename: Grigoriy I
authors.initials: GI
authors.lastname: Kovalev
authors.forename: Adam
authors.initials: A
authors.lastname: Buntzman
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Frelinger
authors.forename: Walter
authors.initials: W
authors.lastname: Barry
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; C505530:CASP8 protein, human; D053181:Caspase 8; D022021:Tacrolimus Binding Proteins