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A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease.

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.

Pubmed ID: 21237170

Authors

  • Washburn ML
  • Bility MT
  • Zhang L
  • Kovalev GI
  • Buntzman A
  • Frelinger JA
  • Barry W
  • Ploss A
  • Rice CM
  • Su L

Journal

Gastroenterology

Publication Data

April 29, 2011

Associated Grants

  • Agency: NIAAA NIH HHS, Id: AA018009
  • Agency: NIAAA NIH HHS, Id: AA018372
  • Agency: NIAID NIH HHS, Id: AI076142
  • Agency: NIAID NIH HHS, Id: AI077454
  • Agency: NIAID NIH HHS, Id: R01 AI077454
  • Agency: NIAID NIH HHS, Id: R01 AI077454-01A2
  • Agency: NIAID NIH HHS, Id: R01 AI080432
  • Agency: NIAID NIH HHS, Id: R01 AI080432-01A2
  • Agency: NIAID NIH HHS, Id: R01 AI095097
  • Agency: NIAAA NIH HHS, Id: R21 AA018009
  • Agency: NIAAA NIH HHS, Id: R21 AA018009-01
  • Agency: NIAAA NIH HHS, Id: R21 AA018009-02
  • Agency: NIAID NIH HHS, Id: R21 AI076142
  • Agency: NIAID NIH HHS, Id: R21 AI076142-01A1
  • Agency: NIAID NIH HHS, Id: R21 AI076142-02
  • Agency: NCRR NIH HHS, Id: RR024143
  • Agency: NIAID NIH HHS, Id: T32 AI007273

Mesh Terms

  • Animals
  • Caspase 8
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Female
  • Hepacivirus
  • Hepatitis C, Chronic
  • Hepatocytes
  • Humans
  • Liver Cirrhosis
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Stem Cells
  • Tacrolimus Binding Proteins
  • Transplantation, Heterologous