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.
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 humanCD34(+) 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/Hepmice 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/Hepmice 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: S Cooper; A L Erickson; E J Adams; J Kansopon; A J Weiner; D Y Chien; M Houghton; P Parham; C M Walker Journal: Immunity Date: 1999-04 Impact factor: 31.745
Authors: P Farci; A Shimoda; A Coiana; G Diaz; G Peddis; J C Melpolder; A Strazzera; D Y Chien; S J Munoz; A Balestrieri; R H Purcell; H J Alter Journal: Science Date: 2000-04-14 Impact factor: 47.728
Authors: Golo Ahlenstiel; Rachel H Titerence; Christopher Koh; Birgit Edlich; Jordan J Feld; Yaron Rotman; Marc G Ghany; Jay H Hoofnagle; T Jake Liang; Theo Heller; Barbara Rehermann Journal: Gastroenterology Date: 2009-09-10 Impact factor: 22.682
Authors: Y Jin; L Fuller; M Carreno; K Zucker; D Roth; V Esquenazi; T Karatzas; S J Swanson; A G Tzakis; J Miller Journal: J Clin Immunol Date: 1997-03 Impact factor: 8.542
Authors: Daniel T Claiborne; Timothy E Dudek; Colby R Maldini; Karen A Power; Musie Ghebremichael; Edward Seung; Elizabeth F Mellors; Vladimir D Vrbanac; Katharine Krupp; Abigail Bisesi; Andrew M Tager; David M Knipe; Christian L Boutwell; Todd M Allen Journal: J Virol Date: 2019-09-30 Impact factor: 5.103
Authors: Andrew Baird; Chenliang Deng; Matthew H Eliceiri; Fatima Haghi; Xitong Dang; Raul Coimbra; Todd W Costantini; Bruce E Torbett; Brian P Eliceiri Journal: Wound Repair Regen Date: 2016-10-04 Impact factor: 3.617
Authors: Adam Drake; Nikhil S Joshi; Gregory L Szeto; Eric Zhu; Herman N Eisen; Darrell J Irvine Journal: Cancer Immunol Res Date: 2013-10 Impact factor: 11.151