title: Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection.
abstract: HCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies.
  
  
  
  Recently, we have established human liver cells with a matched human immune system in NOD-scid Il2rg(-/-) (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated.
  
  
  
  In this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment.
  
  
  
  The HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Choong Tat
authors.initials: CT
authors.lastname: Keng
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Ching Wooen
authors.initials: CW
authors.lastname: Sze
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Dahai
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Kylie Su Mei
authors.initials: KS
authors.lastname: Yong
authors.affiliation: Department of Obstetrics & Gynaecology, KK Women's and Children's Hospital, Singapore, Singapore.
authors.forename: Shu Qi
authors.initials: SQ
authors.lastname: Tan
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Jessica Jie Ying
authors.initials: JJ
authors.lastname: Ong
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Sue Yee
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore.
authors.forename: Eva
authors.initials: E
authors.lastname: Loh
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Megha Haridas
authors.initials: MH
authors.lastname: Upadya
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore.
authors.forename: Chik Hong
authors.initials: CH
authors.lastname: Kuick
authors.affiliation: Division of Microbiology, Kobe University Graduate School of Medicine, Hyogo, Japan.
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Department of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore.
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
authors.affiliation: Department of Obstetrics & Gynaecology, KK Women's and Children's Hospital, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Thiam Chye
authors.initials: TC
authors.lastname: Tan
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Kenneth T E
authors.initials: KT
authors.lastname: Chang
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore, Singapore The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Yee-Joo
authors.initials: YJ
authors.lastname: Tan
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore, Singapore.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D011994:Recombinant Proteins / Q000627:therapeutic use; D015203:Reproducibility of Results
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins
keywords: CYTOKINES; FIBROSIS; HEPATITIS C; IMMUNE-MEDIATED LIVER DAMAGE; IMMUNOLOGY