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      Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection


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          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.

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          Most cited references 44

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          Immunology of hepatitis B virus and hepatitis C virus infection.

          More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus-host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.
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            HCV persistence and immune evasion in the absence of memory T cell help.

            Spontaneous resolution of hepatitis C virus (HCV) infection in humans usually affords long-term immunity to persistent viremia and associated liver diseases. Here, we report that memory CD4+ Tcells are essential for this protection. Antibody-mediated depletion of CD4+ Tcells before reinfection of two immune chimpanzees resulted in persistent, low-level viremia despite functional intra-hepatic memory CD8+ Tcell responses. Incomplete control of HCV replication by memory CD8+ Tcells in the absence of adequate CD4+ Tcell help was associated with emergence of viral escape mutations in class I major histocompatibility complex-restricted epitopes and failure to resolve HCV infection.
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              Hepatitis C virus replication in mice with chimeric human livers.

              Lack of a small animal model of the human hepatitis C virus (HCV) has impeded development of antiviral therapies against this epidemic infection. By transplanting normal human hepatocytes into SCID mice carrying a plasminogen activator transgene (Alb-uPA), we generated mice with chimeric human livers. Homozygosity of Alb-uPA was associated with significantly higher levels of human hepatocyte engraftment, and these mice developed prolonged HCV infections with high viral titers after inoculation with infected human serum. Initial increases in total viral load were up to 1950-fold, with replication confirmed by detection of negative-strand viral RNA in transplanted livers. HCV viral proteins were localized to human hepatocyte nodules, and infection was serially passaged through three generations of mice confirming both synthesis and release of infectious viral particles. These chimeric mice represent the first murine model suitable for studying the human hepatitis C virus in vivo.

                Author and article information

                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                October 2016
                06 July 2015
                : 65
                : 10
                : 1744-1753
                [1 ]Institute of Molecular and Cell Biology , Singapore, Singapore
                [2 ]Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore
                [3 ]Department of Obstetrics & Gynaecology, KK Women's and Children's Hospital , Singapore, Singapore
                [4 ]Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital , Singapore, Singapore
                [5 ]Division of Microbiology, Kobe University Graduate School of Medicine , Hyogo, Japan
                [6 ]Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore
                [7 ]Department of Gastroenterology and Hepatology, National University Health System , Singapore, Singapore
                [8 ]Duke-NUS Graduate Medical School , Singapore, Singapore
                [9 ]Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology , Singapore, Singapore
                [10 ]The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology , Cambridge, Massachusetts, USA
                Author notes
                [Correspondence to ] Dr Qingfeng Chen, Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore; qchen@ 123456imcb.a-star.edu.sg Dr Yee-Joo Tan, Department of Microbiology, MD4, Level 3, 5 Science Drive 2, National University of Singapore, Singapore 117597, Singapore; yee_joo_tan@nuhs.edu.sg
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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