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Science. 2017 Jul 14;357(6347):204-208. doi: 10.1126/science.aal1962.

Mouse models of acute and chronic hepacivirus infection.

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Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, Ohio State University, Columbus, OH, USA.
Department of Pathology, New York University Medical Center, New York, NY, USA.
Department of Pathology, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA.
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.


An estimated 71 million people worldwide are infected with hepatitis C virus (HCV). The lack of small-animal models has impeded studies of antiviral immune mechanisms. Here we show that an HCV-related hepacivirus discovered in Norway rats can establish high-titer hepatotropic infections in laboratory mice with immunological features resembling those seen in human viral hepatitis. Whereas immune-compromised mice developed persistent infection, immune-competent mice cleared the virus within 3 to 5 weeks. Acute clearance was T cell dependent and associated with liver injury. Transient depletion of CD4+ T cells before infection resulted in chronic infection, characterized by high levels of intrahepatic regulatory T cells and expression of inhibitory molecules on intrahepatic CD8+ T cells. Natural killer cells controlled early infection but were not essential for viral clearance. This model may provide mechanistic insights into hepatic antiviral immunity, a prerequisite for the development of HCV vaccines.

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