title: Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice.
abstract: At least 170 million people are chronically infected with hepatitis C virus (HCV). Owing to the narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular determinants of interspecies transmission and establish a novel immunocompetent model system, we examined the ability of HCV to infect hepatocytes from a small nonhuman primate, the rhesus macaque (Macaca mulatta). We show that the rhesus orthologs of critical HCV entry factors support viral glycoprotein-dependent virion uptake. Primary hepatocytes from rhesus macaques are also permissive for HCV-RNA replication and particle production, which is enhanced when antiviral signaling is suppressed. We demonstrate that this may be owing to the diminished capacity of HCV to antagonize mitochondrial antiviral-signaling protein-dependent innate cellular defenses. To test the ability of HCV to establish persistent replication in vivo, we engrafted primary rhesus macaque hepatocytes into immunocompromised xenorecipients. Inoculation of resulting simian liver chimeric mice with either HCV genotype 1a or 2a resulted in HCV serum viremia for up to 10 weeks.
  
  
  CONCLUSIONS
  Together, these data indicate that rhesus macaques may be a viable model for HCV and implicate host immunity as a potential species-specific barrier to HCV infection. We conclude that suppression of host immunity or further viral adaptation may allow robust HCV infection in rhesus macaques and creation of a new animal model for studies of HCV pathogenesis, lentivirus coinfection, and vaccine development.
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Scull
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Chao
authors.initials: C
authors.lastname: Shi
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.|Division of Gastroenterology and Hepatology, Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY.
authors.forename: Ype P
authors.initials: YP
authors.lastname: de Jong
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Gisa
authors.initials: G
authors.lastname: Gerold
authors.affiliation: AIDS Vaccine Research Laboratory, Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Moritz
authors.initials: M
authors.lastname: Ries
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ.
authors.forename: Markus
authors.initials: M
authors.lastname: von Schaewen
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Donovan
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Rachael N
authors.initials: RN
authors.lastname: Labitt
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Horwitz
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Gaska
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Hrebikova
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Jing W
authors.initials: JW
authors.lastname: Xiao
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Brenna
authors.initials: B
authors.lastname: Flatley
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Canny
authors.initials: C
authors.lastname: Fung
authors.affiliation: Department of Pathology, New York University Medical Center, New York, NY.
authors.forename: Luis
authors.initials: L
authors.lastname: Chiriboga
authors.affiliation: Nationwide Children's Hospital, Columbus, OH.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Walker
authors.affiliation: AIDS Vaccine Research Laboratory, Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: David T
authors.initials: DT
authors.lastname: Evans
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY.|Department of Molecular Biology, Princeton University, Princeton, NJ.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C; D022781:Hepatocytes / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008253:Macaca mulatta; D051379:Mice; D053586:Virus Internalization; D014779:Virus Replication
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