title: Completion of the entire hepatitis C virus life cycle in genetically humanized mice.
abstract: More than 130 million people worldwide chronically infected with hepatitis C virus (HCV) are at risk of developing severe liver disease. Antiviral treatments are only partially effective against HCV infection, and a vaccine is not available. Development of more efficient therapies has been hampered by the lack of a small animal model. Building on the observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive to HCV entry, we previously showed that transient expression of these two human genes is sufficient to allow viral uptake into fully immunocompetent inbred mice. Here we demonstrate that transgenic mice stably expressing human CD81 and OCLN also support HCV entry, but innate and adaptive immune responses restrict HCV infection in vivo. Blunting antiviral immunity in genetically humanized mice infected with HCV results in measurable viraemia over several weeks. In mice lacking the essential cellular co-factor cyclophilin A (CypA), HCV RNA replication is markedly diminished, providing genetic evidence that this process is faithfully recapitulated. Using a cell-based fluorescent reporter activated by the NS3-4A protease we visualize HCV infection in single hepatocytes in vivo. Persistently infected mice produce de novo infectious particles, which can be inhibited with directly acting antiviral drug treatment, thereby providing evidence for the completion of the entire HCV life cycle in inbred mice. This genetically humanized mouse model opens new opportunities to dissect genetically HCV infection in vivo and provides an important preclinical platform for testing and prioritizing drug candidates and may also have utility for evaluating vaccine efficacy.
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dorner
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Horwitz
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Donovan
authors.forename: Rachael N
authors.initials: RN
authors.lastname: Labitt
authors.forename: William C
authors.initials: WC
authors.lastname: Budell
authors.forename: Tamar
authors.initials: T
authors.lastname: Friling
authors.forename: Alexander
authors.initials: A
authors.lastname: Vogt
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Catanese
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Mansun
authors.initials: M
authors.lastname: Law
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
mesh_terms: D000818:Animals; D002460:Cell Line; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005818:Genetic Engineering; D016174:Hepacivirus / Q000276:immunology / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency; D060225:Tetraspanin 28 / Q000235:genetics / Q000378:metabolism; D014766:Viremia / Q000821:virology; D014771:Virion / Q000254:growth & development / Q000502:physiology; D014779:Virus Replication
chemical_list: C554798:CD81 protein, human; D062793:Occludin; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D060225:Tetraspanin 28; D021984:Cyclophilin A
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