title: Hepatitis C virus JFH-1 strain infection in chimpanzees is associated with low pathogenicity and emergence of an adaptive mutation.
abstract: The identification of the hepatitis C virus (HCV) strain JFH-1 enabled the successful development of infectious cell culture systems. Although this strain replicates efficiently and produces infectious virus in cell culture, the replication capacity and pathogenesis in vivo are still undefined. To assess the in vivo phenotype of the JFH-1 virus, cell culture-generated JFH-1 virus (JFH-1cc) and patient serum from which JFH-1 was isolated were inoculated into chimpanzees. Both animals became HCV RNA-positive 3 days after inoculation but showed low-level viremia and no evidence of hepatitis. HCV viremia persisted 8 and 34 weeks in JFH-1cc and patient serum-infected chimpanzees, respectively. Immunological analysis revealed that HCV-specific immune responses were similarly induced in both animals. Sequencing of HCV at various times of infection indicated more substitutions in the patient serum-inoculated chimpanzee, and the higher level of sequence variations seemed to be associated with a prolonged infection in this animal. A common mutation G838R in the NS2 region emerged early in both chimpanzees. This mutation enhances viral assembly, leading to an increase in viral production in transfected or infected cells.
  
  
  CONCLUSIONS
  Our study shows that the HCV JFH-1 strain causes attenuated infection and low pathogenicity in chimpanzees and is capable of adapting in vivo with a unique mutation conferring an enhanced replicative phenotype.
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Takanobu
authors: T
authors: Kato
authors: Youkyung
authors: Y
authors: Choi
authors: Gamal
authors: G
authors: Elmowalid
authors: Ronda K
authors: RK
authors: Sapp
authors: Heidi
authors: H
authors: Barth
authors: Akihiro
authors: A
authors: Furusaka
authors: Shunji
authors: S
authors: Mishiro
authors: Takaji
authors: T
authors: Wakita
authors: Krzysztof
authors: K
authors: Krawczynski
authors: T Jake
authors: TJ
authors: Liang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018420:Ape Diseases / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D016174:Hepacivirus / Q000235:genetics* / Q000472:pathogenicity*; D006526:Hepatitis C / Q000473:pathology / Q000662:veterinary* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D002679:Pan troglodytes / Q000821:virology*; D012367:RNA, Viral / Q000097:blood; D013601:T-Lymphocytes / Q000473:pathology; D014162:Transfection; D014779:Virus Replication / Q000235:genetics
chemical_list: D012367:RNA, Viral; D007371:Interferon-gamma