title: Amino Acid Polymorphisms in Hepatitis C Virus Core Affect Infectious Virus Production and Major Histocompatibility Complex Class I Molecule Expression.
abstract: Amino acid (aa) polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis. We investigated the effects of these polymorphisms with genotype 1b/2a chimeric viruses that contained polymorphisms of Arg/Gln at aa 70 and Leu/Met at aa 91. We found that infectious virus production was reduced in cells transfected with chimeric virus RNA that had Gln at aa 70 (aa70Q) compared with RNA with Arg at aa 70 (aa70R). Using flow cytometry analysis, we confirmed that HCV core protein accumulated in aa70Q clone transfected cells, and it caused a reduction in cell-surface expression of major histocompatibility complex (MHC) class I molecules induced by IFN treatment through enhanced protein kinase R phosphorylation. We could not detect any effects due to the polymorphism at aa 91. In conclusion, the polymorphism at aa 70 was associated with efficiency of infectious virus production, and this deteriorated virus production in strains with aa70Q resulted in the intracellular accumulation of HCV proteins and attenuation of MHC class I molecule expression. These observations may explain the strain-associated resistance to IFN-based therapy and hepatocarcinogenesis of HCV.
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.|Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.|Center for Interprofessional Education, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Tasaka-Fujita
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Sugiyama
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea.
authors.forename: Wonseok
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Masaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Masaski
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Murayama
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sugiyama
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Senko
authors.initials: S
authors.lastname: Tsukuda
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.|Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Asahina
authors.affiliation: Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea.
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kato
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D010766:Phosphorylation; D014758:Viral Core Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D019892:eIF-2 Kinase