title: Mutations of the interferon sensitivity-determining region (ISDR) correlate with the complexity of hypervariable region (HVR)-1 in the Japanese variant of hepatitis C virus (HCV) type 1b.
abstract: Hepatitis C virus (HCV) genotype 1b comprises mainly two subtypes in Japan, each named for its geographic prevalence (Japan-specific, J type; worldwide, W type). Because the newly identified subtypes have not been fully characterized, the present study directed this issue from virological viewpoints such as hypervariable region (HVR)-1 as well as interferon (IFN) sensitivity-determining region (ISDR). Fifty chronic hepatitis patients with HCV 1b (31 men and 19 women; mean age 50.5 years) were enrolled, and J/W type was determined according to envelope 1 (E1) sequence as described previously (23 J type and 27 W type). Correlations between age, number of HVR-1 clones, HVR-1 diversity, and ISDR mutations were analyzed in J and W type patients independently. In addition, the sequences of the three HCV regions obtained for the determination of the above genetic factors were studied phylogenetically. The number of HVR-1 clones was significantly higher for J type in comparison with W type (P = 0.044). In the J type-infected patients, the ISDR mutation number was correlated inversely with HVR-1 clone number (P = 0.0001, r = -0.734) and HVR-1 diversity (P = 0.0001, r = -0.722). However, this correlation was not observed in the W type patients. W type patients showed a significant correlation between age and HVR-1 clone number (P = 0.015, r = 0.462). Phylogenetic study revealed that the nonstructural (NS) 5A sequence, which is obtained for ISDR type determination, can distinguish between J and W types. The inverse correlation in J type patients between ISDR mutations and HVR-1 complexity may explain the usefulness of the ISDR for prediction of IFN response only in Japanese patients. This suggests that the ISDR is not directly related to IFN responsiveness, but the degree of HVR-1 complexity may be more important.
authors.affiliation: Second Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan. nakano.isao@nitech.ac.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Nakano
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Katano
authors.forename: Hidenori
authors.initials: H
authors.lastname: Toyoda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakano
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005814:Genes, Viral; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D016415:Sequence Alignment; D017385:Sequence Homology; D014759:Viral Envelope Proteins / Q000235:genetics*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; C087035:E1 protein, Hepatitis C virus; C091015:glycoprotein E2, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase