title: Mutations in carboxy-terminal part of E2 including PKR/eIF2alpha phosphorylation homology domain and interferon sensitivity determining region of nonstructural 5A of hepatitis C virus 1b: their correlation with response to interferon monotherapy and viral load.
abstract: OBJECTIVE
  To study the amino acid substitutions in the carboxy (C)-terminal part of E2 protein and in the interferon (IFN) sensitivity determining region (ISDR) and their correlation with response to IFN and viral load in 85 hepatitis C virus (HCV)-1b-infected patients treated with IFN.
  
  
  METHODS
  The C-terminal part of E2 (codons 617-711) including PKR/eIF2alpha phosphorylation homology domain (PePHD) and ISDR was sequenced in 85 HCV-1b-infected patients treated by IFN monotherapy.
  
  
  RESULTS
  The amino acid substitutions in PePHD detected only in 4 of 85 patients were not correlated either with response to IFN or with viral load. The presence of substitutions in a N-terminal variable region (codons 617-641) in the C-terminal part of E2 was significantly correlated with both small viral load (33.9% vs 13.8%, P = 0.0394) and sustained response to IFN (25.0% vs 6.9%, P = 0.0429). Four or more substitutions in ISDR were significantly correlated with both small viral load (78.6% vs 16.2%, P < 0.0001) and sustained response to IFN (85.7% vs 2.9%, P < 0.0001). In multivariate analysis, ISDR in nonstructural (NS) 5A (OR = 0.39, P < 0.0001) and N-terminal variable region (OR = 0.51, P = 0.039) was selected as the independent predictors for small viral load, and ISDR (OR = 39.0, P < 0.0001) was selected as the only independent predictor for sustained response.
  
  
  CONCLUSIONS
  The N-terminal variable region in the C-terminal part of E2 correlates with both response to IFN monotherapy and viral load and is one of the factors independently associated with a small viral load.
authors.affiliation: Division of Liver and Biliary Diseases, Department of Internal Medicine, Fujita Health University School of Medicine, Kutsukake, Toyoake, Aichi, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ukai
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishigami
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Naoto
authors.initials: N
authors.lastname: Kawabe
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Katano
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Honda
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Yano
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D003062:Codon / Q000032:analysis / Q000235:genetics; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D005260:Female; D016174:Hepacivirus / Q000737:chemistry / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D016896:Treatment Outcome; D014759:Viral Envelope Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D019562:Viral Load; D019892:eIF-2 Kinase / Q000032:analysis / Q000737:chemistry / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D003062:Codon; D004279:DNA, Viral; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D007372:Interferons; D019892:eIF-2 Kinase