title: Mutations in the protein kinase-binding domain of the NS5A protein in patients infected with hepatitis C virus type 1a are associated with treatment response.
abstract: An interaction of the hepatitis C virus (HCV) NS5A protein with the interferon (IFN)-alpha-inducible double-stranded RNA-activated protein kinase (PKR) was demonstrated in vitro. The clinical correlation between amino acid mutations within the HCV NS5A region and response to antiviral treatment is controversial. Thirty-two patients chronically infected with HCV-1a, who were treated with IFN-alpha with or without ribavirin, were studied. The carboxy-terminal half of HCV NS5A was sequenced and was investigated by phylogenetic and conformational analyses. Eight patients achieved a sustained virologic response. An end-of-treatment response but relapse thereafter was observed among 8 patients, whereas 16 patients were nonresponders. The median number of mutations within the PKR-binding domain but not within the previously described IFN sensitivity-determining region was significantly higher for patients with sustained (3 mutations [range, 1-5]) or end-of-treatment (4 mutations [range, 1-5]) virologic response than for nonresponders (2 mutations [range, 0-3]) (P=.0087). Phylogenetic and conformational analyses of NS5A sequences allowed no differentiation between sensitive and resistant strains.
authors.affiliation: Medizinische Klinik II, J. W. Goethe-University, Frankfurt am Main, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Sarrazin
authors.forename: T
authors.initials: T
authors.lastname: Berg
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: B
authors.initials: B
authors.lastname: Rüster
authors.forename: B
authors.initials: B
authors.lastname: Kronenberger
authors.forename: W K
authors.initials: WK
authors.lastname: Roth
authors.forename: S
authors.initials: S
authors.lastname: Zeuzem
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D001665:Binding Sites; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics* / Q000378:metabolism; D018937:Hepatitis C Antibodies / Q000097:blood; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000032:analysis; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D018937:Hepatitis C Antibodies; D007370:Interferon Type I; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase