title: Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1a or 1b.
abstract: Previous studies from Japan have described an association between a conserved sequence within the hepatitis C virus (HCV) genome and resistance to interferon (IFN) therapy for patients infected with HCV genotype 1b [Enomoto et al. (1995): Journal of Clinical Investigation 96: 224-230; Enomoto et al. (1996): New England Journal of Medicine 334:77-81]. The present study examines amino acid sequences surrounding the putative Interferon Sensitivity Determining Region (ISDR) of the NS5A gene of HCV in 21 North American patients with genotype 1a or 1b infection receiving recombinant IFN therapy. The ISDR consensus or intermediate pattern was observed in 13 of 14 NS5A clones from North American patients infected with genotype 1b. However, we found no evidence of the consensus ISDR sequence in any NS5A clones isolated from 15 patients with genotype 1a infection. In select cases, gel shift analysis showed no significant changes in the clonal frequency of the putative ISDR domain of HCV genotype 1a or 1b infected patients who were either nonresponsive to IFN therapy, or relapsed following withdrawal of IFN therapy. These results suggest that a conserved ISDR domain is neither associated with, nor responsible for, IFN resistance in North American patients infected with HCV genotype 1a, and demonstrate a need for further investigation into the reported association between ISDR consensus sequences and IFN resistance in genotype 1b clones.
authors.affiliation: Department of Laboratory Medicine, University of Washington Medical Center, Seattle, USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Hofgärtner
authors.forename: S J
authors.initials: SJ
authors.lastname: Polyak
authors.forename: D G
authors.initials: DG
authors.lastname: Sullivan
authors.forename: R L
authors.initials: RL
authors.lastname: Carithers
authors.forename: D R
authors.initials: DR
authors.lastname: Gretch
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics; D005814:Genes, Viral / Q000235:genetics*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009656:North America; D012367:RNA, Viral / Q000097:blood; D012008:Recurrence; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D015678:Viral Structural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D007372:Interferons; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D015678:Viral Structural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase