Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa

Hepatology. 1997 Mar;25(3):740-4. doi: 10.1002/hep.510250341.


The response rate to interferon alfa (IFN-alpha) in patients infected with hepatitis C virus (HCV) genotype 1 isolates is poor. A region associated with sensitivity to IFN has been identified in subtype HCV-1b isolates from Japanese patients in the carboxyterminal half of the nonstructural protein NS5A (between codon 2209 and 2248). HCV-1b isolates with at least four amino acid changes in this region compared with the HCV-1b prototype sequence were sensitive, whereas isolates identical to the prototype sequence were resistant to IFN-alpha. Patients infected with HCV-1b isolates carrying 1 to 3 mutations in NS5A(2209-2248) showed an intermediate response pattern. Because of the large geographical differences observed for HCV it is unknown whether this putative IFN-alpha sensitivity determining region is also predictive for European isolates. We analyzed 32 patients chronically infected with HCV-1a or HCV-1b isolates who were treated with 3 million units of recombinant IFN-alpha three times per week for 1 year. Before initiation, during, and after treatment serum HCV-RNA levels were assessed by a quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay. The amino acid sequence of NS5A(2209-2248)was determined by direct sequencing of the PCR-amplified HCV genome and was compared with the reference sequence HCV-J. In patients chronically infected with subtype HCV-1a or HCV-1b the initial or sustained response to IFN-alpha was not related to the number of amino acid substitutions in the NS5A(2209-2248) region. In addition, the number of amino acid changes in NS5A(2209-2248) was not related to pretreatment HCV-RNA serum levels. In three patients with a pronounced initial decline of HCV-RNA levels (>3 log) sequence analyses of NS5A(2209-2248) were performed before and after therapy. Compared with the pretreatment amino acid sequence the HCV isolates of these patients revealed more mutations in the NS5A(2209-2248) region after therapy. These findings from European patients indicate that the NS5A(2209-2248) region of HCV does not represent a common interferon sensitivity determining region.

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Antiviral Agents / therapeutic use*
  • Drug Resistance
  • Europe
  • Female
  • Hepacivirus / classification
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics*
  • Hepatitis C / blood
  • Hepatitis C / drug therapy*
  • Hepatitis C / virology
  • Hepatitis, Chronic / blood
  • Hepatitis, Chronic / drug therapy*
  • Hepatitis, Chronic / virology
  • Humans
  • Interferon-alpha / therapeutic use*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • RNA, Viral / blood
  • RNA, Viral / drug effects


  • Antiviral Agents
  • Interferon-alpha
  • RNA, Viral