title: Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa.
abstract: 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.
authors.affiliation: Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt a.M., Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zeuzem
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: W K
authors.initials: WK
authors.lastname: Roth
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D004351:Drug Resistance; D005060:Europe; D005260:Female; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006521:Hepatitis, Chronic / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012367:RNA, Viral / Q000097:blood / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral