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Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa
Author(s) -
Zeuzem S,
Lee J H,
Roth W K
Publication year - 1997
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510250341
Subject(s) - ns5a , virology , hepatitis c virus , interferon , biology , genotype , hepacivirus , gene , flaviviridae , virus , interferon alfa , recombinant dna , polymerase chain reaction , alpha interferon , genetics
The response rate to interferon alfa (IFN‐α) 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‐α. 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‐α 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‐α 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‐α 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.