The Nonstructural 5A Protein of Hepatitis C Virus Genotype 1b Does Not Contain an Interferon Sensitivity–Determining Region

Abstract

The nonstructural (NS) 5A protein of hepatitis C virus (HCV) has been suggested to contain an interferon (IFN) sensitivity-determining region (ISDR). We studied whether the degree of viral decline on day 1 is associated with differences in NS5A amino acid sequences among patients receiving IFN- alpha. Phylogenetic analyses of the full-length protein and of functional domains showed no relationship between the baseline protein sequence and the antiviral response. NS5A quasispecies sequences showed no differences in the number of mutations in the putative ISDR relative to a prototype sequence between responders and nonresponders or according to IFN- alpha antiviral efficacy. No relationship was found between antiviral efficacy at 24 h and the baseline sequence of any NS5A region. Amino acid changes were observed in a few cases at 24 h in both responders and nonresponders, but no consistent pattern of amino acid shifts was observed, ruling out the possibility that IFN- alpha selected IFN-resistant variants. Our findings show that there is no ISDR in the HCV genotype 1 NS5A protein and that the NS5A sequence does not influence the capacity of IFN- alpha to block viral replication. The findings do not rule out a role for NS5A in subsequent viral clearance.