The NS5a gene of hepatitis C virus in patients treated with interferon-alpha

Patients infected with hepatitis C virus (HCV) genotype 3 have a better res ponse to interferon-alpha (IFN-alpha) therapy than those infected with geno type 1. There are extensive sequence differences between genotypes in the 3 ' half of the NS5a gene. An association between IFN-ci response and the int erferon sensitivity-determining region (ISDR) (amino acids 2209-2248) of HC V genotype Ib has been described [Enomoto et al. (1996) New England Journal of Medicine 334:771-776]. A prospective study was conducted to determine w hether the derived NS5A amino acid sequence or quasi-species diversity coul d predict response to IFN-alpha therapy. Serum samples were obtained before , during, and after treatment from 35 IFN-alpha-treated patients chronicall y infected with HCV (eight with type1b,13 with type1a, and 14 with type3a). Nucleotide sequences were determined, and amino acid sequences correspondi ng to residues 2178-2390 of the polyprotein were derived. Quasi-species com plexity was analysed by amplification of the ISDR region (2270-2403), follo wed by single-stranded conformation polymorphism (SSCP). No amino acid sequ ence that could be used to predict response to treatment was found, and the re was no selection of specific amino acid residues during treatment. A str iking lack of variability was seen in HCV genotype 3a, but the small degree of variation could suggest an effect on response. SSCP showed that variati on in the predominant NS5a sequence occurred in the presence and absence of therapeutically administered IFN-alpha. HCV quasi-species diversity pretre atment did not predict IFN-alpha treatment outcome. The conclusion of the s tudy is that the amino acid sequence of NS5a cannot be used to predict the efficacy of treatment with IFN-alpha in HCV-infected patients in Scotland. No evidence was found to support the selection of IFN-alpha-resistant strai ns in the NS5a gene. J. Med. Virol. 60:367-378, 2000. (C) 2000 Wiley-Liss, Inc.