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

Abstract

Patients infected with hepatitis C virus (HCV) genotype 3 have a better response to interferon-alpha (IFN-alpha) therapy than those infected with genotype 1. There are extensive sequence differences between genotypes in the 3' half of the NS5a gene. An association between IFN-alpha response and the interferon sensitivity-determining region (ISDR) (amino acids 2209-2248) of HCV genotype 1b has been described [Enomoto et al. (1996) New England Journal of Medicine 334:771-776]. A prospective study was conducted to determine whether the derived NS5A amino acid sequence or quasi-species diversity could predict response to IFN-alpha therapy. Serum samples were obtained before, during, and after treatment from 35 IFN-alpha-treated patients chronically infected with HCV (eight with type1b,13 with type1a, and 14 with type3a). Nucleotide sequences were determined, and amino acid sequences corresponding to residues 2178-2390 of the polyprotein were derived. Quasi-species complexity was analysed by amplification of the ISDR region (2270-2403), followed by single-stranded conformation polymorphism (SSCP). No amino acid sequence that could be used to predict response to treatment was found, and there was no selection of specific amino acid residues during treatment. A striking lack of variability was seen in HCV genotype 3a, but the small degree of variation could suggest an effect on response. SSCP showed that variation in the predominant NS5a sequence occurred in the presence and absence of therapeutically administered IFN-alpha. HCV quasi-species diversity pretreatment did not predict IFN-alpha treatment outcome. The conclusion of the study 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 strains in the NS5a gene.

Genetic diversity and models of viral evolution for the hepatitis C virus

“…HCV anti‐viral therapy involves either α‐interferon alone, or interferon in combination with ribavirin[46], but about 60% of treated patients fail to clear the virus[47]. Generally, drug response appears to be correlated with HCV diversity during the early stages of the treatment [47–51], although not necessarily with diversity before the onset of treatment [49,52]. Diversity in non‐responders is higher than in responders, suggesting that escape mutants arise[53].…”

Association between HCV amino acid substitutions and outcome of peginterferon and ribavirin combination therapy in HCV genotype 1b and high viral load

“…In the late 1990s, Enomoto et al. reported that mutations in the amino acids at positions 2209–2248 of the NS5A region of HCV were closely associated with the efficacy of IFN monotherapy; 3 however, these results proved controversial 10–22 . Very recently, a few studies have reported an association between other amino acid substitutions and the rate of SVR by the PEG‐IFN/ribavirin therapy in patients with HCV genotype 1b 7,8 .…”