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

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.

Hepatitis C Virus (HCV) Quasispecies Complexity and Selection in HCV/HIV‐Coinfected Subjects Treated with Interferon‐Based Regimens

“…These data further support the concept that both viral load and degree of complexity independently affect viral clearance, as reflected by both RVR and SVR. Identification of specific HCV signature motifs that are more or less prone to early clearance may improve our understanding of mechanisms of interferon resistance, though other groups have found it difficult to reliably identify such motifs[23, 24]. …”

Hepatitis C virus-related resistance mechanisms to interferon α-based antiviral therapy

“…Subsequently, in several studies from Japan, Europe, and the United States, the observed correlation of ISDR mutations and treatment outcome was verified. However, mainly Japanese groups were able to obtain concordant results Komatsu et al, 1997;Chayama et al, 1997) whereas in Europe and the United States, initially no such association was detected for HCV genotype 1b infected patients (Zeuzem et al, 1997;Khorsi et al, 1997;Squadrito et al, 1997;Odeberg et al, 1998;Chung et al, 1999;Hofgartner et al, 1997;McKechnie et al, 2000). Studies from Western countries based on larger patient cohorts and, more recently, results of a metaanalysis could confirm an association of ISDR mutations and treatment outcome.…”

Viral Determinants of Resistance to Treatment in Patients with Hepatitis C

“…Studies from Japan were generally able to confirm the strong correlation between ISDR mutations and treatment response (16,69). Groups from Europe and the United States were initially not able to verify the importance of ISDR mutations in IFN-␣ sensitivity (18,65,84,99,133,154), and in subsequent studies, it turned out that HCV genotype 1b isolates with multiple mutations within the ISDR are rare in Europe and the United States compared to those found in Japan (104,117,121,122). In further studies with larger patient cohorts and in a meta-analysis, the positive correlation of an increasing number of ISDR mutations with a sustained virologic response to IFN-␣-based therapy could be confirmed (102,104,117,121,122).…”