Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1a or 1b

Abstract

Previous studies from Japan have described an association between a conserved sequence within the hepatitis C virus (HCV) genome and resistance to interferon (IFN) therapy for patients infected with HCV genotype 1b [Enomoto et al. (1995): Journal of Clinical Investigation 96: 224-230; Enomoto et al. (1996): New England Journal of Medicine 334:77-81]. The present study examines amino acid sequences surrounding the putative Interferon Sensitivity Determining Region (ISDR) of the NS5A gene of HCV in 21 North American patients with genotype 1a or 1b infection receiving recombinant IFN therapy. The ISDR consensus or intermediate pattern was observed in 13 of 14 NS5A clones from North American patients infected with genotype 1b. However, we found no evidence of the consensus ISDR sequence in any NS5A clones isolated from 15 patients with genotype 1a infection. In select cases, gel shift analysis showed no significant changes in the clonal frequency of the putative ISDR domain of HCV genotype 1a or 1b infected patients who were either nonresponsive to IFN therapy, or relapsed following withdrawal of IFN therapy. These results suggest that a conserved ISDR domain is neither associated with, nor responsible for, IFN resistance in North American patients infected with HCV genotype 1a, and demonstrate a need for further investigation into the reported association between ISDR consensus sequences and IFN resistance in genotype 1b clones.

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

“…18 However, there is substantial discrepancy in the significance of the NS5A structure on interferon efficacy among Western countries. Some studies did not find any correlation between NS5A structures and interferon effect, [19][20][21][22][23][24][25] while other studies did. 26,27 In addition, in HCV genotype 1a, [21][22][23] 2c, 23 or 3a, 19,23,27 no clear association has been found.…”

“…Similarly, NS5A of HCV-1b, -1a, -2c, or -3a in Western countries is less variable compared with Japanese HCV-1b or HCV-2a. [19][20][21][22][23][24][25]27 These findings suggest the different mode of NS5A evolution in various genotypes, or even in the same genotype in different geographical areas. Recent studies demonstrated that the NS5A sequence is rather stable in each patient, 24 suggesting that more divergent genotypes would have an older history in the specific human populations.…”

“…The role of NS5A mutations in interferon resistance of HCV-1b, 19-25 -1a, [21][22][23]25 -2c, 23 and -3a 19,23,27 is not clear in European and North American studies like HCV-2b in the present study. This might suggest that other viral factors, such as HCV genetic changes other than the ISDR 56 or host factors, 51 might have a more profound influence on the outcome of interferon therapy in cases in which NS5A is not divergent.…”

Viral Factors Associated with Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection

“…Mutation number in ISDR had no significant effect on response to IFN-based therapy in G1a [37,38] and G3a [36]. However, mutations in the region corresponding to the ISDR of G1b (2126-2228) was reported to be associated with outcome of therapy in HCV G2a, and more than two mutations in ISDR were associated with good response to PEG-IFN plus RBV [39].…”

Genetic variability in the 5' UTR and NS5A regions of hepatitis C virus RNA isolated from non-responding and responding patients with chronic HCV genotype 1 infection

“…In conclusion, virological response to HCV is a complex issue (Enomoto et al 1995, Yamamoto et al 1997, Hofgartner et al 1997 and is believed to be better correlated to host factors than to genetic variability of the virus. However, this issue deserves further investigation, including tests of other viral markers and wholegenome screening.…”