NS5A Sequences of Hepatitis C Virus Genotype 1 and Interferon Resistance: Where Are We?

To the Editor—In an article recently published in the Journal, Dal Pero et al. [1] showed a relationship between the frequency of mutations in NS5A sequences of hepatitis C virus genotype 1a (HCV-1a), early viral kinetics, and pegylated interferon-␣ (pegIFN) efficacy, represented mostly by amino acid substitutions in the V3 region at the C terminus of NS5A. However, no specific selection of particular NS5A sequences after a single dose of pegIFN occurred in any patient, and no correlation was uncovered between specific altered amino acid configurations in NS5A sequences and the second viral kinetic phase that is associated with more sustained responses. The interference of HCV proteins with IFN-induced intracellular signalling could be an important mechanism that results in viral persistence and treatment resistance. The interference of viral proteins with the Jak-Stat pathway could be responsible for IFN resistance in patients with chronic HCV infection [2], although this hypothesis remains unproven. In the past, several groups have reported that the HCV proteins NS5A and E2 can interfere with the IFN-␣–induced antiviral effector protein PKR [3,4]. A relationship has been reported between the sequence of the central region of the NS5A and the likelihood of sustained virologic responses in patients infected with HCV-1b, and a meta-analysis of conflicting reports confirmed that viral amino acid sequences from patients with sustained viro-logical response differ more markedly from a prototype Japanese HCV-1b sequence than do sequences from patients who fail to eradicate infection [5]. The corresponding 40-aa region was designated the " IFN-sensitivity determining region " (ISDR) solely on the basis of this observed relationship. However, in a study of NS5A gene quasi species, no HCV-1b NS5A sequence appeared to be intrinsically resistant or sensitive to IFN-␣ [6]. Furthermore, the role of the NS5A-PKR interaction was not confirmed in another in vitro model [7]. In addition, another study found no relationship between NS5A functional-site amino acid sequences (in particular the so-called ISDR, the PKR-binding site, and the V3 variable region) and IFN-␣ blocking efficiency on day 1 of treatment in HCV genotype 1–infected patients [8]. Phylogenetic analyses of the full-length protein and functional domains showed no relationship between the baseline protein sequence and the antiviral response. Relative to a prototype sequence, NS5A quasi species sequences from viral re-sponders and nonresponders showed no differences in the number of mutations in the putative ISDR, nor did they show any difference according to IFN-␣ antiviral efficacy. No …