Mutations in the E2–Pephd and Ns5a Region of Hepatitis C Virus Type 1 and the Dynamics of Hepatitis C Viremia Decline During Interferon Alfa Treatment

<jats:sec><jats:title/><jats:p>Both a double–stranded RNA–dependent protein kinase (PKR)–phosphorylation homology domain (PePHD) within the E2 protein and a PKR–binding domain within the nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) genotype 1 isolates inhibit the function of the interferon alfa (IFN–α)–induced antiviral effector protein PKR<jats:italic toggle="yes">in vitro</jats:italic>. We investigated whether the mutational pattern of the E2 region (codons 618–681, including PePHD) of 81 HCV genotype 1–infected patients (HCV–1b [n = 54], HCV–1a [n = 27]) influences the response to IFN–α. Initial viral decline (ΔHCV RNA) was determined at week 1 hereby covering the effector reactions of IFN–α–mediated first phase and the immune–mediated second phase. ΔHCV RNA less than 50% (group 1); ΔHCV RNA greater than 50% but less than 90% (group 2); and ΔHCV RNA ≥90% (group 3) were differentiated. The PePHD region was highly conserved; the few mutations (5 patients) did not correlate with ΔHCV RNA or sustained virologic response to IFN–α. Within the flanking regions before and after PePHD (codons 618–681) 72 of 81 patients (89%) had 2.6 ± 0.17 mutations (median, 3; range, 1–8) that did not correlate with treatment response. Sequence analysis of the NS5A protein (codons 2,209–2,274, including interferon sensitivity determining region [ISDR]) in 39 of 81 patients showed a higher mean number of mutations in the ISDR (codons 2,209–2,248) in groups 2 (1.28 ± 0.43 [n = 18]) and 3 (1.89 ± 0.54 [n = 9]) than in group 1 (0.67 ± 0.19 [n = 12];<jats:italic toggle="yes">P</jats:italic>= .049 group 1 vs. 3) and a mutant type ISDR (<jats:italic toggle="yes">e.g.</jats:italic>, ≥4 mutations) was significantly more frequent in sustained virologic responders than in nonresponders or relapsers (2 of 4 [50%] vs. 2 of 35 [6%];<jats:italic toggle="yes">P</jats:italic>= .045). Thus, NS5A appears to be functionally relevant in IFN–α–induced effector reactions.</jats:p></jats:sec>