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

Both a double-stranded RNA-dependent protein kinase (PKR)-phosphorylation h omology domain (PePHD) within the E2 protein and a PKR-binding domain withi n the nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) genotype 1 isolates inhibit the function of the interferon alfa (IFN-alpha)-induced a ntiviral effector protein PKR in vitro. We investigated whether the mutatio nal pattern of the E2 region (codons 618-681, including PePHD) of 81 HCV ge notype 1-infected patients (HCV-lb [n = 54], HCV-la [n = 27]) influences th e response to IFN-alpha. Initial viral decline (Delta HCV RNA) was determin ed at week 1 hereby covering the effector reactions of IFN-alpha -mediated first phase and the immune-mediated second phase. Delta HCV RNA less than 5 0% (group 1); Delta HCV RNA greater than 50% but less than 90% (group 2); a nd Delta HCV RNA greater than or equal to 90% (group 3) were differentiated . The PePHD region was highly conserved; the few mutations (5 patients) did not correlate with Delta HCV RNA or sustained virologic response to IFN-al pha. Within the flanking regions before and after PePHD (codons 618-681) 72 of 81 patients (89%) had 2.6 a 0.17 mutations (median, 3; range, 1-8) that did not correlate with treatment response. Sequence analysis of the NS5A p rotein (codons 2,209-2,274, including interferon sensitivity determining re gion [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 a 0.43 [n = 18]) and 3 ( 1.89 a 0.54 [n = 9]) than in group 1 (0.67 a 0.19 [n = 12]; P = .049 group 1 vs. 3) and a mutant type ISDR (e.g., greater than or equal to4 mutations) was significantly more frequent in sustained virologic responders than in nonresponders or relapsers (2 of 4 [50%] vs. 2 of 35; [6%]; P = .045). Thus , NS5A appears to be functionally relevant in IFN-alpha -induced effector r eactions.