Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon

Background & Aims: The NS5A and the E2 proteins of hepatitis 0 virus (HCV)- 1b can bind and inhibit in vitro the interferon (IFN)-induced cellular kina se PHR. The role of such interaction in modulating the antiviral effect of IFN is still controversial. We have analyzed the E2 and the NS5A sequences in HCV-lb-infected patients treated with IFN to assess whether and how diff erent combinations of wild-type and mutant proteins correlated with early a nd long-term virological response. Methods: in 30 patients, sequences of pr etreatment and on-treatment E2-PePHD and NS5A-PKR binding domain (including the putative ISDR) were analyzed in parallel by sequencing cDNA-polymerase chain reaction products and up to 25 independent clones. Results: The E2-P ePHD sequence was highly conserved with a homogeneous quasispecies and was identical in 29 of 30 cases with no association with the pattern of respons e and no evidence of evolution during therapy. Patients with a mutated NS5A -ISDR had a higher rate of early virological response (67%) than cases with wild-type ISDR (17%). This association was lost in long-term responders (3 3% vs. 17%). Conclusions: Although the highly conserved E2-PePHD motif migh t contribute to reduce IFN responsiveness, variations within this region do not seem to play a role in modulating IFN sensitivity. The NS5A-ISDR seque nce influenced the early, but not the sustained response, to IFN, suggestin g that other factors may be more important for the long-term outcome of the rapy.