Association of amino acid sequence in the PKR-eIF2 phosphorylation homology domain and response to interferon therapy

Hepatitis C virus (HCV) genotype 1b and high pretreatment virus load are we ll known predictive factors of poor response to interferon (IFN) therapy. I n addition, a sparsity of amino acid substitutions in the interferon sensit ivity determining region (ISDR) is also predictive of a poor response to IF N in patients with genotype 1b, although this issue is still controversial. Recently, a 12 amino acid domain in the E2 protein of HCV (PKR-eIF2 alpha phosphorylation homology domain [PePHD]) has been reported to bind with and block the virus replication inhibition ability of PKR, suggesting that the interaction of E2 and PKR may be one mechanism by which HCV circumvents th e antiviral effect of IFN, To clarify the significance of amino-acid sequen ces in this domain in predicting the effect of IFN therapy, we analyzed 82 patients with genotype 1b, Eleven patients (13.4%) responded to treatment w hereas the remaining 71 patients (86.6%) were nonresponders. Multivariate a nalysis showed that only HCV load and amino-acid substitutions in the ISDR were predictive of sustained response to IFN, Amino-acid substitutions in t he PePHD were detected in only eight of 82 patients (9.8%), and did not cor relate with the therapeutic effect of IFN, However, amino-acid-sequence ana lyses of quasispecies before and after 1 week of IFN therapy showed elimina tion of clones with substitutions in this domain. Our results suggest that aminoacid sequences of the PePHD domain may be related to viral resistance to IFN but do not predict the outcome of IFN therapy as amino-acid substitu tions in this domain are rare.