SEQUENCE-ANALYSIS OF THE NS5A PROTEIN OF EUROPEAN HEPATITIS-C VIRUS 1B ISOLATES AND RELATION TO INTERFERON SENSITIVITY

Japanese studies have defined the discrete 2209-2248 amino acid region of the non-structural 5A protein (NS5A(2209-2248)) of hepatitis C vir us genotype 1b (HCV 1b) isolates as the interferon sensitivity determi ning region (ISDR), European studies did not confirm these results sin ce most of the ISDR sequences harboured an intermediate profile. Recen tly, a direct interaction between the NS5A protein, involving the ISDR , and the interferon-induced protein kinase (PKR) has been reported an d presented as a possible explanation of HCV interferon resistance, In the present study, the entire NS5A amino acid sequence from 11 resist ant and eight sensitive strains from European HCV 1b isolates was infe rred from direct sequencing, The previously described important amino acid stretches and positions in NS5A were compared between the resista nt and sensitive groups. Although some variations were observed, no cl ear differences could be directly correlated with the interferon sensi tivity. However, sensitive strains were different, owing to more amino acid changes when compared to a consensus sequence from all strains. The carboxyterminal region and especially the previously reported NS5A /V3 region showed most of the variations. Moreover, the conformational analysis of NS5A by secondary structure prediction allowed the differ entiation of most sensitive strains from resistant ones. It was conclu ded that other regions different from ISDR were involved in resistance to interferon maybe via the interaction between NSSA and PKR.