MUTATIONS IN THE NS5A GENE OF HEPATITIS-C VIRUS IN NORTH-AMERICAN PATIENTS INFECTED WITH HCV GENOTYPE 1A OR 1B

Previous studies from japan have described an association between a co nserved sequence within the hepatitis C virus (HCV) genome and resista nce to interferon (IFN) therapy for patients infected with HCV genotyp e 1b [Enomoto et al. (1995): Journal of Clinical Investigation 96: 224 -230; Enomoto et al. (1996): New England Journal of Medicine 334:77-81 ]. The present study examines amino acid sequences surrounding the put ative Interferon Sensitivity Determining Region (ISDR) of the NS5A gen e of HCV in 21 North American patients with genotype 1a or 1b infectio n receiving recombinant IFN therapy. The ISDR consensus or intermediat e pattern was observed in 13 of 14 NS5A clones from North American pat ients infected with genotype 1b. However, we found no evidence of the consensus ISDR sequence in any NS5A clones isolated from 15 patients w ith genotype 1a infection. In select cases, gel shift analysis showed no significant changes in the clonal frequency of the putative ISDR do main of HCV genotype 1a or 1b infected patients who were either nonres ponsive to IFN therapy, or relapsed following withdrawal of IFN therap y, These results suggest that a conserved ISDR domain is neither assoc iated with, nor responsible for, IFN resistance in North American pati ents infected with HCV genotype 1a, and demonstrate a need for further investigation into the reported association between ISDR consensus se quences and IFN resistance in genotype 1b clones. (C) Wiley-Liss, Inc.