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Mutations in the NS5A region and response to interferon in HCV genotype 3a and 1a infection.

Background: The response rate to interferon in patients with chronic hepatitis C infection genotype 1b is poor. A region associated with sensitivity to interferon has been identified between codon 2209-2248 in the carboxyterminal half of the nonstructural protein NS5A (Interferon Sensitivity Determining Region, or ISDR) in Japanese patients infected with HCV 1b. Patients with more than 4 amino acid changes in this region in comparison to the reference sequence HCV-J had a 100% response rate to interferon. Those with no changes had no response to interferon. As there is significant sequence variability in the HCV genome between genotypes and between countries, it is unclear whether this putative ISDR is predictive for isolates of different genotypes and from other countries. We investigated whether these amino acid changes were present in the ISDR in Australian patients infected with genotypes 1a and 3a, and their relationship to interferon response.

Methods: Pretreatment NS5A 2209-2248 sequence was determined in patients infected with HCV genotype 1a and 3a by direct sequencing of RT-PCR product obtained using genotype specific primers designed from published sequences.

Results: We determined a consensus sequence for the ISDR of the NS5A region of genotype 3a and 1a. Patients with genotype 3a had 8 amino acids in the ISDR which differed from the reference sequence HCV-J (genotype 1b). Patients with genotype 1a had 4-6 amino acid differences. The amino acid differences in genotypes 1a and 3a were similar to changes seen in genotype 1b patients who responded to interferon. The correlation between amino acid changes in the region from codon 2209 to 2248 and response to interferon is being investigated currently.

Conclusions: These results demonstrate there are significant amino acid differences between genotypes 1a, 3a, and 1b in the putative ISDR. It is interesting to speculate that this may represent the molecular basis for differences in response rates to interferon between genotypes.

From: American Gastroenterology Association Digestive Disease Week meeting in Washington in May 1997
SJ Bell, SA Locarnini, KJ Watson, PV Desmond, AI Bartholomeusz. St. Vincent's Hospital, and the Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia.

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