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
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
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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