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abstract 177. TIMING THE ANCESTRY OF HEPATITIS C VIRUS GENOTYPE 1A STRAINS IN
THE UNITED STATES: the number of mutations don't seem to be associated with
disease progression
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Yasuhito Tanaka, National Inst of Health, Bethesda, MD; Masashi Mizokami,
Nagoya City Univ Med Sch, Nagoya Japan; James W Shih, Harvey J Alter,
National Inst of Health, Bethesda, MD
Background/aims: Long-term, prospective studies demonstrate that hepatitis C
virus (HCV) is generally a slowly progressive disease that causes relatively
low mortality and overt morbidity during the first 25 years after infection.
This study investigates the molecular evolution of HCV in serial samples from
patients with long-term chronic infection.
Materials and Methods: Serial samples were obtained from subjects enrolled in
prospective studies of transfusion-associated hepatitis conducted at the NIH
since 1972 and from anti-HCV positive blood donors whose exposure history
suggested infection of >20 years duration. 37 serial samples (2-7 serial
samples each) from 11 subjects with HCV genotype 1a, which is the most
prevalent in USA, were studied. The sample intervals for each subject ranged
from 7-21.6 (mean, 14.6±5.4) years. Some of the samples were obtained within
the first 6 months of infection. Sequences in the core, E1, E2, and NS5B
regions of each isolate were determined directly or after cloning and then
the numbers of nucleotide substitutions per site were estimated and the
genetic distances determined.
Results: A phylogenetic ancestral comparison using these long-term serial
sequences showed mutation rates that ranged from 0.491 to 0.949 (mean, 0.777)
10(3) bases per site per year in E1, 1.163-2.624 (mean, 2.010) 10(3) in E2
and 0.183 to 0.983 (mean, 0.531) 10(3) in NS5B region. These rates of HCV
molecular evolution appear to be slower than previously reported. The origin
of the major current ancestral sequence of HCV genotype 1a is estimated to
have occurred around 1930 in the USA as also supported by a
maximum-likelihood phylogenetic analysis. The divergent ancestral points
calculated for each subject suggests that most HCV 1a expanded in the US
population between 1960 and 1980, consistent with increased illegal drug use
during that period. Among these subjects, there was no apparent correlation
between the individual mutation rate and clinical outcome; for instance one
patient with mild, non-progressive chronic hepatitis had the most rapid
evolutionary rate and one patient with cirrhosis had a slow evolutionary
rate. In addition, some subjects indicated different mutation rates during
the course of infection.
Conclusions: Current genotype 1a appears to have emerged in the USA around
1930 and to have further diversified in the 1960s and 70's. The overall
mutation rate may be slower than previously reported and may vary at
different stages of infection. There is no apparent association between HCV
mutation rate and the clinical course of hepatitis C, but more subjects need
to be studied over longer intervals to better elucidate the effect of viral
mutation on clinical outcome.
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