icon_folder.gif   Conference Reports for NATAP  
  AASLD ( American Association for the Study of Liver Diseases)
November 9-13, 2001, Dallas
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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
  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, 14.65.4) 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.