Sequence Variation in the Gene Encoding the Nonstructural 3 Protein of Hepatitis C Virus: Evidence for Immune Selection |
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Authors: | Huiru Wang Tonghua Bian Stephen J Merrill David D Eckels |
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Institution: | (1) Blood Research Institute, The Blood Center, P.O. Box 2178, Milwaukee, WI 53201-2178, USA, US;(2) Department of MSCS, Marquette University, Milwaukee, WI 53233, USA, US |
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Abstract: | To determine whether the persistent nature of hepatitis C infection is related to the emergence of antigenic variants driven
by immune selection, we examined the sequence heterogeneity in a portion of the hepatitis C virus (HCV) nonstructural 3 (NS3)
gene of a patient infected over the course of more than 2 years. By PCR amplification, cloning, and sequencing, we observed
several variable and conserved regions in the NS3 segment of the HCV genome. All variable regions had higher ratios of nonsynonymous/synonymous
mutations and encompassed immunodominant epitopes, and their locations were not essential to maintain the known function of
HCV RNA helicase. In contrast, the regions that are critical for HCV RNA helicase activity were found to be conserved with
lower heterogeneity or lower ratios of nonsynonymous/synonymous mutations, and none except one of these regions was encoded
within immunodominant epitopes. Our results are consistent with immune selection of viral variants at the epitope and molecular
levels that may enable HCV to evade host defenses over time. Plotting the relatedness of sequence variants revealed a star
topology suggesting that a wild-type HCV sequence is maintained, unlike HIV.
Received: 2 November 2000 / Accepted: 1 October 2001 |
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Keywords: | : HCV-NS3 — Chronic hepatitis C — Sequencing — Escape variant — Positive selection |
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