Sequence variation in the gene encoding the nonstructural 3 protein of hepatitis C virus: evidence for immune selection.
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.
Wang
Huiru
H
Blood Research Institute, The Blood Center, P.O. Box 2178, Milwaukee, WI 53201-2178, USA.
Bian
Tonghua
T
Merrill
Stephen J
SJ
Eckels
David D
DD
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes / Q000235:genetics; D014644:Genetic Variation; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D020365:RNA Helicases / Q000235:genetics; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D016207:Cytokines; D000939:Epitopes; D020365:RNA Helicases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases