The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes.
CD8(+) cytotoxic T lymphocytes (CTL) are thought to control hepatitis C virus (HCV) replication and so we investigated why this response fails in persistently infected individuals. The HCV quasispecies in three persistently infected chimpanzees acquired mutations in multiple epitopes that impaired class I MHC binding and/or CTL recognition. Most escape mutations appeared during acute infection and remained fixed in the quasispecies for years without further diversification. A statistically significant increase in the amino acid replacement rate was observed in epitopes versus adjacent regions of HCV proteins. In contrast, most epitopes were intact when hepatitis C resolved spontaneously. We conclude that CTL exert positive selection pressure against the HCV quasispecies and the outcome of infection is predicted by mutations in class I MHC restricted epitopes.
Erickson
A L
AL
Children's Research Institute, Children's Hospital W503, 700 Children's Drive, Columbus, OH 43205, USA.
Kimura
Y
Y
Igarashi
S
S
Eichelberger
J
J
Houghton
M
M
Sidney
J
J
McKinney
D
D
Sette
A
A
Hughes
A L
AL
Walker
C M
CM
D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation / Q000235:genetics*; D002460:Cell Line / Q000276:immunology; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D018936:Hepatitis C Antigens / Q000235:genetics* / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D002679:Pan troglodytes; D012367:RNA, Viral / Q000235:genetics; D012075:Remission, Spontaneous; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D000939:Epitopes; D018936:Hepatitis C Antigens; D015395:Histocompatibility Antigens Class I; D012367:RNA, Viral; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; C097010:NS2 protein, Hepatitis C virus; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C091015:glycoprotein E2, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase