Positive selection of cytotoxic T lymphocyte escape variants during acute hepatitis C virus infection.
Cellular immune responses are induced during hepatitis C virus (HCV) infection and acute-phase CD8+ T cells are supposed to play an important role in controlling viral replication. In chimpanzees, failure of CD8+ T cells to control HCV replication has been associated with acquisition of mutations in MHC class I-restricted epitopes. In humans, although selection of escape mutations in an immunodominant CTL epitope has been recently described, the overall impact of immune escape during acute HCV infection is unclear. Here, by performing an in depth analysis of the relationship between early cellular immune responses and viral evolution in a chronically evolving HCV acutely infected individual, we demonstrate: (i) the presence of a potent and focused CD8(+ T cell response against a novel epitope in the NS3 protein, (ii) the elimination of the quasi-species harboring the original amino acid sequence within this epitope, and (iii) the selection for a virus population bearing amino acid changes at a single residue within the cytotoxic T cell epitope that strongly diminished T cell recognition. These results support the view that acute-phase CD8+ T cell responses exert a biologically relevant pressure on HCV replication and that viruses escaping this host response could have a significant survival advantage.
Guglietta
Silvia
S
Department of Cellular and Developmental Biology University of Rome La Sapienza, Rome, Italy.
Garbuglia
Anna Rosa
AR
Pacciani
Valentina
V
Scottà
Cristiano
C
Perrone
Maria Paola
MP
Laurenti
Luca
L
Spada
Enea
E
Mele
Alfonso
A
Capobianchi
Maria Rosaria
MR
Taliani
Gloria
G
Folgori
Antonella
A
Vitelli
Alessandra
A
Ruggeri
Lionello
L
Nicosia
Alfredo
A
Piccolella
Enza
E
Del Porto
Paola
P
D000328:Adult; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D019143:Evolution, Molecular; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D017361:Viral Nonstructural Proteins; D007371:Interferon-gamma