Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity.
OBJECTIVE
High rate of chronicity after acute hepatitis C virus (HCV) infection cannot be explained in the presence of a multispecific cytotoxic T lymphocyte (CTL) response. The aim of this study was to investigate the effect of virus variants on CTL activity in patients in whom chronicity developed.


METHODS
CTL clones specific to a decapeptide epitope derived from hypervariable region 1 were generated from 5 HLA-A2-positive patients with acute hepatitis C by in vitro stimulation with synthetic peptides. The sequential change of this CTL epitope and its influence on the CTL recognition were examined.


RESULTS
Virus variants did not appear in 3 patients with recovery, whereas variants with altered peptide ligands capable of antagonizing CTL activity emerged rapidly in the remaining 2 patients in whom chronicity developed. Importantly, these HLA-A2-restricted, hypervariable region 1-specific CTL clones shared the use of T-cell receptor (TCR) genes AV6 and BV17.


CONCLUSIONS
These data suggest that there is only a narrow T-cell repertoire responding to a single viral peptide/HLA ligand. The emergence of HCV variants with altered peptide ligands as TCR antagonists accompanied by a limited TCR repertoire may provide a mechanism for HCV chronicity.
Tsai
S L
SL
Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
Chen
Y M
YM
Chen
M H
MH
Huang
C Y
CY
Sheen
I S
IS
Yeh
C T
CT
Huang
J H
JH
Kuo
G C
GC
Liaw
Y F
YF
D000208:Acute Disease; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D005260:Female; D014644:Genetic Variation / Q000502:physiology*; D015789:HLA-A2 Antigen / Q000032:analysis; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000503:physiopathology* / Q000821:virology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D014764:Viral Proteins / Q000276:immunology
D015789:HLA-A2 Antigen; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014764:Viral Proteins