HEPATITIS-C VIRUS VARIANTS CIRCUMVENTING CYTOTOXIC T-LYMPHOCYTE ACTIVITY AS A MECHANISM OF CHRONICITY

Background & Aims: High rate of chronicity after acute hepatitis C vir us (HCV) infection cannot be explained in the presence of a multispeci fic cytotoxic T lymphocyte (CTL) response. The aim of this study was t o investigate the effect of virus variants on CTL activity in patients in whom chronicity developed. Methods: CTL clones specific to a decap eptide epitope derived from hypervariable region 1 were generated from 5 HLA-A(2)-positive patients with acute hepatitis C by in vitro stimu lation with synthetic peptides. The sequential change of this CTL epit ope and its influence on the CTL recognition were examined. Results: V irus variants did not appear in 3 patients with recovery, whereas vari ants with altered peptide ligands capable of antagonizing CTL activity emerged rapidly in the remaining 2 patients in whom chronicity develo ped. Importantly, these HLA-A,restricted, hypervariable region 1-speci fic CTL clones shared the use of T-cell receptor (TCR) genes AV6 and B V17, Conclusions: These data suggest that there is only a narrow T-cel l repertoire responding to a single viral peptide/HLA ligand. The emer gence of HCV variants with altered peptide ligands as TCR antagonists accompanied by a limited TCR repertoire may provide a mechanism for HC V chronicity.