Molecular mimicry of human cytochrome P450 by hepatitis C virus at the level of cytotoxic T cell recognition

Hepatitis C virus (HCV) is thought to be involved in the pathogenesis of au toimmune hepatitis (AIH) type 2, which is defined by the presence of type I antiliver kidney microsome autoantibodies directed mainly against cytochro me P450 (CYP)2D6 and by autoreactive Liver infiltrating T cells. Virus-spec ific CD8(+) cytotoxic T lymphocytes (CTLs) that recognize infected cells an d contribute to viral clearance and tissue injury during HCV infection coul d be involved in the induction of AIH. To explore whether the antiviral cel lular immunity may rum against self-antigens, we characterized the primary CTL response against an HLA-A*0201-restricted HCV-derived epitope, i.e., HC V core 178-187, which shows sequence homology with human CYP2A6 and CYP2A7 8-17. To determine the relevance of these homologies for the pathogenesis o f HCV-associated AIH, we used synthetic peptides to induce primary CTL resp onses in peripheral blood mononuclear cells of healthy blood donors and pat ients with chronic HCV infection. We found that the naive CTL repertoire of both groups contains cross-reactive CTLs inducible by the HCV peptide reco gnizing both CYP2A6 and CYP2A7 peptides as well as endogenously processed C YP2A6 protein. Importantly, we failed to induce CTLs with the CYP derived p eptides that showed a lower capacity to form stable complexes with the HLA- A2 molecule. These findings demonstrate the potential of HCV to induce auto reactive CD8(+) CTLs by molecular mimicry, possibly contributing to virus-a ssociated autoimmunity.