Molecular Mimicry of Human Cytochrome P450 by Hepatitis C Virus at the Level of Cytotoxic T Cell Recognition

Kammer, Andreas R.; van der Burg, Sjoerd H.; Grabscheid, Benno; Hunziker, Isabelle P.; Kwappenberg, Kitty M.C.; Reichen, Jürg; Melief, Cornelis J.M.; Cerny, Andreas

We have shown that the signal induced by the unstable complexes of HLA-A2 and CYP-derived self-peptides is not sufficient to activate naive CTLs. In the same way there is evidence that the CYP peptides neither induce negative selection during thymic development nor lead to anergy, as we detected cross-reactive CTL precursors in the peripheral blood. On the other hand, the HCV core 178 peptide that forms stable MHC-peptide complexes is able to induce full activation including maturation of CTLs. In the activated cross-reactive CTLs, cytolytic functions can then be induced by the HCV peptide, and also by the CYPderived APLs, as cytotoxicity requires a lower threshold of activation than proliferation. Once activated, a subpopulation of cross-reactive CTLs that shows no differences in recognition of the three peptide ligands, because they recognize the HCV core 178 and the CYP peptides at similar peptide concentrations, can be found.