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

The HCV core 176 peptide has been described as a target epitope for CTLs that are present in the peripheral blood of patients with chronic HCV infection (10) . This peptide is processed and presented via the endogenous MHC class I pathway (11) . We used PBMCs from healthy, HCV-seronegative individuals as well as from patients with chronic HCV infection to induce primary CTL responses against this epitope and two homologous CYP-derived peptides. CTLs induced with the HCV core 178 peptide not only recognized the inducing HCV peptide, but also showed autoreactivity, lysing targets presenting CYP-derived selfpeptides and target cells stably transfected with a plasmid coding for the whole CYP2A6 protein, showing that the CYP epitope is also presented via the endogenous MHC class I pathway. Among the CTLs we could distinguish three different functional types in the same individual: cells recognizing HCV core 178 only, cells with cross-reaction between HCV core 178 and CYP2A7, and cells recognizing HCV core and both CYP epitopes, indicating a polyclonal response against HCV core 178 with a distinct hierarchy.