HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients

Background & Aims: Spontaneous resolution of hepatitis C virus (HCV) infection depends upon a broad T cell response to multiple viral epitopes. However, most patients fail to clear infections spontaneously and develop chronic disease. The elevated number and function of CD3(+)CD4(+)CD25(+)FoxP3(+) regulatory T cells (T-(reg)) in HCV-infected patients suggest a role of Treg cells in impaired viral clearance. The factors contributing to increased T-reg cell activity in chronic hepatitis C cases remain to be delineated. Methods: Immunoinformatics tools were used to predict promiscuous, highly-conserved HLA-DRB1-restricted immunogenic consensus sequences (ICS), each composed of multiple T cell epitopes. These sequences were synthesized and added to cultures of peripheral blood mononuclear cells (PBMCs), derived from patients who resolved HCV infection spontaneously, patients with persistent infection, and non-infected individuals. The cells were collected and following 5 days incubation, quantified and characterized by flow cytometry. Results: One immunogenic consensus sequence (ICS), HCV_G1_p7_794, induced a marked increase in Treg cells in PBMC cultures derived from infected patients, but not in patients who spontaneously cleared HCV or in non-infected individuals. An analogous human peptide (p7_794), on the other hand, induced a significant increase in Treg cells among PBMCs derived from both HCV-infected and non-infected individuals. Janus Matrix analyses determined that HCV_G1_p7_794 is comprised of Treg cell epitopes that exhibit extensive cross-reactivity with the human proteome. Conclusions: A virus-encoded peptide (HCV_G1_p7_794) with extensive human homology activates cross-reactive CD3+CD4+CD25+FoxP3+ natural Treg cells, which potentially contributes to immunosuppression and to the development of chronic hepatitis C. (C) 2014 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.