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 T reg 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 5days incubation, quantified and characterized by flow cytometry. Results One immunogenic consensus sequence(ICS), HCV_G1_p7_794, induced a marked increase in T reg 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 T reg cells among PBMCs derived from both HCV-infected and non-infected individuals. JanusMatrix analyses determined that HCV_G1_p7_794 is comprised of T reg cell epitopes that exhibit extensive cross-reactivitywith the human proteome. Conclusions A virus-encoded peptide (HCV_G1_p7_794) with extensive human homology activates cross-reactiveCD3 + CD4 + CD25 + FoxP3+ natural T reg cells, which potentially contributes to immunosuppression and to the development of chronic hepatitis C.