P.T. Losikoff, S. Mishra, F. Terry F, A. Gutierrez, M.T. Ardito, L. Fast, M. Nevola, W.D. Martin WD2, C. Bailey-Kellogg, A.S. De Groot, and S.H. Gregory , "HCV Epitope, Homologous to Multiple Human Protein Sequences, Induces a Regulatory T Cell Response in Infected Patients", J. Hepatol., 2014, 62:48-55. [pubmed]

BACKGROUND & AIMS: Spontaneous resolution of hepatitis C virus (HCV) infections depends upon a broad T cell response to multiple viral epitopes. Most patients fail to clear infections spontaneously, however, and develop chronic disease. The elevated number and function of CD3+CD4+CD25+FoxP3+ regulatory T(reg) cells in HCV-infected patients suggest the role of Treg cells in impaired viral clearance. The factors contributing to increased Treg 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 following 5 days incubation, quantified and characterized by flow cytometry.

RESULTS: One ICS, HCV_G1_p7_794, induced a marked increase in Treg cells in PBMC cultures derived from infected patients, but not patients who spontaneously cleared HCV or 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. JanusMatrix analyses determined that HCV_G1_p7_794 is comprised of Treg cell epitopes that exhibit extensive cross-reactivity with the human proteome.

CONCLUSION: A virus-encoded peptide (HCV_G1_p7_794) with extensive human homology activates cross-reactive CD3+CD4+CD25+FoxP3+ nTreg cells, which potentially contribute to immunosuppression and chronic hepatitis C.