HCV Epitope, Homologous to Multiple Human Protein Sequences, Induces a Regulatory T Cell Response in Infected Patients

Authors

Phyllis T. Losikoff
Sasmita Mishra
Francis Terry
Andres Gutierrez
Matt T. Ardito
Loren Fast
Martha Nevola
William D. Martin
Chris Bailey-Kellogg
Anne S. De Groot, University of Rhode IslandFollow
Stephen H. Gregory

Document Type

Article

Date of Original Version

2014

Abstract

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 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 following 5 days incubation, quantified and characterized by flow cytometry.

Results: One ICS, HCV_G1_p7_794, induced a marked increase in T_reg 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 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-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⁺ nT_reg cells, which potentially contribute to immunosuppression and chronic hepatitis C.

Citation/Publisher Attribution

Losikoff, P. T., Mishra, S., Terry, F., Gutierrez, A., Ardito, M. T., Fast, L., Nevola, M., Martin, W. D., Bailey-Kellogg, C., De Groot, A. S., & Gregory, S. H. (2014). HCV Epitope, Homologous to Multiple Human Protein Sequences, Induces a Regulatory T Cell Response in Infected Patients. Journal of Hepatology, 62(1), 48-55.

Available at: http://dx.doi.org/10.1016/j.jhep.2014.08.026