title: HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients.
abstract: OBJECTIVE
  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 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 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 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. JanusMatrix 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.
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Phyllis T
authors.initials: PT
authors.lastname: Losikoff
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Sasmita
authors.initials: S
authors.lastname: Mishra
authors.affiliation: EpiVax, Inc., Providence, RI, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Terry
authors.affiliation: Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Gutierrez
authors.affiliation: EpiVax, Inc., Providence, RI, USA.
authors.forename: Matt T
authors.initials: MT
authors.lastname: Ardito
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA; Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA.
authors.forename: Loren
authors.initials: L
authors.lastname: Fast
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Nevola
authors.affiliation: EpiVax, Inc., Providence, RI, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Martin
authors.affiliation: Dartmouth College, Hanover, NH, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey-Kellogg
authors.affiliation: EpiVax, Inc., Providence, RI, USA; Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA.
authors.forename: Anne S
authors.initials: AS
authors.lastname: De Groot
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA. Electronic address: Stephen_Gregory@brown.edu.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gregory
mesh_terms: D000328:Adult; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D018984:Epitopes, T-Lymphocyte
keywords: Cross-reactive; Epitope; Hepatitis C; Regulatory T cells