Peptide-pulsed dendritic cells induce the hepatitis C viral epitope-specific responses of naïve human T cells.
Hepatitis C virus (HCV) is a major cause of liver disease. Spontaneous resolution of infection is associated with broad, MHC class I- (CD8(+)) and class II-restricted (CD4(+)) T cell responses to multiple viral epitopes. Only 20% of patients clear infection spontaneously, however, most develop chronic disease. The response to chemotherapy varies; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success in clinical trials. Vector-mediated vaccination with multi-epitope-expressing DNA constructs provides an improved approach. Highly-conserved, HLA-A2-restricted HCV epitopes and HLA-DRB1-restricted immunogenic consensus sequences (ICS, each composed of multiple overlapping and highly conserved epitopes) were predicted using bioinformatics tools and synthesized as peptides. HLA binding activity was determined in competitive binding assays. Immunogenicity and the ability of each peptide to stimulate naïve human T cell recognition and IFN-γ production were assessed in cultures of total PBMCs and in co-cultures composed of peptide-pulsed dendritic cells (DCs) and purified T lymphocytes, cell populations derived from normal blood donors. Essentially all predicted HLA-A2-restricted epitopes and HLA-DRB1-restricted ICS exhibited HLA binding activity and the ability to elicit immune recognition and IFN-γ production by naïve human T cells. The ability of DCs pulsed with these highly-conserved HLA-A2- and -DRB1-restricted peptides to induce naïve human T cell reactivity and IFN-γ production ex vivo demonstrates the potential efficacy of a multi-epitope-based HCV vaccine targeted to dendritic cells.
Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903, United States.
Sasmita
S
Mishra
Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903, United States.
Phyllis T
PT
Losikoff
Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903, United States.
Alyssa A
AA
Self
EpiVax, Inc., Providence, RI, United States.
Frances
F
Terry
EpiVax, Inc., Providence, RI, United States.
Matthew T
MT
Ardito
EpiVax, Inc., Providence, RI, United States.
Ryan
R
Tassone
EpiVax, Inc., Providence, RI, United States.
William D
WD
Martin
EpiVax, Inc., Providence, RI, United States; Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, United States.
Anne S
AS
De Groot
Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903, United States. Electronic address: sgregory@lifespan.org.
Stephen H
SH
Gregory
D000595:Amino Acid Sequence; D019295:Computational Biology; D003713:Dendritic Cells / Q000276:immunology*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015789:HLA-A2 Antigen; D059811:HLA-DRB1 Chains; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014761:Viral Hepatitis Vaccines / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D059811:HLA-DRB1 Chains; D010455:Peptides; D014761:Viral Hepatitis Vaccines; D007371:Interferon-gamma
Dendritic cell; EpiMatrix; Epitope; HCV; T cell; Vaccine