HLA-A*0201-restricted CD8+ cytotoxic T lymphocyte epitopes identified from herpes simplex virus glycoprotein D.
Evidence obtained from both animal models and humans suggests that T cells specific for HSV-1 and HSV-2 glycoprotein D (gD) contribute to protective immunity against herpes infection. However, knowledge of gD-specific human T cell responses is limited to CD4+ T cell epitopes, with no CD8+ T cell epitopes identified to date. In this study, we screened the HSV-1 gD amino acid sequence for HLA-A*0201-restricted epitopes using several predictive computational algorithms and identified 10 high probability CD8+ T cell epitopes. Synthetic peptides corresponding to four of these epitopes, each nine to 10 amino acids in length, exhibited high-affinity binding in vitro to purified human HLA-A*0201 molecules. Three of these four peptide epitopes, gD53-61, gD70-78, and gD278-286, significantly stabilized HLA-A*0201 molecules on T2 cell lines and are highly conserved among and between HSV-1 and HSV-2 strains. Consistent with this, in 33 sequentially studied HLA-A*0201-positive, HSV-1-seropositive, and/or HSV-2-seropositive healthy individuals, the most frequent and robust CD8+ T cell responses, assessed by IFN-gamma ELISPOT, CD107a/b cytotoxic degranulation, and tetramer assays, were directed mainly against gD53-61, gD70-78, and gD278-286 epitopes. In addition, CD8+ T cell lines generated by gD53-61, gD70-78, and gD278-286 peptides recognized infected target cells expressing native gD. Lastly, CD8+ T cell responses specific to gD53-61, gD70-78, and gD278-286 epitopes were induced in HLA-A*0201 transgenic mice following ocular or genital infection with either HSV-1 or HSV-2. The functional gD CD8+ T cell epitopes described herein are potentially important components of clinical immunotherapeutic and immunoprophylactic herpes vaccines.
Chentoufi
Aziz Alami
AA
Laboratory of Cellular and Molecular Immunology, Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697, USA.
Zhang
Xiuli
X
Lamberth
Kasper
K
Dasgupta
Gargi
G
Bettahi
Ilham
I
Nguyen
Alex
A
Wu
Michelle
M
Zhu
Xiaoming
X
Mohebbi
Amir
A
Buus
Søren
S
Wechsler
Steven L
SL
Nesburn
Anthony B
AB
BenMohamed
Lbachir
L
D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D019295:Computational Biology; D003602:Cytotoxicity, Immunologic; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen; D022283:Herpesvirus Vaccines / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000276:immunology*
D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D022283:Herpesvirus Vaccines; D010455:Peptides; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1; C040570:glycoprotein D-herpes simplex virus type 2; C069093:herpes simplex virus-1 glycoprotein D vaccine