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L. Benmohamed, X. Zhang, M. Wu, M. Podberezin, T.V. Ramos, I. Bettahi, R.E. Afifi, A. Mohebbi, B. Maillère, A.B. Nesburn; Multiple Promiscuous Human Leukocyte Antigen HLA–DR–Restricted Epitopes Identified in Herpes Simplex Virus Type 1 Glycoprotein D . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3057.
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© ARVO (1962-2015); The Authors (2016-present)
Increasing evidence suggests that the herpes simplex virus type 1 (HSV–1) glycoprotein D (gD) has great potential as a vaccine candidate. As a first step in the development of a lipopeptide T cell epitope–based HSV vaccine with the potential for human use, this study has identified and characterized the human leukocyte antigen class II molecules (HLA–DR)–restricted gD–derived epitopes.
A computer–assisted algorithm based on known HLA–peptide–TCR interactions was used to predict T cell epitope regions on gD. Predicted epitope peptides were synthesized and tested in affinity binding assays with a panel of soluble HLA–DRB1 class II molecules. Preclinical T cell antigenicity and immunogenicity of high affinity binding epitope peptides were assessed in HSV seropositive individuals and in a HSV–infected humanized HLA–DRB1*0101 transgenic (tg) mouse model, respectively. The protective efficacy of epitope peptides was evaluated in HLA–DRB1*0101 tg mice, following an ocular HSV–1 challenge.
Twelve gD regions bearing potential HLA–DR–restricted epitopes were predicted. Six peptides behaved as promiscuous epitopes that bound to a large panel of human HLA–DRB1 molecules. These included the DRB1*0101, DRB1*0401 and DRB1*0701 molecules, predominant in Caucasian populations. On average, three gD regions, which displayed similar, high in vitro binding capacities to HLA–DRB1 molecules, showed widespread T cell antigenicity in up to 45% of HSV seropositive individuals, demonstrating that T cell responses could be naturally mounted to multiple promiscuous gD epitopes. After HSV–1 ocular infection in DRB1*0101 tg mice every mouse developed HLA–DR–restricted T cell responses directed at the same epitopes identified in naturally infected humans. Multiepitopic peptide immunization in DRB1*0101 tg mice, confirmed these immuno–dominant epitopes as eliciting statistically significant protective T–cell immunity against ocular HSV–1 challenge.
The immunological parameters used in this study permitted the identification of multiple promiscuous HLA–DR–restricted epitopes from the HSV–1 gD. These well–characterized human gD epitopes could help to broaden and enhance in vivo HSV–specific T–cell responses if incorporated in immunotherapeutic or immunoprophylactic ocular herpes vaccines.
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