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HLA-A*0201-Restricted CD8⁺ Cytotoxic T Lymphocyte Epitopes Identified from Herpes Simplex Virus Glycoprotein D¹

Aziz Alami Chentoufi^2,*, Xiuli Zhang^2,*, Kasper Lamberth, Gargi Dasgupta^*, Ilham Bettahi^*, Alex Nguyen^*, Michelle Wu^*, Xiaoming Zhu^*, Amir Mohebbi^*, Søren Buus, Steven L. Wechsler^*, Anthony B. Nesburn^* and Lbachir BenMohamed^3,*,

^* Laboratory of Cellular and Molecular Immunology, Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697; Institute for Medical Microbiology and Immunology, Panum Institute, Copenhagen, Denmark; and Center for Immunology, University of California Irvine, Irvine, CA 92697

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, gD_53–61, gD_70–78, and gD_278–286, 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- ELISPOT, CD107a/b cytotoxic degranulation, and tetramer assays, were directed mainly against gD_53–61, gD_70–78, and gD_278–286 epitopes. In addition, CD8⁺ T cell lines generated by gD_53–61, gD_70–78, and gD_278–286 peptides recognized infected target cells expressing native gD. Lastly, CD8⁺ T cell responses specific to gD_53–61, gD_70–78, and gD_278–286 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Research Grants EY14900, EY14017, EY013191, and EY16663 from the National Institutes of Health, by the Discovery Eye Foundation, and an by unrestricted grant from Research to Prevent Blindness. L.B.M. is a Research to Prevent Blindness Special Award Investigator. S.L.W. is a Research to Prevent Blindness Senior Scientific Investigator.

² A.A.C. and X.Z. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Lbachir BenMohamed, Laboratory of Cellular and Molecular Immunology, University of California Irvine, College of Medicine, Building 55, Room 202, Orange, CA 92868. E-mail address: Lbenmoha{at}uci.edu

⁴ Abbreviations used in this paper: gD, glycoprotein D; LCL, lymphoblastoid cell line; MFI, mean fluorescence intensity; rVV, recombinant vaccinia virus; SFU, spot-forming unit; Tg, transgenic; VVgD, vaccinia virus expressing gD.

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