title: HLA-A02:01-restricted epitopes identified from the herpes simplex virus tegument protein VP11/12 preferentially recall polyfunctional effector memory CD8+ T cells from seropositive asymptomatic individuals and protect humanized HLA-A*02:01 transgenic mice against ocular herpes.
abstract: The HSV type 1 tegument virion phosphoprotein (VP) 11/12 (VP11/12) is a major Ag targeted by CD8(+) T cells from HSV-seropositive individuals. However, whether and which VP11/12 epitope-specific CD8(+) T cells play a role in the "natural" protection seen in seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we used multiple prediction computer-assisted algorithms to identify 10 potential HLA-A*02:01-restricted CD8(+) T cell epitopes from the 718-aa sequence of VP11/12. Three of 10 epitopes exhibited high-to-moderate binding affinity to HLA-A*02:01 molecules. In 10 sequentially studied HLA-A*02:01-positive and HSV-1-seropositive ASYMP individuals, the most frequent, robust, and polyfunctional effector CD8(+) T cell responses, as assessed by a combination of tetramer frequency, granzyme B, granzyme K, perforin, CD107(a/b) cytotoxic degranulation, IFN-γ, and multiplex cytokines assays, were predominantly directed against three epitopes: VP11/1266-74, VP11/12220-228, and VP11/12702-710. Interestingly, ASYMP individuals had a significantly higher proportion of CD45RA(low)CCR7(low)CD44(high)CD62L(low)CD27(low)CD28(low)CD8(+) effector memory CD8(+) T cells (TEMs) specific to the three epitopes, compared with symptomatic individuals (with a history of numerous episodes of recurrent ocular herpetic disease). Moreover, immunization of HLA-A*02:01 transgenic mice with the three ASYMP CD8(+) TEM cell epitopes induced robust and polyfunctional epitope-specific CD8(+) TEM cells that were associated with a strong protective immunity against ocular herpes infection and disease. Our findings outline phenotypic and functional features of protective HSV-specific CD8(+) T cells that should guide the development of an effective T cell-based herpes vaccine.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Ruchi
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Arif A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Doran
authors.initials: D
authors.lastname: Spencer
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Hawa
authors.initials: H
authors.lastname: Vahed
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Lopes
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Nhi Thi Uyen
authors.initials: NT
authors.lastname: Thai
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Christine
authors.initials: C
authors.lastname: Wang
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Thanh T
authors.initials: TT
authors.lastname: Pham
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Jiawei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Stem Cell Research Center, University of California Irvine, Irvine, CA 92697;
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Scarfone
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697;
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Nesburn
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697; Virology Research, Gavin Herbert Eye Institute and Department of Ophthalmology, University of California Irvine, School of Medicine, Irvine, CA 92697; Department of Microbiology and Molecular Genetics, University of California Irvine, School of Medicine, Irvine, CA 92697; Center for Virus Research, University of California Irvine, Irvine, CA 92697;
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wechsler
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697; Department of Molecular Biology and Biochemistry, University of California Irvine, School of Medicine, Irvine, CA 92697; and Institute for Immunology, University of California Irvine, School of Medicine, Irvine, CA 92697 Lbenmoha@uci.edu.
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology*; D058070:Asymptomatic Diseases; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000737:chemistry / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007114:Immunization; D007156:Immunologic Memory; D016849:Keratitis, Herpetic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; C414831:UL46 protein, Human herpesvirus 1; D014764:Viral Proteins