title: Asymptomatic human CD4+ cytotoxic T-cell epitopes identified from herpes simplex virus glycoprotein B.
abstract: The identification of "asymptomatic" (i.e., protective) epitopes recognized by T cells from herpes simplex virus (HSV)-seropositive healthy individuals is a prerequisite for an effective vaccine. Using the PepScan epitope mapping strategy, a library of 179 potential peptide epitopes (15-mers overlapping by 10 amino acids) was identified from HSV type 1 (HSV-1) glycoprotein B (gB), an antigen that induces protective immunity in both animal models and humans. Eighteen groups (G1 to G18) of 10 adjacent peptides each were first screened for T-cell antigenicity in 38 HSV-1-seropositive but HSV-2-seronegative individuals. Individual peptides within the two immunodominant groups (i.e., G4 and G14) were further screened with T cells from HLA-DR-genotyped and clinically defined symptomatic (n = 10) and asymptomatic (n = 10) HSV-1-seropositive healthy individuals. Peptides gB(161-175) and gB(166-180) within G4 and gB(661-675) within G14 recalled the strongest HLA-DR-dependent CD4(+) T-cell proliferation and gamma interferon production. gB(166-180), gB(661-675), and gB(666-680) elicited ex vivo CD4(+) cytotoxic T cells (CTLs) that lysed autologous HSV-1- and vaccinia virus (expressing gB)-infected lymphoblastoid cell lines. Interestingly, gB(166-180) and gB(666-680) peptide epitopes were strongly recognized by CD4(+) T cells from 10 of 10 asymptomatic patients but not by CD4(+) T cells from 10 of 10 symptomatic patients (P < 0.0001; analysis of variance posttest). Inversely, CD4(+) T cells from symptomatic patients preferentially recognized gB(661-675) (P < 0.0001). Thus, we identified three previously unrecognized CD4(+) CTL peptide epitopes in HSV-1 gB. Among these, gB(166-180) and gB(666-680) appear to be "asymptomatic" peptide epitopes and therefore should be considered in the design of future herpes vaccines.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, The Gavin S. Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California 92697-4375, USA.
authors.forename: Aziz Alami
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Binder
authors.forename: Noureddine
authors.initials: N
authors.lastname: Berka
authors.forename: Guillaume
authors.initials: G
authors.lastname: Durand
authors.forename: Alex
authors.initials: A
authors.lastname: Nguyen
authors.forename: Ilham
authors.initials: I
authors.lastname: Bettahi
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillère
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006561:Herpes Simplex / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; C044525:glycoprotein B, herpes simplex virus type 2; D007371:Interferon-gamma
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