title: A novel HLA (HLA-A*0201) transgenic rabbit model for preclinical evaluation of human CD8+ T cell epitope-based vaccines against ocular herpes.
abstract: We introduced a novel humanized HLA-A*0201 transgenic (HLA Tg) rabbit model to assess the protective efficacy of a human CD8(+) T cell epitope-based vaccine against primary ocular herpes infection and disease. Each of the three immunodominant human CD8(+) T cell peptide epitopes from HSV-1 glycoprotein D (gD(53-61), gD(70-78), and gD(278-286)) were joined with a promiscuous human CD4(+) T cell peptide epitope (gD(49-82)) to construct three separate pairs of CD4-CD8 peptides. Each CD4-CD8 peptide pair was then covalently linked to an N(epsilon)-palmitoyl-lysine residue via a functional base lysine amino group to construct CD4-CD8 lipopeptides. HLA Tg rabbits were immunized s.c. with a mixture of the three CD4-CD8 HSV-1 gD lipopeptides. The HSV-gD-specific T cell responses induced by the mixture of CD4-CD8 lipopeptide vaccine and the protective efficacy against acute virus replication and ocular disease were determined. Immunization induced HSV-gD(49-82)-specific CD4(+) T cells in draining lymph node (DLN); induced HLA-restricted HSV-gD(53-61), gD(70-78), and gD(278-286)-specific CD8(+) T cells in DLN, conjunctiva, and trigeminal ganglia and reduced HSV-1 replication in tears and corneal eye disease after ocular HSV-1 challenge. In addition, the HSV-1 epitope-specific CD8(+) T cells induced in DLNs, conjunctiva, and the trigeminal ganglia were inversely proportional with corneal disease. The humanized HLA Tg rabbits appeared to be a useful preclinical animal model for investigating the immunogenicity and protective efficacy of human CD8(+) T cell epitope-based prophylactic vaccines against ocular herpes. The relevance of HLA Tg rabbits for future investigation of human CD4-CD8 epitope-based therapeutic vaccines against recurrent HSV-1 is discussed.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, The Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Aziz A
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Gargi
authors.initials: G
authors.lastname: Dasgupta
authors.forename: Neil D
authors.initials: ND
authors.lastname: Christensen
authors.forename: Jiafen
authors.initials: J
authors.lastname: Hu
authors.forename: Zareen S
authors.initials: ZS
authors.lastname: Choudhury
authors.forename: Arfan
authors.initials: A
authors.lastname: Azeem
authors.forename: James V
authors.initials: JV
authors.lastname: Jester
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Nesburn
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wechsler
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003228:Conjunctiva / Q000276:immunology / Q000378:metabolism / Q000821:virology; D003315:Cornea / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007114:Immunization; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011817:Rabbits; D012668:Trigeminal Ganglion / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D022301:Herpes Simplex Virus Vaccines; C104968:N(epsilon)-palmitoyllysine; D010446:Peptide Fragments; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1; D008239:Lysine