title: Protective immunity to genital herpes simplex virus type 1 and type 2 provided by self-adjuvanting lipopeptides that drive dendritic cell maturation and elicit a polarized Th1 immune response.
abstract: Genital herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections are a significant health problem worldwide. While it is believed that CD4+ Th1 cells are among the effectors to herpes immunity, developing an epitope-based clinical vaccine capable of inducing an effective anti-herpes CD4+ Th1-mediated protection is still under investigation. Few molecules achieve this target without the aid of external immuno-adjuvant. The present study was undertaken to examine the immunogenicity in mice of five CD4+ T cell epitope peptides (gD1-29, gD49-82, gD146-179, gD228-257, and gD332-358), recently identified from the HSV-1 glycoprotein D (gD), covalently linked to a palmitic acid moiety (lipopeptides) using the high-yielding chemoselective ligation method and delivered subcutaneously in free-adjuvant saline. Their protective efficacy was evaluated in a progestin-induced susceptibility mouse model of genital herpes following intravaginal challenge with either HSV-1 or HSV-2. Four out of five gD lipopeptides effectively induced virus-specific CD4+ Th1 responses associated with a reduction of virus replication in the genital tract and protection from overt signs of genital disease. A cocktail of three highly immunogenic lipopeptides provoked maturation of dendritic cells, induced interferon gamma (IFN-gamma)-producing CD4+ T cells, and protected against both HSV- 1 and HSV-2 infections. Depletion of specific T cell subsets from lipopeptideimmunized mice before intravaginal HSV challenges demonstrated that CD4+ T cells were primarily responsible for this protection. The strength of induced T cell immunity, together with the ease of construction and safety of these totally synthetic self-adjuvanting lipopeptides, provide a molecularly defined formulation that could combat genital herpes and other human viral infections for which induction of Th1 immunity is crucial.
authors.affiliation: Cellular and Molecular Immunology Laboratory, The Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Ilham
authors.initials: I
authors.lastname: Bettahi
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.forename: Rasha E
authors.initials: RE
authors.lastname: Afifi
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000276:Adjuvants, Immunologic; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology / Q000517:prevention & control*; D006561:Herpes Simplex / Q000276:immunology / Q000517:prevention & control*; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000472:pathogenicity; D018258:Herpesvirus 2, Human / Q000472:pathogenicity; D008074:Lipoproteins / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000737:chemistry
chemical_list: D000276:Adjuvants, Immunologic; D022301:Herpes Simplex Virus Vaccines; D008074:Lipoproteins; D010455:Peptides; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1