title: HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates.
abstract: Induction and maintenance of antibody and T cell responses will be critical for developing a successful vaccine against HIV. A rational approach for generating such responses is to design vaccines or adjuvants that have the capacity to activate specific antigen-presenting cells. In this regard, dendritic cells (DCs) are the most potent antigen-presenting cells for generating primary T cell responses. Here, we report that Toll-like receptor (TLR) agonists and ligands that activate DCs in vitro influence the magnitude and quality of the cellular immune response in nonhuman primates (NHPs) when administered with HIV Gag protein. NHPs immunized with HIV Gag protein and a TLR7/8 agonist or a TLR9 ligand [CpG oligodeoxynucleotides (CpG ODN)] had significantly increased Gag-specific T helper 1 and antibody responses, compared with animals immunized with HIV Gag protein alone. Importantly, conjugating the HIV Gag protein to the TLR7/8 agonist (Gag-TLR7/8 conjugate) dramatically enhanced the magnitude and altered the quality of the T helper 1 response, compared with animals immunized with HIV Gag protein and the TLR7/8 agonist or CpG ODN. Furthermore, immunization with the Gag-TLR7/8 conjugate vaccine elicited Gag-specific CD8+ T responses. Collectively, our results show that conjugating HIV Gag protein to a TLR7/8 agonist is an effective way to elicit broad-based adaptive immunity in NHPs. This type of vaccine formulation should have utility in preventive or therapeutic vaccines in which humoral and cellular immunity is required.
authors.affiliation: Cellular Immunology Section, Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wille-Reece
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Flynn
authors.forename: Karin
authors.initials: K
authors.lastname: Loré
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.forename: Ross M
authors.initials: RM
authors.lastname: Kedl
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Mattapallil
authors.forename: Walter R
authors.initials: WR
authors.lastname: Weiss
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology*; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008024:Ligands; D019590:Nucleocapsid Proteins / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000276:immunology; D011323:Primates; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D015683:Gene Products, gag; D015488:HIV Antigens; D007376:Interleukin-2; D008024:Ligands; D019590:Nucleocapsid Proteins; D009838:Oligodeoxyribonucleotides; D007371:Interferon-gamma