title: Immunization with HIV-1 Gag protein conjugated to a TLR7/8 agonist results in the generation of HIV-1 Gag-specific Th1 and CD8+ T cell responses.
abstract: One strategy to induce optimal cellular and humoral immune responses following immunization is to use vaccines or adjuvants that target dendritic cells and B cells. Activation of both cell types can be achieved using specific TLR ligands or agonists directed against their cognate receptor. In this study, we compared the ability of the TLR7/8 agonist R-848, which signals only via TLR7 in mice, with CpG oligodeoxynucleotides for their capacity to induce HIV-1 Gag-specific T cell and Ab responses when used as vaccine adjuvants with HIV-1 Gag protein in mice. Injection of R-848 and CpG oligodeoxynucleotides alone enhanced the innate immune responses in vivo as demonstrated by high serum levels of inflammatory cytokines, including IL-12p70 and IFN-alpha, and increased expression of CD80, CD86, and CD40 on CD11c(+) dendritic cells. By contrast, R-848 was a relatively poor adjuvant for inducing primary Th1 or CD8(+) T cell responses when administered with HIV-1 Gag protein. However, when a TLR7/8 agonist structurally and functionally similar to R-848 was conjugated to HIV-1 Gag protein both Th1 and CD8(+) T cells responses were elicited as determined by intracellular cytokine and tetramer staining. Moreover, within the population of HIV-1 Gag-specific CD8(+) CD62(low) cells, approximately 50% of cells expressed CD127, a marker shown to correlate with the capacity to develop into long-term memory cells. Overall, these data provide evidence that TLR7/8 agonists can be effective vaccine adjuvants for eliciting strong primary immune responses with a viral protein in vivo, provided vaccine delivery is optimized.
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wille-Reece
authors.forename: Chang-You
authors.initials: CY
authors.lastname: Wu
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Flynn
authors.forename: Ross M
authors.initials: RM
authors.lastname: Kedl
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D015683:Gene Products, gag / Q000008:administration & dosage / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D007093:Imidazoles / Q000008:administration & dosage / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D011956:Receptors, Cell Surface / Q000819:agonists*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051199:Toll-Like Receptor 7; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D007093:Imidazoles; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D018074:Vaccines, Conjugate; C402365:resiquimod