title: Polyinosinic-polycytidylic acid is the most effective TLR adjuvant for SIV Gag protein-induced T cell responses in nonhuman primates.
abstract: Prime-boost immunization with heterologous vaccines elicits potent cellular immunity. In this study, we assessed the influence of various TLR ligands on SIV Gag-specific T cell immunity and protection following prime-boost immunization. Rhesus macaques (RMs) were primed with SIV Gag protein emulsified in Montanide ISA51 with or without TLR3 (polyinosinic-polycytidylic acid [poly-IC]), TLR4 (monophosphoryl lipid A), TLR7/8 (3M-012), TLR9 (CpG), or TLR3 (poly-IC) combined with TLR7/8 ligands, then boosted with replication defective adenovirus 5 expressing SIV Gag (rAd5-Gag). After priming, RMs that received SIV Gag protein plus poly-IC developed significantly higher frequencies of SIV Gag-specific CD4(+) Th1 responses in blood and bronchoalveolar lavage (BAL) fluid lymphocytes compared with all other adjuvants, and low-level SIV Gag-specific CD8(+) T cell responses. After the rAd5-Gag boost, the magnitude and breadth of SIV Gag-specific CD8(+) T cell responses were significantly increased in RM primed with SIV Gag protein plus poly-IC, with or without the TLR7/8 ligand, or CpG. However, the anamnestic, SIV Gag-specific CD8(+) T cell response to SIVmac251 challenge was not significantly enhanced by SIV Gag protein priming with any of the adjuvants. In contrast, the anamnestic SIV Gag-specific CD4(+) T cell response in BAL was enhanced by SIV Gag protein priming with poly-IC or CpG, which correlated with partial control of early viral replication after SIVmac251 challenge. These results demonstrate that prime-boost vaccination with SIV Gag protein/poly-IC improves magnitude, breadth, and durability of CD4(+) T cell immune responses, which could have a role in the control of SIV viral replication.
authors.affiliation: Department of Pathology, Vaccine and Gene Therapy Institute, and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
authors.forename: Haesun
authors.initials: H
authors.lastname: Park
authors.forename: Lauren
authors.initials: L
authors.lastname: Adamson
authors.forename: Tae
authors.initials: T
authors.lastname: Ha
authors.forename: Karl
authors.initials: K
authors.lastname: Mullen
authors.forename: Shoko I
authors.initials: SI
authors.lastname: Hagen
authors.forename: Arys
authors.initials: A
authors.lastname: Nogueron
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Sylwester
authors.forename: Michael K
authors.initials: MK
authors.lastname: Axthelm
authors.forename: Al
authors.initials: A
authors.lastname: Legasse
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Juliana M
authors.initials: JM
authors.lastname: McElrath
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Picker
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D015683:Gene Products, gag / Q000008:administration & dosage* / Q000276:immunology; D008253:Macaca mulatta; D008353:Mannitol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D009829:Oleic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D011070:Poly I-C / Q000008:administration & dosage* / Q000627:therapeutic use; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology
chemical_list: D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D009829:Oleic Acids; D011948:Receptors, Antigen, T-Cell; C477385:montanide ISA 51; D008353:Mannitol; D011070:Poly I-C