title: Contribution of TLR4 and MyD88 for adjuvant monophosphoryl lipid A (MPLA) activity in a DNA prime-protein boost HIV-1 vaccine.
abstract: Recombinant protein vaccines are commonly formulated with an immune-stimulatory compound, or adjuvant, to boost immune responses to a particular antigen. Recent studies have shown that, through recognition of molecular motifs, receptors of the innate immune system are involved in the functions of adjuvants to generate and direct adaptive immune responses. However, it is not clear to which degree those receptors are also important when the adjuvant is used as part of a novel heterologous prime-boost immunization process in which the priming and boosting components are not the same type of vaccines. In the current study, we compared the immune responses elicited by a pentavalent HIV-1 DNA prime-protein boost vaccine in mice deficient in either Toll-like receptor 4 (TLR4) or myeloid differentiation primary response gene 88 (MyD88) to wildtype mice. HIV gp120 protein administered in the boost phase was formulated with either monophosphoryl lipid A (MPLA), QS-21, or Al(OH)3. Endpoint antibody titer, serum cytokine response and T-cell memory response were assessed. Neither TLR4 nor MyD88 deficiency had a significant effect on the immune response of mice given vaccine formulated with QS-21 or Al(OH)3. However, TLR4- and MyD88-deficiency decreased both the antibody and T-cell responses in mice administered HIV gp120 formulated with MPLA. These results further our understanding of the activation of TLR4 and MyD88 by MPLA in the context of a DNA prime/protein boost immunization strategy.
authors.affiliation: Division of Infectious Diseases and Immunology, Program in Innate Immunity, Worcester, MA 01605, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Pouliot
authors.affiliation: Laboratory of Nucleic Acid Vaccines, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Buglione-Corbett
authors.affiliation: Division of Infectious Diseases and Immunology, Program in Innate Immunity, Worcester, MA 01605, United States.
authors.forename: Robyn
authors.initials: R
authors.lastname: Marty-Roix
authors.affiliation: Division of Infectious Diseases and Immunology, Program in Innate Immunity, Worcester, MA 01605, United States.
authors.forename: Sara
authors.initials: S
authors.lastname: Montminy-Paquette
authors.affiliation: Laboratory of Nucleic Acid Vaccines, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors.forename: Kim
authors.initials: K
authors.lastname: West
authors.affiliation: Laboratory of Nucleic Acid Vaccines, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors.forename: Shixia
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Nucleic Acid Vaccines, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.affiliation: Division of Infectious Diseases and Immunology, Program in Innate Immunity, Worcester, MA 01605, United States; Centre of Molecular Inflammation Research, Dept. of Cancer and Molecular Medicine, NTNU, 7491 Trondheim, Norway. Electronic address: egil.lien@umassmed.edu.
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000536:Aluminum Hydroxide / Q000008:administration & dosage; D000818:Animals; D016207:Cytokines / Q000276:immunology; D015483:HIV Antibodies / Q000097:blood; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000097:blood; D007156:Immunologic Memory; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D012503:Saponins / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D016207:Cytokines; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G; D008050:Lipid A; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012503:Saponins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019444:Vaccines, DNA; C514793:gp120 protein, Human immunodeficiency virus 1; D000536:Aluminum Hydroxide; C078785:saponin QA-21V1; C048436:monophosphoryl lipid A
keywords: Antibody response; DNA Prime-protein boost vaccine; MPLA; MyD88; TLR4