title: Toll-like receptor 3 adjuvant in combination with virus-like particles elicit a humoral response against HIV.
abstract: Human Immunodeficiency Virus (HIV) Virus-Like Particles (VLPs) composed of HIVIIIBGag and HIVBaLgp120/gp41 envelope are a pseudovirion vaccine capable of presenting antigens in their native conformations. To enhance the immunogenicity of the HIV Env antigen, VLPs were coupled to VesiVax Conjugatable Adjuvant Lipid Vesicles (CALV) containing one of four toll-like-receptor (TLR) ligands, each activating a receptor with distinct cellular localization and downstream pathways. C57BL/6 mice were vaccinated by intranasal prime followed by two sub-cheek boosts and their sera immunoglobulin and neutralizing potency were measured over a duration of 3months after vaccination. PBS control, VLPs alone, CALV+VLPs, and VLPs complexed with CALV and ligands for TLR2 (PAM3CAG), TLR3 (dsRNA), TLR4 (MPLA), or TLR7/8 (resiquimod) were evaluated based on antibody titer, IgG1 and IgG2c class switching, germinal center formation, T follicular cells and potency of neutralizing antibodies. Consistently, the TLR3 ligand dsRNA complexed to CALV and in combination with VLPs (CALV(dsRNA)+VLPs) induced the strongest response. CALV(dsRNA)+VLPs induced the highest titers against the recombinant vaccine antigens clade B Bal gp120 and pr55 Gag. Additionally, CALV(dsRNA)+VLPs induced cross-clade antibodies, represented by high titers of antibody to clade c 96ZM651 gp120. CALV(dsRNA)+VLPs induced predominantly IgG2c over IgG1, a response associated with T helper type 1 (Th1)-like cytokines. In turn, CALV(dsRNA)+VLP immunized mice generated the most potent neutralizing antibodies against HIV strain MN.3. Finally, at time of sacrifice, a significant increase in germinal center B cells and T follicular cells was detected in mice which received CALV(dsRNA)+VLPs compared to PBS. Our results indicate that CALV(dsRNA) is a superior adjuvant for HIV VLPs in generating a Th1-like immunoglobulin profile, while prolonging lymph node germinal centers, T follicular cells and generating neutralizing antibodies to a highly sensitive tier 1A variant of HIV.
authors.affiliation: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Poteet
authors.affiliation: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Phoebe
authors.initials: P
authors.lastname: Lewis
authors.affiliation: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Changyi
authors.initials: C
authors.lastname: Chen
authors.affiliation: Molecular Express, Inc., Rancho Domínguez, CA 90220, USA.
authors.forename: Sam On
authors.initials: SO
authors.lastname: Ho
authors.affiliation: Molecular Express, Inc., Rancho Domínguez, CA 90220, USA.
authors.forename: Thai
authors.initials: T
authors.lastname: Do
authors.affiliation: Molecular Express, Inc., Rancho Domínguez, CA 90220, USA.
authors.forename: SuMing
authors.initials: S
authors.lastname: Chiang
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: Labranche
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.affiliation: Molecular Express, Inc., Rancho Domínguez, CA 90220, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Fujii
authors.affiliation: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX 77030, USA; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA. Electronic address: qizhiyao@bcm.edu.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yao
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000737:chemistry; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D015683:Gene Products, gag / Q000276:immunology; D018858:Germinal Center / Q000276:immunology; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology; D056724:Immunity, Humoral; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000737:chemistry / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D015683:Gene Products, gag; D015483:HIV Antibodies; D008024:Ligands; D051196:Toll-Like Receptor 3; D014614:Vaccines, Synthetic; D058425:Vaccines, Virus-Like Particle
keywords: Germinal center; HIV; Neutralizing antibody; TLR3; Vaccine; Virus Like Particle (VLP)