title: DNA vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers.
abstract: Broadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNA-protein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1.
  
  
  OBJECTIVE
  Recent identification of antibodies that neutralize most HIV-1 strains has revived hopes and efforts to create novel vaccines that can effectively stimulate HIV-1 neutralizing antibodies. However, the multiple immune evasion properties of HIV have hampered these efforts. These include the instability of the gp120 trimer, the inaccessibility of the conserved sequences, highly variable protein sequences, and the loss of HIV-1-specific antibody-producing cells during development. We have shown previously that tumor necrosis factor (TNF) superfamily ligands, including BAFF and APRIL, can be multitrimerized using the lung protein SP-D (surfactant protein D), enhancing immune responses. Here we show that DNA or DNA-protein vaccines encoding BAFF or APRIL multitrimers, IL-12p70, and membrane-bound HIV-1 Env gp140 induced tier 1 and tier 2 neutralizing antibodies in a mouse model. BAFF and APRIL enhanced the immune reaction, improved antibody binding, and increased the numbers of anti-HIV-1 antibody-secreting cells. Adaptation of this vaccine design may prove useful in designing preventive HIV-1 vaccines for humans.
authors: Department of Microbiology and Immunology and Miami Center for AIDS Research, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Sachin
authors: S
authors: Gupta
authors: Department of Microbiology and Immunology and Miami Center for AIDS Research, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Emily S
authors: ES
authors: Clark
authors: Department of Microbiology and Immunology and Miami Center for AIDS Research, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: James M
authors: JM
authors: Termini
authors: Department of Microbiology and Immunology and Miami Center for AIDS Research, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Justin
authors: J
authors: Boucher
authors: Department of Microbiology and Immunology and Miami Center for AIDS Research, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Saravana
authors: S
authors: Kanagavelu
authors: Department of Surgery, Duke University, Durham, North Carolina, USA.
authors: Celia C
authors: CC
authors: LeBranche
authors: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Sakhi
authors: S
authors: Abraham
authors: Department of Surgery, Duke University, Durham, North Carolina, USA.
authors: David C
authors: DC
authors: Montefiori
authors: Department of Microbiology and Immunology and Miami Center for AIDS Research, University of Miami Miller School of Medicine, Miami, Florida, USA gstone@med.miami.edu WNKhan@med.miami.edu.
authors: Wasif N
authors: WN
authors: Khan
authors: Department of Microbiology and Immunology and Miami Center for AIDS Research, University of Miami Miller School of Medicine, Miami, Florida, USA gstone@med.miami.edu WNKhan@med.miami.edu.
authors: Geoffrey W
authors: GW
authors: Stone
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing / Q000187:drug effects*; D053264:B-Cell Activating Factor / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000187:drug effects / Q000276:immunology*; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D010957:Plasmids / Q000235:genetics; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D053264:B-Cell Activating Factor; D015699:HIV Envelope Protein gp120; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D019444:Vaccines, DNA; D018664:Interleukin-12
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