title: Multimeric scaffolds displaying the HIV-1 envelope MPER induce MPER-specific antibodies and cross-neutralizing antibodies when co-immunized with gp160 DNA.
abstract: Developing a vaccine that overcomes the diversity of HIV-1 is likely to require a strategy that directs antibody (Ab) responses toward conserved regions of the viral Envelope (Env). However, the generation of neutralizing Abs (NAbs) targeting these regions through vaccination has proven to be difficult. One conserved region of particular interest is the membrane proximal external region (MPER) of Env located within the gp41 ectodomain. In order to direct the immune response to this region, the MPER and gp41 ectodomain were expressed separately as N-terminal fusions to the E2 protein of Geobacillus stearothermophilus. The E2 protein acts as a scaffold by self-assembling into 60-mer particles, displaying up to 60 copies of the fused target on the surface. Rabbits were immunized with E2 particles displaying MPER and/or the gp41 ectodomain in conjunction with DNA encoding full-length gp160. Only vaccines including E2 particles displaying MPER elicited MPER-specific Ab responses. NAbs were elicited after two immunizations that largely targeted the V3 loop. To overcome V3 immunodominance in the DNA component, E2 particles displaying MPER were used in conjunction with gp160 DNA lacking hypervariable regions V2, V3, or combined V1V2V3. All rabbits had HIV binding Ab responses and NAbs following the second vaccination. Using HIV-2/HIV-1 MPER chimeric viruses as targets, NAbs were detected in 12/16 rabbits after three immunizations. Low levels of NAbs specific for Tier 1 and 2 viruses were observed in all groups. This study provides evidence that co-immunizing E2 particles displaying MPER and gp160 DNA can focus Ab responses toward conserved regions of Env.
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, United States of America.
authors.forename: Shelly J
authors.initials: SJ
authors.lastname: Krebs
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, United States of America.
authors.forename: Sean P
authors.initials: SP
authors.lastname: McBurney
authors.affiliation: Viral Vaccines Program, Seattle Biomedical Research Institute, Seattle, WA, United States of America.
authors.forename: Dina N
authors.initials: DN
authors.lastname: Kovarik
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, United States of America.
authors.forename: Chelsea D
authors.initials: CD
authors.lastname: Waddell
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, United States of America.
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Jaworski
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, United States of America.
authors.forename: William F
authors.initials: WF
authors.lastname: Sutton
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, United States of America.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Gomes
authors.affiliation: Institute of Protein Biochemistry, C.N.R., Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Trovato
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, United States of America.
authors.forename: Garret
authors.initials: G
authors.lastname: Waagmeester
authors.affiliation: Novartis Vaccines & Diagnostics, Emeryville, CA, United States of America.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Barnett
authors.affiliation: Institute of Protein Biochemistry, C.N.R., Naples, Italy.
authors.forename: Piergiuseppe
authors.initials: P
authors.lastname: DeBerardinis
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, OR, United States of America; Viral Vaccines Program, Seattle Biomedical Research Institute, Seattle, WA, United States of America.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Haigwood
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D001426:Bacterial Proteins / Q000378:metabolism; D019470:Biolistics; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D001411:Geobacillus stearothermophilus; D019302:HIV Envelope Protein gp160 / Q000235:genetics / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000235:genetics; D015497:HIV-1 / Q000378:metabolism*; D009500:Neutralization Tests; D010957:Plasmids / Q000235:genetics; D011817:Rabbits
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D001426:Bacterial Proteins; D017931:DNA Primers; D019302:HIV Envelope Protein gp160; D015700:HIV Envelope Protein gp41