title: Co-immunization with multimeric scaffolds and DNA rapidly induces potent autologous HIV-1 neutralizing antibodies and CD8+ T cells.
abstract: To obtain proof of concept for HIV vaccines, we generated recombinant multimeric particles displaying the HIV-1 Envelope (Env) third hypervariable region (V3) as an N-terminal fusion protein on the E2 subunit of the pyruvate dehydrogenase complex of Geobacillus stearothermophilus. The E2 scaffold self-assembles into a 60-mer core that is 24 nm in diameter, with a molecular weight of 1.5 MDa, similar to a virus like particle with up to 60 copies of a heterologous protein accessible on the surface. Env(V3)-E2 multimers were tested alone and in combination with Env(gp160) DNA in mice and rabbits. Following two or more co-immunizations with Env(V3)-E2 and Env gp160 DNA, all 18 rabbits developed potent autologous neutralizing antibodies specific for V3 in six weeks. These neutralizing antibodies were sustained for 16 weeks without boosting, and comparable responses were obtained when lipopolysaccharide, a contaminant from expression in E. coli, was removed. Co-immunizations of Env(V3)-E2 and DNA expressing gp160 elicited moderate CD8-specific responses and Env-specific antibodies in mice. Co-immunization with DNA and E2 was superior to individual or sequential vaccination with these components in eliciting both neutralizing antibodies in rabbits and CD8(+) T cell responses in mice. Co-immunization with DNA and multimeric E2 scaffolds appears to offer a highly effective means of eliciting rapid, specific, and sustained immune responses that may be a useful approach for other vaccine targets.
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, United States of America.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Jaworski
authors.forename: Shelly J
authors.initials: SJ
authors.lastname: Krebs
authors.forename: Maria
authors.initials: M
authors.lastname: Trovato
authors.forename: Dina N
authors.initials: DN
authors.lastname: Kovarik
authors.forename: Zachary
authors.initials: Z
authors.lastname: Brower
authors.forename: William F
authors.initials: WF
authors.lastname: Sutton
authors.forename: Garrett
authors.initials: G
authors.lastname: Waagmeester
authors.forename: Rossella
authors.initials: R
authors.lastname: Sartorius
authors.forename: Luciana
authors.initials: L
authors.lastname: D'Apice
authors.forename: Antonella
authors.initials: A
authors.lastname: Caivano
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doria-Rose
authors.forename: Delphine
authors.initials: D
authors.lastname: Malherbe
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Susan
authors.initials: S
authors.lastname: Barnett
authors.forename: Piergiuseppe
authors.initials: P
authors.lastname: De Berardinis
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Haigwood
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004247:DNA / Q000008:administration & dosage; D015686:Gene Products, env; D015483:HIV Antibodies / Q000096:biosynthesis*; D019302:HIV Envelope Protein gp160 / Q000008:administration & dosage / Q000235:genetics; D015497:HIV-1; D006801:Humans; D007114:Immunization / Q000379:methods*; D051379:Mice; D010316:Particle Size; D011817:Rabbits
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015686:Gene Products, env; D015483:HIV Antibodies; D019302:HIV Envelope Protein gp160; D004247:DNA