title: Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens.
abstract: Advancement in immunogen selection and vaccine design that will rapidly elicit a protective Ab response is considered critical for HIV vaccine protective efficacy. Vaccine-elicited Ab responses must therefore have the capacity to prevent infection by neutralization-resistant phenotypes of transmitted/founder (T/F) viruses that establish infection in humans. Most vaccine candidates to date have been ineffective at generating Abs that neutralize T/F or early variants. In this study, we report that coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from native envelope gene sequences (envs) induced neutralizing Abs against Tier 2 autologous viruses expressing cognate envelope (Env). The Env immunogens were selected from envs emerging during the earliest stages of neutralization breadth developing within the first 2 years of infection in two clade B-infected human subjects. Moreover, the IgG responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed within the human subjects. Furthermore, we measured increasing affinity of macaque polyclonal IgG responses over the course of the immunization regimen that correlated with Tier 1 neutralization. In addition, we report firm correlations between Tier 2 autologous neutralization and Tier 1 heterologous neutralization, as well as overall TZM-bl breadth scores. Additionally, the activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques correlated with Tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements.
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
authors.forename: Ann J
authors.identifier: http://orcid.org/0000-0001-7471-9366
authors.initials: AJ
authors.lastname: Hessell
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
authors.forename: Delphine C
authors.initials: DC
authors.lastname: Malherbe
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Military HIV Research Program, Silver Spring, MD 20889;
authors.forename: Franco
authors.initials: F
authors.lastname: Pissani
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
authors.forename: Sean
authors.initials: S
authors.lastname: McBurney
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR 97239;
authors.forename: Shelly J
authors.initials: SJ
authors.lastname: Krebs
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
authors.forename: Michelle
authors.initials: M
authors.lastname: Gomes
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
authors.forename: Shilpi
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
authors.forename: William F
authors.initials: WF
authors.lastname: Sutton
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR 97239;
authors.forename: Benjamin J
authors.identifier: http://orcid.org/0000-0001-7767-022X
authors.initials: BJ
authors.lastname: Burwitz
authors.affiliation: Seattle BioMed, Seattle, WA 98109;
authors.forename: Matthew
authors.initials: M
authors.lastname: Gray
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Harlan
authors.initials: H
authors.lastname: Robins
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006;
authors.forename: Byung S
authors.identifier: http://orcid.org/0000-0003-3516-7516
authors.initials: BS
authors.lastname: Park
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR 97239;
authors.forename: Jonah B
authors.identifier: http://orcid.org/0000-0002-7633-3122
authors.initials: JB
authors.lastname: Sacha
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27708;
authors.forename: Celia C
authors.initials: CC
authors.lastname: LaBranche
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195; and.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Fuller
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27708;
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.affiliation: Seattle BioMed, Seattle, WA 98109;
authors.forename: D Noah
authors.identifier: http://orcid.org/0000-0002-9128-172X
authors.initials: DN
authors.lastname: Sather
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Molecular Microbiology and Immunology, School of Medicine, Oregon Health & Science University, Portland, OR 97239 haigwoon@ohsu.edu.
authors.forename: Nancy L
authors.identifier: http://orcid.org/0000-0002-1477-9575
authors.initials: NL
authors.lastname: Haigwood
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D007114:Immunization; D007115:Immunization Schedule; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology; D008253:Macaca mulatta; D009500:Neutralization Tests; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014611:Vaccination; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D007074:Immunoglobulin G; D054299:env Gene Products, Human Immunodeficiency Virus