title: Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes.
abstract: The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility and transient exposure of non-neutralizing, immunodominant epitopes could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs.
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Steven W
authors.initials: SW
authors.lastname: de Taeye
authors.affiliation: Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ozorowski
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Alba
authors.initials: A
authors.lastname: Torrents de la Peña
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Miklos
authors.initials: M
authors.lastname: Guttman
authors.affiliation: Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Julien
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Tom L G M
authors.initials: TL
authors.lastname: van den Kerkhof
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Pritchard
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Pugach
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Anila
authors.initials: A
authors.lastname: Yasmeen
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, Center for HIV-1/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, CA 92037, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Crampton
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, Center for HIV-1/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, CA 92037, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Ilja
authors.initials: I
authors.lastname: Bontjer
authors.affiliation: Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Torres
authors.affiliation: International AIDS Vaccine Initiative, New York, NY 10004, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Arendt
authors.affiliation: International AIDS Vaccine Initiative, New York, NY 10004, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: DeStefano
authors.affiliation: International AIDS Vaccine Initiative, New York, NY 10004, USA.
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Koff
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Eggink
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Ben
authors.initials: B
authors.lastname: Berkhout
authors.affiliation: International AIDS Vaccine Initiative, New York, NY 10004, USA.
authors.forename: Hansi
authors.initials: H
authors.lastname: Dean
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: LaBranche
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, Center for HIV-1/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, CA 92037, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Max
authors.initials: M
authors.lastname: Crispin
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Klasse
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.affiliation: Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA. Electronic address: r.w.sanders@amc.uva.nl.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry* / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing; D000939:Epitopes / Q000737:chemistry; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics; D015497:HIV-1; D057927:Hydrophobic and Hydrophilic Interactions; D007074:Immunoglobulin G / Q000737:chemistry; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D011817:Rabbits; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015700:HIV Envelope Protein gp41; D007074:Immunoglobulin G; D054299:env Gene Products, Human Immunodeficiency Virus