Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

Steven W de Taeye; Gabriel Ozorowski; Alba Torrents de la Peña; Miklos Guttman; Jean-Philippe Julien; Tom L G M van den Kerkhof; Judith A Burger; Laura K Pritchard; Pavel Pugach; Anila Yasmeen; Jordan Crampton; Joyce Hu; Ilja Bontjer; Jonathan L Torres; Heather Arendt; Joanne DeStefano; Wayne C Koff; Hanneke Schuitemaker; Dirk Eggink; Ben Berkhout; Hansi Dean; Celia LaBranche; Shane Crotty; Max Crispin; David C Montefiori; P J Klasse; Kelly K Lee; John P Moore; Ian A Wilson; Andrew B Ward; Rogier W Sanders

doi:10.1016/j.cell.2015.11.056

Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

Cell. 2015 Dec 17;163(7):1702-15. doi: 10.1016/j.cell.2015.11.056.

Authors

Steven W de Taeye¹, Gabriel Ozorowski², Alba Torrents de la Peña¹, Miklos Guttman³, Jean-Philippe Julien², Tom L G M van den Kerkhof⁴, Judith A Burger¹, Laura K Pritchard⁵, Pavel Pugach⁶, Anila Yasmeen⁶, Jordan Crampton⁷, Joyce Hu⁷, Ilja Bontjer¹, Jonathan L Torres², Heather Arendt⁸, Joanne DeStefano⁸, Wayne C Koff⁸, Hanneke Schuitemaker⁹, Dirk Eggink¹, Ben Berkhout¹, Hansi Dean⁸, Celia LaBranche¹⁰, Shane Crotty⁷, Max Crispin⁵, David C Montefiori¹⁰, P J Klasse⁶, Kelly K Lee³, John P Moore⁶, Ian A Wilson¹¹, Andrew B Ward², Rogier W Sanders¹²

Affiliations

¹ Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
² 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.
³ Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
⁴ 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.
⁵ Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
⁶ Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
⁷ 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.
⁸ International AIDS Vaccine Initiative, New York, NY 10004, USA.
⁹ Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
¹⁰ Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
¹¹ 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.
¹² 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AIDS Vaccines / chemistry*
AIDS Vaccines / immunology*
Animals
Antibodies, Neutralizing
Epitopes / chemistry
HIV Envelope Protein gp41 / chemistry
HIV Envelope Protein gp41 / genetics
HIV-1
Hydrophobic and Hydrophilic Interactions
Immunoglobulin G / chemistry
Models, Molecular
Mutagenesis
Protein Conformation
Rabbits
env Gene Products, Human Immunodeficiency Virus / chemistry

Substances

AIDS Vaccines
Antibodies, Neutralizing
Epitopes
HIV Envelope Protein gp41
Immunoglobulin G
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding