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Title: Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization

Abstract

The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs).

Authors:
 [1];  [2];  [1];  [3];  [4];  [5];  [6];  [6];  [7];  [1];  [1];  [1];  [8];  [8];  [8];  [5];  [5];  [1];  [1];  [9] more »;  [9];  [7];  [6];  [8];  [4];  [8];  [5];  [5];  [10] « less
  1. Univ. of Amsterdam (Netherlands)
  2. The Scripps Research Inst., La Jolla, CA (United States); The Hospital for Sick Children Research Inst., Toronto, ON (Canada); Univ. of Toronto, ON (Canada)
  3. The Scripps Research Inst., La Jolla, CA (United States); Amgen, Inc., Thousand Oaks, CA (United States)
  4. Univ. of Washington, Seattle, WA (United States)
  5. The Scripps Research Inst., La Jolla, CA (United States)
  6. Univ. of Oxford (United Kingdom)
  7. Univ. of Kansas, Lawrence, KS (United States)
  8. Cornell Univ., Ithaca, NY (United States). Weill Medical College
  9. Duke Univ. Medical Center, Durham, NC (United States)
  10. Univ. of Amsterdam (Netherlands); Cornell Univ., Ithaca, NY (United States). Weill Medical College
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS); SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Org.:
National Institutes of Health (NIH); The Scripps Research Institute; International AIDS Vaccine Initiative (IAVI); Aids fonds Netherlands; Canadian Institutes of Health Research (CIHR); Netherlands Organization for Scientific Research (NWO); European Research Council (ERC); Collaboration for AIDS Vaccine Discovery (CAVD); USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1499807
Grant/Contract Number:  
P01 AI110657; CHAVI-ID UM1 AI100663; 2012041; THA-118628; ERC-StG-2011–280829-SHEV; OPP1084519; OPP1115782; AC02-76SF00515
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 20; Journal Issue: 8; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Torrents de la Peña, Alba, Julien, Jean-Philippe, de Taeye, Steven W., Garces, Fernando, Guttman, Miklos, Ozorowski, Gabriel, Pritchard, Laura K., Behrens, Anna-Janina, Go, Eden P., Burger, Judith A., Schermer, Edith E., Sliepen, Kwinten, Ketas, Thomas J., Pugach, Pavel, Yasmeen, Anila, Cottrell, Christopher A., Torres, Jonathan L., Vavourakis, Charlotte D., van Gils, Marit J., LaBranche, Celia, Montefiori, David C., Desaire, Heather, Crispin, Max, Klasse, Per Johan, Lee, Kelly K., Moore, John P., Ward, Andrew B., Wilson, Ian A., and Sanders, Rogier W. Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization. United States: N. p., 2017. Web. doi:10.1016/j.celrep.2017.07.077.
Torrents de la Peña, Alba, Julien, Jean-Philippe, de Taeye, Steven W., Garces, Fernando, Guttman, Miklos, Ozorowski, Gabriel, Pritchard, Laura K., Behrens, Anna-Janina, Go, Eden P., Burger, Judith A., Schermer, Edith E., Sliepen, Kwinten, Ketas, Thomas J., Pugach, Pavel, Yasmeen, Anila, Cottrell, Christopher A., Torres, Jonathan L., Vavourakis, Charlotte D., van Gils, Marit J., LaBranche, Celia, Montefiori, David C., Desaire, Heather, Crispin, Max, Klasse, Per Johan, Lee, Kelly K., Moore, John P., Ward, Andrew B., Wilson, Ian A., & Sanders, Rogier W. Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization. United States. https://doi.org/10.1016/j.celrep.2017.07.077
Torrents de la Peña, Alba, Julien, Jean-Philippe, de Taeye, Steven W., Garces, Fernando, Guttman, Miklos, Ozorowski, Gabriel, Pritchard, Laura K., Behrens, Anna-Janina, Go, Eden P., Burger, Judith A., Schermer, Edith E., Sliepen, Kwinten, Ketas, Thomas J., Pugach, Pavel, Yasmeen, Anila, Cottrell, Christopher A., Torres, Jonathan L., Vavourakis, Charlotte D., van Gils, Marit J., LaBranche, Celia, Montefiori, David C., Desaire, Heather, Crispin, Max, Klasse, Per Johan, Lee, Kelly K., Moore, John P., Ward, Andrew B., Wilson, Ian A., and Sanders, Rogier W. 2017. "Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization". United States. https://doi.org/10.1016/j.celrep.2017.07.077. https://www.osti.gov/servlets/purl/1499807.
@article{osti_1499807,
title = {Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization},
author = {Torrents de la Peña, Alba and Julien, Jean-Philippe and de Taeye, Steven W. and Garces, Fernando and Guttman, Miklos and Ozorowski, Gabriel and Pritchard, Laura K. and Behrens, Anna-Janina and Go, Eden P. and Burger, Judith A. and Schermer, Edith E. and Sliepen, Kwinten and Ketas, Thomas J. and Pugach, Pavel and Yasmeen, Anila and Cottrell, Christopher A. and Torres, Jonathan L. and Vavourakis, Charlotte D. and van Gils, Marit J. and LaBranche, Celia and Montefiori, David C. and Desaire, Heather and Crispin, Max and Klasse, Per Johan and Lee, Kelly K. and Moore, John P. and Ward, Andrew B. and Wilson, Ian A. and Sanders, Rogier W.},
abstractNote = {The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs).},
doi = {10.1016/j.celrep.2017.07.077},
url = {https://www.osti.gov/biblio/1499807}, journal = {Cell Reports},
issn = {2211-1247},
number = 8,
volume = 20,
place = {United States},
year = {Tue Aug 22 00:00:00 EDT 2017},
month = {Tue Aug 22 00:00:00 EDT 2017}
}

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Works referenced in this record:

Redox regulation in the endoplasmic reticulum
journal, August 2014


Modeling the role of disulfide bonds in protein folding: Entropic barriers and pathways
journal, May 1995


Immunogenicity of a Prefusion HIV-1 Envelope Trimer in Complex with a Quaternary-Structure-Specific Antibody
journal, December 2015


Disulphide bonds and protein stability
journal, February 1988


Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes
journal, December 2015


Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer
journal, March 2015


Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans
journal, December 2015


Early development of broadly neutralizing antibodies in HIV-1–infected infants
journal, May 2014


CD4-Induced Activation in a Soluble HIV-1 Env Trimer
journal, July 2014


Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface
journal, September 2014


Crystal Structure of a Soluble Cleaved HIV-1 Envelope Trimer
journal, October 2013


Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens
journal, September 2015


Sequential and Simultaneous Immunization of Rabbits with HIV-1 Envelope Glycoprotein SOSIP.664 Trimers from Clades A, B and C
journal, September 2016


Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability
journal, June 2016


Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env
journal, June 2015


Cryo-EM structure of a native, fully glycosylated, cleaved HIV-1 envelope trimer
journal, March 2016


Nature Versus Nurture: Developing Enzymes That Function Under Extreme Conditions
journal, July 2012


Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer
journal, October 2013


Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies
journal, August 2016


Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody
journal, April 2013


Structure and immune recognition of trimeric pre-fusion HIV-1 Env
journal, October 2014


Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers
journal, June 2015


Cell- and Protein-Directed Glycosylation of Native Cleaved HIV-1 Envelope
journal, June 2015


A Native-Like SOSIP.664 Trimer Based on an HIV-1 Subtype B env Gene
journal, January 2015


A stamp on the envelope
journal, October 2014


Stabilization of the Soluble, Cleaved, Trimeric Form of the Envelope Glycoprotein Complex of Human Immunodeficiency Virus Type 1
journal, September 2002


HIV-1 neutralizing antibodies induced by native-like envelope trimers
journal, June 2015


Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env
journal, September 2015


HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies
journal, September 2016


Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G
journal, May 2016


Broadly neutralizing antibodies against HIV-1: Templates for a vaccine
journal, January 2013


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The expanding array of HIV broadly neutralizing antibodies
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Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle
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Targeted selection of HIV-specific antibody mutations by engineering B cell maturation
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Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics
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Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence
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Antibody responses to viral infections: a structural perspective across three different enveloped viruses
journal, March 2019


Antibody Responses Elicited by Immunization with BG505 Trimer Immune Complexes
journal, August 2019


Strategies for inducing effective neutralizing antibody responses against HIV-1
journal, November 2019


Capturing the inherent structural dynamics of the HIV-1 envelope glycoprotein fusion peptide
journal, February 2019


Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements
journal, January 2020


Conformational Engineering of HIV-1 Env Based on Mutational Tolerance in the CD4 and PG16 Bound States
journal, March 2019


Structural and immunologic correlates of chemically stabilized HIV-1 envelope glycoproteins
journal, May 2018


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journal, April 2020