skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms9167· OSTI ID:1252760
 [1];  [1];  [1];  [2];  [2];  [3];  [2];  [1];  [2];  [1];  [4];  [5];  [4];  [1];  [3];  [3];  [6];  [1];  [1];  [1]
  1. The Scripps Research Inst., La Jolla, CA (United States)
  2. Academic Medical Center, Amsterdam, AZ (The Netherlands)
  3. Weill Medical College of Cornell Univ., New York, NY (United States)
  4. The Rockefeller Univ., New York, NY (United States)
  5. The Scripps Research Inst., La Jolla, CA (United States); Ragon Institute of MGH, MIT and Harvard, Boston, MA (United States)
  6. Academic Medical Center, Amsterdam, AZ (The Netherlands); Weill Medical College of Cornell University, New York, NY (United States)

The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120–gp41 interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. By using biochemical, biophysical and computational methods, we map the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176. A cryo-EM reconstruction of a soluble Env trimer bound to 3BC315 Fab at 9.3 Å resolution reveals that the antibody binds between two gp41 protomers, and neutralizes the virus by accelerating trimer decay. In contrast, bnAb 35O22 binding to a partially overlapping quaternary epitope at the gp120–gp41 interface does not induce decay. A conserved gp41-proximal glycan at N88 was also shown to play a role in the binding kinetics of 3BC176 and 3BC315. Finally, our data suggest that the dynamic structure of the Env trimer influences exposure of bnAb epitopes.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); U.S. National Inst. of Health (NIH); National Inst. of General Medical Sciences (NIGMS); Howard Hughes Medical Inst.
Grant/Contract Number:
AC02-05CH11231; U54 GM094586; RR017573; P01 AI082362; UM1 AI100663; R01 AI084817; R01 AI114401; R01 AI098602
OSTI ID:
1252760
Journal Information:
Nature Communications, Vol. 6, Issue 1; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 61 works
Citation information provided by
Web of Science

References (65)

Structure and immune recognition of trimeric pre-fusion HIV-1 Env journal October 2014
Structural Families in Loops of Homologous Proteins: Automatic Classification, Modelling and Application to Antibodies journal November 1996
Atomic structure of the ectodomain from HIV-1 gp41 journal May 1997
Broad and potent neutralization of HIV-1 by a gp41-specific human antibody journal September 2012
Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9 journal November 2011
Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface journal September 2014
Broadly Neutralizing Antibody PGT121 Allosterically Modulates CD4 Binding via Recognition of the HIV-1 gp120 V3 Base and Multiple Surrounding Glycans journal May 2013
Antibody 8ANC195 Reveals a Site of Broad Vulnerability on the HIV-1 Envelope Spike journal May 2014
Broad neutralization coverage of HIV by multiple highly potent antibodies journal September 2011
Accurate determination of local defocus and specimen tilt in electron microscopy journal June 2003
DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy journal May 2009
Structural Delineation of a Quaternary, Cleavage-Dependent Epitope at the gp41-gp120 Interface on Intact HIV-1 Env Trimers journal May 2014
Prevention of overfitting in cryo-EM structure determination journal July 2012
Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein journal July 2012
Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding journal July 2011
Conformations of immunoglobulin hypervariable regions journal December 1989
Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus journal October 2013
Inhibition of the HIV-1 Spike by Single-PG9/16-Antibody Binding Suggests a Coordinated-Activation Model for Its Three Protomeric Units journal April 2013
Broadly Neutralizing HIV Antibodies Define a Glycan-Dependent Epitope on the Prefusion Conformation of gp41 on Cleaved Envelope Trimers journal May 2014
A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies journal September 2013
Viral Escape from HIV-1 Neutralizing Antibodies Drives Increased Plasma Neutralization Breadth through Sequential Recognition of Multiple Epitopes and Immunotypes journal October 2013
Crystal Structure of a Soluble Cleaved HIV-1 Envelope Trimer journal October 2013
Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors journal March 2013
Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer journal October 2013
A Blueprint for HIV Vaccine Discovery journal October 2012
Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation journal October 2013
Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex journal November 2014
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 journal July 2010
Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV journal May 2014
MPER-specific antibodies induce gp120 shedding and irreversibly neutralize HIV-1 journal February 2011
Antibody to gp41 MPER Alters Functional Properties of HIV-1 Env without Complete Neutralization journal July 2014
Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9 journal February 2013
UCSF Chimera?A visualization system for exploratory research and analysis journal January 2004
Partial Enzymatic Deglycosylation Preserves the Structure of Cleaved Recombinant HIV-1 Envelope Glycoprotein Trimers journal May 2012
Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01 journal July 2010
A clustering approach to multireference alignment of single-particle projections in electron microscopy journal August 2010
Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions journal October 2014
Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies journal July 2014
A Bayesian View on Cryo-EM Structure Determination journal January 2012
Coot model-building tools for molecular graphics journal November 2004
Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target journal September 2009
CD4-Induced Activation in a Soluble HIV-1 Env Trimer journal July 2014
Accelerating Next-Generation Vaccine Development for Global Disease Prevention journal May 2013
RELION: Implementation of a Bayesian approach to cryo-EM structure determination journal December 2012
Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies journal March 2013
A Native-Like SOSIP.664 Trimer Based on an HIV-1 Subtype B env Gene journal January 2015
Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits journal January 2014
HIV-1 Envelope Glycoprotein Trimers Display Open Quaternary Conformation When Bound to the gp41 Membrane-Proximal External-Region-Directed Broadly Neutralizing Antibody Z13e1 journal April 2013
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Refinement of Protein Structures into Low-Resolution Density Maps Using Rosetta journal September 2009
Structural Insights on the Role of Antibodies in HIV-1 Vaccine and Therapy journal February 2014
Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer journal March 2015
Structural Evolution of Glycan Recognition by a Family of Potent HIV Antibodies journal September 2014
Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization journal March 2013
Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120 journal May 2013
Leginon: An Automated System for Acquisition of Images from Vitreous Ice Specimens journal October 2000
Expressed Murine and Human CDR-H3 Intervals of Equal Length Exhibit Distinct Repertoires that Differ in their Amino Acid Composition and Predicted Range of Structures journal December 2003
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Structural repertoire of the human VH segments journal October 1992
A Conformational Switch in Human Immunodeficiency Virus gp41 Revealed by the Structures of Overlapping Epitopes Recognized by Neutralizing Antibodies journal June 2009
B Cell Liaison Confounds HIV-1 Evolution journal July 2014
A stamp on the envelope journal October 2014
A Bayesian view on cryo-EM structure determination conference May 2012
Anti-Human Immunodeficiency Virus Type 1 (HIV-1) Antibodies 2F5 and 4E10 Require Surprisingly Few Crucial Residues in the Membrane-Proximal External Region of Glycoprotein gp41 To Neutralize HIV-1 journal December 2004
PHENIX: a comprehensive Python-based system for macromolecular structure solution. text January 2010

Cited By (21)

Transient opening of trimeric prefusion RSV F proteins journal May 2019
Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence journal May 2019
Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle journal September 2019
Non-neutralizing Antibodies Targeting the V1V2 Domain of HIV Exhibit Strong Antibody-Dependent Cell-mediated Cytotoxic Activity journal October 2017
Strategies for inducing effective neutralizing antibody responses against HIV-1 journal November 2019
Adaption of human antibody λ and κ light chain architectures to CDR repertoires journal March 2019
Cryo-EM structure of a native, fully glycosylated, cleaved HIV-1 envelope trimer journal March 2016
Structural and molecular basis for Ebola virus neutralization by protective human antibodies journal February 2016
Recent advances in retroviruses via cryo-electron microscopy journal February 2018
Engineering and characterising a novel, highly potent bispecific antibody iMab-CAP256 that targets HIV-1 journal November 2019
CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity journal January 2019
Structural and immunologic correlates of chemically stabilized HIV-1 envelope glycoproteins journal May 2018
Glycoengineering HIV-1 Env creates ‘supercharged’ and ‘hybrid’ glycans to increase neutralizing antibody potency, breadth and saturation journal May 2018
In silico Identification of High-Affinity Ligands of the Hiv-1 Gp120 Protein, Potential Peptidomimetics of Neutralizing Antibody N6 journal October 2019
Development of Protein- and Peptide-Based HIV Entry Inhibitors Targeting gp120 or gp41 journal August 2019
Dynamic Viral Glycoprotein Machines: Approaches for Probing Transient States That Drive Membrane Fusion journal January 2016
HIV envelope trimer-elicited autologous neutralizing antibodies bind a region overlapping the N332 glycan supersite journal June 2020
CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity text January 2019
Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability journal November 2019
Identification and specificity of broadly neutralizing antibodies against HIV journal January 2017
Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens journal January 2016