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Title: Alternative conformations of a major antigenic site on RSV F

Journal Article · · PLoS Pathogens
 [1]; ORCiD logo [2];  [3]; ORCiD logo [4];  [4]; ORCiD logo [5];  [6]
  1. Geisel School of Medicine at Dartmouth, Hanover, NH (United States); Univ. of Texas, Austin, TX (United States)
  2. Geisel School of Medicine at Dartmouth, Hanover, NH (United States); Adimab LLC, Lebanon, NH (United States)
  3. Geisel School of Medicine at Dartmouth, Hanover, NH (United States)
  4. Humabs BioMed SA, Bellinzona (Switzerland)
  5. Univ. of Texas, Austin, TX (United States)
  6. Vanderbilt Univ., Nashville, TN (United States)

The respiratory syncytial virus (RSV) fusion (F) glycoprotein is a major target of neutralizing antibodies arising from natural infection, and antibodies that specifically bind to the prefusion conformation of RSV F generally demonstrate the greatest neutralization potency. Prefusion-stabilized RSV F variants have been engineered as vaccine antigens, but crystal structures of these variants have revealed conformational differences in a key antigenic site located at the apex of the trimer, referred to as antigenic site Ø. Currently, it is unclear if flexibility in this region is an inherent property of prefusion RSV F or if it is related to inadequate stabilization of site Ø in the engineered variants. Therefore, we set out to investigate the conformational flexibility of antigenic site Ø, as well as the ability of the human immune system to recognize alternative conformations of this site, by determining crystal structures of prefusion RSV F bound to neutralizing human-derived antibodies AM22 and RSD5. Both antibodies bound with high affinity and were specific for the prefusion conformation of RSV F. Crystal structures of the complexes revealed that the antibodies recognized distinct conformations of antigenic site Ø, each diverging at a conserved proline residue located in the middle of an α-helix. These data suggest that antigenic site Ø exists as an ensemble of conformations, with individual antibodies recognizing discrete states. Collectively, these results have implications for the refolding of pneumovirus and paramyxovirus fusion proteins and should inform development of prefusion-stabilized RSV F vaccine candidates.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); NIGMS
Grant/Contract Number:
AC02-06CH11357; AC02-98CH10886; P20GM113132
OSTI ID:
1591911
Journal Information:
PLoS Pathogens, Vol. 15, Issue 7; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 15 works
Citation information provided by
Web of Science

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Cited By (5)

Characterization of potent RSV neutralizing antibodies isolated from human memory B cells and identification of diverse RSV/hMPV cross-neutralizing epitopes journal August 2019
Alternative Virus-Like Particle-Associated Prefusion F Proteins as Maternal Vaccines for Respiratory Syncytial Virus journal September 2019
Crystal Structure and Immunogenicity of the DS-Cav1-Stabilized Fusion Glycoprotein From Respiratory Syncytial Virus Subtype B journal September 2019
Antibody Epitopes of Pneumovirus Fusion Proteins journal November 2019
Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition journal March 2020

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