Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM

Aleksandar Antanasijevic, Leigh M. Sewall, Christopher A. Cottrell, Diane G. Carnathan, Luis E. Jimenez, Julia T. Ngo, Jennifer B. Silverman, Bettina Groschel, Erik Georgeson, Jinal Bhiman, Raiza Bastidas, Celia LaBranche, Joel D. Allen, Jeffrey Copps, Hailee R. Perrett, Kimmo Rantalainen, Fabien Cannac, Yuhe R. Yang, Alba Torrents Peña, Rebeca Froes Rocha, Zachary T. Berndsen, David Baker, Neil P. King, Rogier W. Sanders, John P. Moore, Shane Crotty, Max Crispin, David C. Montefiori, Dennis R. Burton, William R. Schief, Guido Silvestri and Andrew B. Ward ()
Additional contact information
Aleksandar Antanasijevic: The Scripps Research Institute
Leigh M. Sewall: The Scripps Research Institute
Christopher A. Cottrell: The Scripps Research Institute
Diane G. Carnathan: Emory University
Luis E. Jimenez: Emory University
Julia T. Ngo: Emory University
Jennifer B. Silverman: Emory University
Bettina Groschel: The Scripps Research Institute
Erik Georgeson: The Scripps Research Institute
Jinal Bhiman: The Scripps Research Institute
Raiza Bastidas: The Scripps Research Institute
Celia LaBranche: Duke University Medical Center
Joel D. Allen: University of Southampton
Jeffrey Copps: The Scripps Research Institute
Hailee R. Perrett: The Scripps Research Institute
Kimmo Rantalainen: The Scripps Research Institute
Fabien Cannac: The Scripps Research Institute
Yuhe R. Yang: The Scripps Research Institute
Alba Torrents Peña: The Scripps Research Institute
Rebeca Froes Rocha: The Scripps Research Institute
Zachary T. Berndsen: The Scripps Research Institute
David Baker: University of Washington
Neil P. King: University of Washington
Rogier W. Sanders: University of Amsterdam
John P. Moore: Weill Cornell Medicine, Cornell University
Shane Crotty: La Jolla Institute for Immunology
Max Crispin: University of Southampton
David C. Montefiori: Duke University Medical Center
Dennis R. Burton: The Scripps Research Institute
William R. Schief: The Scripps Research Institute
Guido Silvestri: Emory University
Andrew B. Ward: The Scripps Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity of several stabilized BG505 SOSIP constructs both as free trimers and presented on a nanoparticle. We applied a cryoEM-based method for high-resolution mapping of polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralization assays were used to probe the neutralization potential at each epitope. We demonstrate that cryoEMPEM data can be used for rapid, high-resolution analysis of polyclonal antibody responses without the need for monoclonal antibody isolation. This approach allowed to resolve structurally distinct classes of antibodies that bind overlapping sites. In addition to comprehensive mapping of commonly targeted neutralizing and non-neutralizing epitopes in BG505 SOSIP immunogens, our analysis revealed that epitopes comprising engineered stabilizing mutations and of partially occupied glycosylation sites can be immunogenic.

Date: 2021
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DOI: 10.1038/s41467-021-25087-4

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