Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM

Author:

Antanasijevic Aleksandar,Sewall Leigh M.,Cottrell Christopher A.ORCID,Carnathan Diane G.,Jimenez Luis E.,Ngo Julia T.,Silverman Jennifer B.ORCID,Groschel Bettina,Georgeson ErikORCID,Bhiman Jinal,Bastidas Raiza,LaBranche CeliaORCID,Allen Joel D.ORCID,Copps JeffreyORCID,Perrett Hailee R.ORCID,Rantalainen KimmoORCID,Cannac Fabien,Yang Yuhe R.,de la Peña Alba Torrents,Rocha Rebeca Froes,Berndsen Zachary T.,Baker DavidORCID,King Neil P.ORCID,Sanders Rogier W.,Moore John P.ORCID,Crotty ShaneORCID,Crispin MaxORCID,Montefiori David C.,Burton Dennis R.ORCID,Schief William R.ORCID,Silvestri Guido,Ward Andrew B.ORCID

Abstract

AbstractEngineered 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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases

Bill and Melinda Gates Foundation

National Science Foundation

EC | Horizon 2020 Framework Programme

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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