Epitopes for neutralizing antibodies induced by HIV-1 envelope glycoprotein BG505 SOSIP trimers in rabbits and macaques

• Type of Material: Article
• Authors: P. J. Klasse, Weill Cornell Medical College; Thomas J.. Ketas, Weill Cornell Medical College; Christopher Cottrell, Scripps Research Institute; Gabriel Ozorowski, Scripps Research Institute; Gargi Debnath, Weill Cornell Medical College; Diawoye Camara, Weill Cornell Medical College; Erik Francomano, Weill Cornell Medical College; Pavel Pugach, Weill Cornell Medical College; Rajesh P. Ringe, Weill Cornell Medical College; Celia C. LaBranche, Duke University; Marit J. van Gils, University of Amsterdam; Christine A. Bricault, Beth Israel Deaconess Medical Center; Dan H. Barouch, Beth Israel Deaconess Medical Center; Shane Crotty, La Jolla Institute for Allergy and Immunology; Guido Silvestri, Emory University; Sudhir Kasturi, Emory University; Bali Pulendran, Emory University; Ian A. Wilson, Scripps Research Institute; David C. Montefiori, Duke University; Roger W. Sanders, Weill Cornell Medical College; Andrew B. Ward, Scripps Research Institute; John P. Moore, Weill Cornell Medical College
• Language: English
• Date: 2018-02-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Klasse et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1006913
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 14
• Issue: 2
• Start Page: e1006913
• End Page: e1006913
• Grant/Funding Information: CAC is supported by NIH F31 Ruth L. Kirschstein Predoctoral Award Al131873 and by the Achievement Rewards for College Scientists Foundation.; RWS is a recipient of a Starting Investigator Grant from the European Research Council (ERC-StG-2011–280829-SHEV).; The animal studies were supported by NIH award 1UM1 AI100663 to the Scripps CHAVI-ID (DHB, BP, SC), National Primate Research Center funding P51 RR000165/OD011132 to the Yerkes National Primate Research Center (SC, GS) and by the Bill and Melinda Gates Foundation grants OPP1132237 (JPM, RWS). https://www.gatesfoundation.org; The non-animal research was supported by National Institutes of Health (NIH) grants P01 AI110657 (JPM, IAW, ABW, RWS) and R37 AI036082 (JPM and TJK), https://www.nih.gov/ and by the NIH-NIAID NHP Humoral Immunology Laboratory Contract HHSN27201100016C (DCM).
• Keywords: Microbiology; ENV TRIMERS; CLADE-C; TARGET; VACCINE DEVELOPMENT; Life Sciences & Biomedicine; RESPONSES; Virology; Parasitology; VARIABLE REGIONS; CRYO-EM STRUCTURE; GP120; Science & Technology; ELICITATION; IMMUNODEFICIENCY-VIRUS TYPE-1
• Research Categories: Biology, Microbiology; Biology, Virology; Health Sciences, Immunology

Abstract

The native-like, soluble SOSIP.664 trimer based on the BG505 clade A env gene of HIV-1 is immunogenic in various animal species, of which the most studied are rabbits and rhesus macaques. The trimer induces autologous neutralizing antibodies (NAbs) consistently but at a wide range of titers and with incompletely determined specificities. A precise delineation of immunogenic neutralization epitopes on native-like trimers could help strategies to extend the NAb response to heterologous HIV-1 strains. One autologous NAb epitope on the BG505 Env trimer is known to involve residues lining a hole in the glycan shield that is blocked by adding a glycan at either residue 241 or 289. This glycan-hole epitope accounts for the NAb response of most trimer-immunized rabbits but not for that of a substantial subset. Here, we have used a large panel of mutant BG505 Env-pseudotyped viruses to define additional sites. A frequently immunogenic epitope in rabbits is blocked by adding a glycan at residue 465 near the junction of the gp120 V5 loop and β24 strand and is influenced by amino-acid changes in the structurally nearby C3 region. We name this new site the “C3/465 epitope”. Of note is that the C3 region was under selection pressure in the infected infant from whom the BG505 virus was isolated. A third NAb epitope is located in the V1 region of gp120, although it is rarely immunogenic. In macaques, NAb responses induced by BG505 SOSIP trimers are more often directed at the C3/465 epitope than the 241/289-glycan hole.