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Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM.

<div class='caption-title'>Immunization experiments with the stabilized BG505 SOSIP trimers.</div>
<div class='caption-title'>CryoEMPEM analysis of polyclonal antibodies elicited by BG505 SOSIP trimer immunogens.</div>
<div class='caption-title'>Structural analysis of neutralizing and potentially neutralizing antibody responses.</div>
Antanasijevic A, Sewall LM, Cottrell CA, Carnathan DG, Jimenez LE, Ngo JT, Silverman JB, Groschel B, Georgeson E, Bhiman J, Bastidas R, LaBranche C, Allen JD, Copps J, Perrett HR, Rantalainen K, Cannac F, Yang YR, de la Peña AT, Rocha RF, Berndsen ZT, Baker D, King NP, Sanders RW, Moore JP, Crotty S, Crispin M, Montefiori DC, Burton DR, Schief WR, Silvestri G, Ward AB
OpenAccess logo Nat Commun 12 4817 (2021)
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Cited: 27 times
EuropePMC logo PMID: 34376662

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.

Reviews citing this publication (5)

  1. Bringing immunofocusing into focus. Musunuri S, Weidenbacher PAB, Kim PS. NPJ Vaccines 9 11 (2024)
  2. Influence of glycosylation on the immunogenicity and antigenicity of viral immunogens. Newby ML, Allen JD, Crispin M. Biotechnol Adv 70 108283 (2024)
  3. Structural Biology Illuminates Molecular Determinants of Broad Ebolavirus Neutralization by Human Antibodies for Pan-Ebolavirus Therapeutic Development. Murin CD, Gilchuk P, Crowe JE, Ward AB. Front Immunol 12 808047 (2021)
  4. Discovery medicine - the HVTN's iterative approach to developing an HIV-1 broadly neutralizing vaccine. Martin TM, Robinson ST, Huang Y. Curr Opin HIV AIDS 18 290-299 (2023)
  5. Cryo-electron microscopy in the study of virus entry and infection. Dutta M, Acharya P. Front Mol Biosci 11 1429180 (2024)

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  2. Sequential immunization of macaques elicits heterologous neutralizing antibodies targeting the V3-glycan patch of HIV-1 Env. Escolano A, Gristick HB, Gautam R, DeLaitsch AT, Abernathy ME, Yang Z, Wang H, Hoffmann MAG, Nishimura Y, Wang Z, Koranda N, Kakutani LM, Gao H, Gnanapragasam PNP, Raina H, Gazumyan A, Cipolla M, Oliveira TY, Ramos V, Irvine DJ, Silva M, West AP, Keeffe JR, Barnes CO, Seaman MS, Nussenzweig MC, Martin MA, Bjorkman PJ. Sci Transl Med 13 eabk1533 (2021)
  3. Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimmers as HIV-1 vaccine candidates. Zhang YN, Paynter J, Antanasijevic A, Allen JD, Eldad M, Lee YZ, Copps J, Newby ML, He L, Chavez D, Frost P, Goodroe A, Dutton J, Lanford R, Chen C, Wilson IA, Crispin M, Ward AB, Zhu J. Nat Commun 14 1985 (2023)
  4. Antibody responses induced by SHIV infection are more focused than those induced by soluble native HIV-1 envelope trimers in non-human primates. van Schooten J, van Haaren MM, Li H, McCoy LE, Havenar-Daughton C, Cottrell CA, Burger JA, van der Woude P, Helgers LC, Tomris I, Labranche CC, Montefiori DC, Ward AB, Burton DR, Moore JP, Sanders RW, Crotty S, Shaw GM, van Gils MJ. PLoS Pathog 17 e1009736 (2021)
  5. From structure to sequence: Antibody discovery using cryoEM. Antanasijevic A, Bowman CA, Kirchdoerfer RN, Cottrell CA, Ozorowski G, Upadhyay AA, Cirelli KM, Carnathan DG, Enemuo CA, Sewall LM, Nogal B, Zhao F, Groschel B, Schief WR, Sok D, Silvestri G, Crotty S, Bosinger SE, Ward AB. Sci Adv 8 eabk2039 (2022)
  6. Characterization of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Conformational States on Infectious Virus Particles. Nguyen HT, Wang Q, Anang S, Sodroski JG. J Virol 97 e0185722 (2023)
  7. Mapping the neutralizing specificity of human anti-HIV serum by deep mutational scanning. Radford CE, Schommers P, Gieselmann L, Crawford KHD, Dadonaite B, Yu TC, Dingens AS, Overbaugh J, Klein F, Bloom JD. Cell Host Microbe 31 1200-1215.e9 (2023)
  8. Defining and Studying B Cell Receptor and TCR Interactions. Rappazzo CG, Fernández-Quintero ML, Mayer A, Wu NC, Greiff V, Guthmiller JJ. J Immunol 211 311-322 (2023)
  9. High-resolution structural analysis of enterovirus-reactive polyclonal antibodies in complex with whole virions. Antanasijevic A, Schulze AJ, Reddy VS, Ward AB. PNAS Nexus 1 pgac253 (2022)
  10. Structural and computational design of a SARS-CoV-2 spike antigen with improved expression and immunogenicity. Williams JA, Biancucci M, Lessen L, Tian S, Balsaraf A, Chen L, Chesterman C, Maruggi G, Vandepaer S, Huang Y, Mallett CP, Steff AM, Bottomley MJ, Malito E, Wahome N, Harshbarger WD. Sci Adv 9 eadg0330 (2023)
  11. Vaccine induction of CD4-mimicking HIV-1 broadly neutralizing antibody precursors in macaques. Saunders KO, Counts J, Thakur B, Stalls V, Edwards R, Manne K, Lu X, Mansouri K, Chen Y, Parks R, Barr M, Sutherland L, Bal J, Havill N, Chen H, Machiele E, Jamieson N, Hora B, Kopp M, Janowska K, Anasti K, Jiang C, Van Itallie E, Venkatayogi S, Eaton A, Henderson R, Barbosa C, Alam SM, Santra S, Weissman D, Moody MA, Cain DW, Tam YK, Lewis M, Williams WB, Wiehe K, Montefiori DC, Acharya P, Haynes BF. Cell 187 79-94.e24 (2024)
  12. Protocol for analyzing antibody responses to glycoprotein antigens using electron-microscopy-based polyclonal epitope mapping. Turner HL, Jackson AM, Richey ST, Sewall LM, Antanasijevic A, Hangartner L, Ward AB. STAR Protoc 4 102476 (2023)
  13. Increasing sensitivity of antibody-antigen interactions using photo-cross-linking. Torrents de la Peña A, Sewall LM, de Paiva Froes Rocha R, Jackson AM, Pratap PP, Bangaru S, Cottrell CA, Mohanty S, Shaw AC, Ward AB. Cell Rep Methods 3 100509 (2023)
  14. Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge. Hsieh CL, Leist SR, Miller EH, Zhou L, Powers JM, Tse AL, Wang A, West A, Zweigart MR, Schisler JC, Jangra RK, Chandran K, Baric RS, McLellan JS. Nat Commun 15 1553 (2024)
  15. A tool for evaluating heterogeneity in avidity of polyclonal antibodies. Li K, Dodds M, Spreng RL, Abraha M, Huntwork RHC, Dahora LC, Nyanhete T, Dutta S, Wille-Reece U, Jongert E, Ewer KJ, Hill AVS, Jin C, Hill J, Pollard AJ, Munir Alam S, Tomaras GD, Dennison SM. Front Immunol 14 1049673 (2023)
  16. Cryo EM structures map a post vaccination polyclonal antibody response to canine parvovirus. Hartmann SR, Charnesky AJ, Früh SP, López-Astacio RA, Weichert WS, DiNunno N, Cho SH, Bator CM, Parrish CR, Hafenstein SL. Commun Biol 6 955 (2023)
  17. Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses. Ray R, Nait Mohamed FA, Maurer DP, Huang J, Alpay BA, Ronsard L, Xie Z, Han J, Fernandez-Quintero M, Phan QA, Ursin RL, Vu M, Kirsch KH, Prum T, Rosado VC, Bracamonte-Moreno T, Okonkwo V, Bals J, McCarthy C, Nair U, Kanekiyo M, Ward AB, Schmidt AG, Batista FD, Lingwood D. Immunity 57 1141-1159.e11 (2024)
  18. Evaluating the antibody response elicited by diverse HIV envelope immunogens in the African green monkey (Vervet) model. Moyo-Gwete T, Ayres F, Mzindle NB, Makhado Z, Manamela NP, Richardson SI, Kitchin D, van Graan S, van Heerden J, Parbhoo N, Chege GK, Moore PL. Sci Rep 14 13311 (2024)
  19. Priming antibody responses to the fusion peptide in rhesus macaques. Cottrell CA, Pratap PP, Cirelli KM, Carnathan DG, Enemuo CA, Antanasijevic A, Ozorowski G, Sewall LM, Gao H, Allen JD, Nogal B, Silva M, Bhiman J, Pauthner M, Irvine DJ, Montefiori D, Crispin M, Burton DR, Silvestri G, Crotty S, Ward AB. NPJ Vaccines 9 126 (2024)
  20. Congress Respiratory viruses: New frontiers-a Keystone Symposia report. Cable J, Sun J, Cheon IS, Vaughan AE, Castro IA, Stein SR, López CB, Gostic KM, Openshaw PJM, Ellebedy AH, Wack A, Hutchinson E, Thomas MM, Langlois RA, Lingwood D, Baker SF, Folkins M, Foxman EF, Ward AB, Schwemmle M, Russell AB, Chiu C, Ganti K, Subbarao K, Sheahan TP, Penaloza-MacMaster P, Eddens T. Ann N Y Acad Sci 1522 60-73 (2023)
  21. Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies. Hahn WO, Parks KR, Shen M, Ozorowski G, Janes H, Ballweber-Fleming L, Woodward Davis AS, Duplessis C, Tomai M, Dey AK, Sagawa ZK, De Rosa SC, Seese A, Kallur Siddaramaiah L, Stamatatos L, Lee WH, Sewall LM, Karlinsey D, Turner HL, Rubin V, Furth S, MacPhee K, Duff M, Corey L, Keefer MC, Edupuganti S, Frank I, Maenza J, Baden LR, Hyrien O, Sanders RW, Moore JP, Ward AB, Tomaras GD, Montefiori DC, Rouphael N, McElrath MJ. J Exp Med 221 e20240604 (2024)
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