HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design

Dam, Kim-Marie A.; Barnes, Christopher O.; Gristick, Harry B.; Schoofs, Till; Gnanapragasam, Priyanthi P.; Nussenzweig, Michel C.; Bjorkman, Pamela J.

doi:10.1038/s41467-022-33860-2

HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design

Journal Article · Mon Oct 17 00:00:00 EDT 2022 · Nature Communications

DOI:https://doi.org/10.1038/s41467-022-33860-2· OSTI ID:2423906

^[1]; ^[1]; Gristick, Harry B. ^[1]; Schoofs, Till ^[2]; Gnanapragasam, Priyanthi P. ^[1]; ^[3]; ^[1]

California Institute of Technology (CalTech), Pasadena, CA (United States)
Rockefeller Univ., New York, NY (United States). Laboratory of Molecular Immunology; Univ. of Cologne (Germany). University Hospital; German Center for Infection Research, Cologne (Germany). Partner Site Bonn-Cologne
Rockefeller Univ., New York, NY (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States)

BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 Å and 3.4 Å single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24_iGL and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24_iGL variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276_gp120 glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: Bill and Melinda Gates Foundation; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2423906

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (68)

UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
Broadly neutralizing monoclonal antibodies for HIV prevention Miner, Maurine D.; Corey, Lawrence; Montefiori, David Journal of the International AIDS Society, Vol. 24, Issue S7 https://doi.org/10.1002/jia2.25829	journal	November 2021
UCSF ChimeraX: Meeting modern challenges in visualization and analysis: UCSF ChimeraX Visualization System Goddard, Thomas D.; Huang, Conrad C.; Meng, Elaine C. Protein Science, Vol. 27, Issue 1 https://doi.org/10.1002/pro.3235	journal	September 2017
UCSF ChimeraX : Structure visualization for researchers, educators, and developers Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Protein Science, Vol. 30, Issue 1 https://doi.org/10.1002/pro.3943	journal	October 2020
Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens Xiao, Xiaodong; Chen, Weizao; Feng, Yang Biochemical and Biophysical Research Communications, Vol. 390, Issue 3 https://doi.org/10.1016/j.bbrc.2009.09.029	journal	December 2009
Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors Zhou, Tongqing; Lynch, Rebecca M.; Chen, Lei Cell, Vol. 161, Issue 6 https://doi.org/10.1016/j.cell.2015.05.007	journal	June 2015
Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env Scharf, Louise; Wang, Haoqing; Gao, Han Cell, Vol. 162, Issue 6 https://doi.org/10.1016/j.cell.2015.08.035	journal	September 2015
Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies Briney, Bryan; Sok, Devin; Jardine, Joseph G. Cell, Vol. 166, Issue 6 https://doi.org/10.1016/j.cell.2016.08.005	journal	September 2016
Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody Schommers, Philipp; Gruell, Henning; Abernathy, Morgan E. Cell, Vol. 180, Issue 3 https://doi.org/10.1016/j.cell.2020.01.010	journal	February 2020
Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation Zhou, Tongqing; Doria-Rose, Nicole A.; Cheng, Cheng Cell Reports, Vol. 19, Issue 4 https://doi.org/10.1016/j.celrep.2017.04.013	journal	April 2017
Soluble Prefusion Closed DS-SOSIP.664-Env Trimers of Diverse HIV-1 Strains Joyce, M. Gordon; Georgiev, Ivelin S.; Yang, Yongping Cell Reports, Vol. 21, Issue 10 https://doi.org/10.1016/j.celrep.2017.11.016	journal	December 2017
Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization Parks, K. Rachael; MacCamy, Anna J.; Trichka, Josephine Cell Reports, Vol. 29, Issue 10 https://doi.org/10.1016/j.celrep.2019.10.071	journal	December 2019
Development of a VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies Seydoux, Emilie; Wan, Yu-Hsin; Feng, Junli Cell Reports, Vol. 35, Issue 5 https://doi.org/10.1016/j.celrep.2021.109084	journal	May 2021
Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies Zhou, Tongqing; Zhu, Jiang; Wu, Xueling Immunity, Vol. 39, Issue 2 https://doi.org/10.1016/j.immuni.2013.04.012	journal	August 2013
Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth Huang, Jinghe; Kang, Byong H.; Ishida, Elise Immunity, Vol. 45, Issue 5 https://doi.org/10.1016/j.immuni.2016.10.027	journal	November 2016
A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic β-Hairpin Structure Lee, Jeong Hyun; Andrabi, Raiees; Su, Ching-Yao Immunity, Vol. 46, Issue 4 https://doi.org/10.1016/j.immuni.2017.03.017	journal	April 2017
Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier Bonsignori, Mattia; Scott, Eric; Wiehe, Kevin Immunity, Vol. 49, Issue 6 https://doi.org/10.1016/j.immuni.2018.10.015	journal	December 2018
Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan Umotoy, Jeffrey; Bagaya, Bernard S.; Joyce, Collin Immunity, Vol. 51, Issue 1 https://doi.org/10.1016/j.immuni.2019.06.004	journal	July 2019
HIV-1 VRC01 Germline-Targeting Immunogens Select Distinct Epitope-Specific B Cell Receptors Lin, Yu-Ru; Parks, K. Rachael; Weidle, Connor Immunity, Vol. 53, Issue 4 https://doi.org/10.1016/j.immuni.2020.09.007	journal	October 2020
Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1 Sarzotti-Kelsoe, Marcella; Bailer, Robert T.; Turk, Ellen Journal of Immunological Methods, Vol. 409 https://doi.org/10.1016/j.jim.2013.11.022	journal	July 2014
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
RELION: Implementation of a Bayesian approach to cryo-EM structure determination Scheres, Sjors H. W. Journal of Structural Biology, Vol. 180, Issue 3, p. 519-530 https://doi.org/10.1016/j.jsb.2012.09.006	journal	December 2012
Gctf: Real-time CTF determination and correction Zhang, Kai Journal of Structural Biology, Vol. 193, Issue 1 https://doi.org/10.1016/j.jsb.2015.11.003	journal	January 2016
HIV vaccinology: 2021 update Lee, Jeong Hyun; Crotty, Shane Seminars in Immunology, Vol. 51 https://doi.org/10.1016/j.smim.2021.101470	journal	January 2021
Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing Nature, Vol. 496, Issue 7446 https://doi.org/10.1038/nature12053	journal	April 2013
Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice McGuire, Andrew T.; Gray, Matthew D.; Dosenovic, Pia Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms10618	journal	February 2016
Prevention of overfitting in cryo-EM structure determination Scheres, Sjors H. W.; Chen, Shaoxia Nature Methods, Vol. 9, Issue 9 https://doi.org/10.1038/nmeth.2115	journal	July 2012
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination Punjani, Ali; Rubinstein, John L.; Fleet, David J. Nature Methods, Vol. 14, Issue 3 https://doi.org/10.1038/nmeth.4169	journal	February 2017
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy Zheng, Shawn Q.; Palovcak, Eugene; Armache, Jean-Paul Nature Methods, Vol. 14, Issue 4 https://doi.org/10.1038/nmeth.4193	journal	February 2017
Addressing preferred specimen orientation in single-particle cryo-EM through tilting Tan, Yong Zi; Baldwin, Philip R.; Davis, Joseph H. Nature Methods, Vol. 14, Issue 8 https://doi.org/10.1038/nmeth.4347	journal	July 2017
Advancing an HIV vaccine; advancing vaccinology Burton, Dennis R. Nature Reviews Immunology, Vol. 19, Issue 2 https://doi.org/10.1038/s41577-018-0103-6	journal	December 2018
Combination therapy with anti-HIV-1 antibodies maintains viral suppression Mendoza, Pilar; Gruell, Henning; Nogueira, Lilian Nature, Vol. 561, Issue 7724 https://doi.org/10.1038/s41586-018-0531-2	journal	September 2018
Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques Escolano, Amelia; Gristick, Harry B.; Abernathy, Morgan E. Nature, Vol. 570, Issue 7762 https://doi.org/10.1038/s41586-019-1250-z	journal	May 2019
Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals Bar-On, Yotam; Gruell, Henning; Schoofs, Till Nature Medicine, Vol. 24, Issue 11 https://doi.org/10.1038/s41591-018-0186-4	journal	September 2018
Asymmetric opening of HIV-1 Env bound to CD4 and a coreceptor-mimicking antibody Yang, Zhi; Wang, Haoqing; Liu, Albert Z. Nature Structural & Molecular Biology, Vol. 26, Issue 12 https://doi.org/10.1038/s41594-019-0344-5	journal	December 2019
Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption Bar, Katharine J.; Sneller, Michael C.; Harrison, Linda J. New England Journal of Medicine, Vol. 375, Issue 21 https://doi.org/10.1056/NEJMoa1608243	journal	November 2016
Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies Mouquet, H.; Scharf, L.; Euler, Z. Proceedings of the National Academy of Sciences, Vol. 109, Issue 47 https://doi.org/10.1073/pnas.1217207109	journal	October 2012
Structural basis for HIV-1 gp120 recognition by a germ-line version of a broadly neutralizing antibody Scharf, L.; West, A. P.; Gao, H. Proceedings of the National Academy of Sciences, Vol. 110, Issue 15 https://doi.org/10.1073/pnas.1303682110	journal	March 2013
Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues West, A. P.; Scharf, L.; Horwitz, J. Proceedings of the National Academy of Sciences, Vol. 110, Issue 26 https://doi.org/10.1073/pnas.1309215110	journal	June 2013
B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models Huang, Deli; Abbott, Robert K.; Havenar-Daughton, Colin Proceedings of the National Academy of Sciences, Vol. 117, Issue 37 https://doi.org/10.1073/pnas.2004489117	journal	September 2020
Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo Medina-Ramírez, Max; Garces, Fernando; Escolano, Amelia The Journal of Experimental Medicine, Vol. 214, Issue 9 https://doi.org/10.1084/jem.20161160	journal	August 2017
Progress toward active or passive HIV-1 vaccination Escolano, Amelia; Dosenovic, Pia; Nussenzweig, Michel C. The Journal of Experimental Medicine, Vol. 214, Issue 1 https://doi.org/10.1084/jem.20161765	journal	December 2016
Anti-idiotypic antibodies elicit anti-HIV-1–specific B cell responses Dosenovic, Pia; Pettersson, Anna-Klara; Wall, Abigail Journal of Experimental Medicine, Vol. 216, Issue 10 https://doi.org/10.1084/jem.20190446	journal	July 2019
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Integration, scaling, space-group assignment and post-refinement Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 133-144 https://doi.org/10.1107/S0907444909047374	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Real-space refinement in PHENIX for cryo-EM and crystallography Afonine, Pavel V.; Poon, Billy K.; Read, Randy J. Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 6 https://doi.org/10.1107/S2059798318006551	journal	May 2018
Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults: VRC01 HIV-1 mAb in healthy adults Ledgerwood, J. E.; Coates, E. E.; Yamshchikov, G. Clinical & Experimental Immunology, Vol. 182, Issue 3 https://doi.org/10.1111/cei.12692	journal	September 2015
Native-like Env trimers as a platform for HIV-1 vaccine design Sanders, Rogier W.; Moore, John P. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12481	journal	January 2017
Germline-targeting immunogens Stamatatos, Leonidas; Pancera, Marie; McGuire, Andrew T. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12483	journal	January 2017
A naturally arising broad and potent CD4-binding site antibody with low somatic mutation Barnes, Christopher O.; Schoofs, Till; Gnanapragasam, Priyanthi N. P. Science Advances, Vol. 8, Issue 32 https://doi.org/10.1126/sciadv.abp8155	journal	August 2022
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 Wu, X.; Yang, Z. -Y.; Li, Y. Science, Vol. 329, Issue 5993 https://doi.org/10.1126/science.1187659	journal	July 2010
Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01 Zhou, T.; Georgiev, I.; Wu, X. Science, Vol. 329, Issue 5993 https://doi.org/10.1126/science.1192819	journal	July 2010
Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding Scheid, J. F.; Mouquet, H.; Ueberheide, B. Science, Vol. 333, Issue 6049 https://doi.org/10.1126/science.1207227	journal	July 2011
Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors Jardine, J.; Julien, J. -P.; Menis, S. Science, Vol. 340, Issue 6133 https://doi.org/10.1126/science.1234150	journal	March 2013
Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen Jardine, J. G.; Ota, T.; Sok, D. Science, Vol. 349, Issue 6244 https://doi.org/10.1126/science.aac5894	journal	June 2015
HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen Jardine, J. G.; Kulp, D. W.; Havenar-Daughton, C. Science, Vol. 351, Issue 6280 https://doi.org/10.1126/science.aad9195	journal	March 2016
Sequential immunization of macaques elicits heterologous neutralizing antibodies targeting the V3-glycan patch of HIV-1 Env Escolano, Amelia; Gristick, Harry B.; Gautam, Rajeev Science Translational Medicine, Vol. 13, Issue 621 https://doi.org/10.1126/scitranslmed.abk1533	journal	November 2021
Global Panel of HIV-1 Env Reference Strains for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies deCamp, A.; Hraber, P.; Bailer, R. T. Journal of Virology, Vol. 88, Issue 5 https://doi.org/10.1128/JVI.02853-13	journal	December 2013
Analysis of a Clonal Lineage of HIV-1 Envelope V2/V3 Conformational Epitope-Specific Broadly Neutralizing Antibodies and Their Inferred Unmutated Common Ancestors Bonsignori, M.; Hwang, K. -K.; Chen, X. Journal of Virology, Vol. 85, Issue 19 https://doi.org/10.1128/JVI.05045-11	journal	July 2011
Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial Mayer, Kenneth H.; Seaton, Kelly E.; Huang, Yunda PLOS Medicine, Vol. 14, Issue 11 https://doi.org/10.1371/journal.pmed.1002435	journal	November 2017
Optimizing the production and affinity purification of HIV-1 envelope glycoprotein SOSIP trimers from transiently transfected CHO cells Cupo, Albert; Cruz Portillo, Victor M.; Gelfand, Paul PLOS ONE, Vol. 14, Issue 4 https://doi.org/10.1371/journal.pone.0215106	journal	April 2019
A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies Sanders, Rogier W.; Derking, Ronald; Cupo, Albert PLoS Pathogens, Vol. 9, Issue 9, Article No. e1003618 https://doi.org/10.1371/journal.ppat.1003618	journal	September 2013
Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design Jardine, Joseph G.; Sok, Devin; Julien, Jean-Philippe PLOS Pathogens, Vol. 12, Issue 8 https://doi.org/10.1371/journal.ppat.1005815	journal	August 2016
Therapeutic antibodies, vaccines and antibodyomes Dimitrov, Dimiter S. mAbs, Vol. 2, Issue 3 https://doi.org/10.4161/mabs.2.3.11779	journal	May 2010
New tools for automated high-resolution cryo-EM structure determination in RELION-3 Zivanov, Jasenko; Nakane, Takanori; Forsberg, Björn O. eLife, Vol. 7 https://doi.org/10.7554/eLife.42166	journal	November 2018

Similar Records

Structural basis for germline antibody recognition of HIV-1 immunogens

Journal Article · Sun Mar 20 20:00:00 EDT 2016 · eLife · OSTI ID:1628850

Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core

Journal Article · Tue Nov 06 19:00:00 EST 2018 · eLife · OSTI ID:1628887

Development of a VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies

Journal Article · Mon May 03 20:00:00 EDT 2021 · Cell Reports · OSTI ID:1816187

Related Subjects

60 APPLIED LIFE SCIENCES
Cryoelectron microscopy
immunochemistry
vaccines
virus structures

HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design

Citation Formats

References (68)

Similar Records

Related Subjects