Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer

Yang, Zhi; Dam, Kim-Marie A.; Bridges, Michael D.; Hoffmann, Magnus A. G.; DeLaitsch, Andrew T.; Gristick, Harry B.; Escolano, Amelia; Gautam, Rajeev; Martin, Malcolm A.; Nussenzweig, Michel C.; Hubbell, Wayne L.; Bjorkman, Pamela J.

doi:10.1038/s41467-022-28424-3

Title: Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer

Journal Article · 08 February 2022 · Nature Communications

DOI: https://doi.org/10.1038/s41467-022-28424-3 · OSTI ID:1982102

Yang, Zhi ^[1];

^[1]; Bridges, Michael D. ^[2];

^[1];

^[1]; Gristick, Harry B. ^[1]; Escolano, Amelia ^[3]; Gautam, Rajeev ^[4]; Martin, Malcolm A. ^[4]; Nussenzweig, Michel C. ^[5]; Hubbell, Wayne L. ^[2];

^[1]

California Institute of Technology (CalTech), Pasadena, CA (United States)
Univ. of California, Los Angeles, CA (United States)
Rockefeller Univ., New York, NY (United States)
National Institutes of Health (NIH), Bethesda, MD (United States). National Institute of Allergy and Infectious Diseases
Rockefeller Univ., New York, NY (United States). Howard Hughes Medical Institute

Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterize Ab1303 and Ab1573, heterologously-neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding is observed only when Env trimers are not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures show that both antibodies recognize the CD4bs on Env trimer with an ‘occluded-open’ conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation includes outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, does not exhibit V1V2 displacement, 4-stranded gp120 bridging sheet, or co-receptor binding site exposure. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggest an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.

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

Sponsoring Organization:: Gates CAVD; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1982102

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 (66)

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
Recombination in AIDS viruses Robertson, David L.; Hahn, Beatrice H.; Sharp, Paul M. Journal of Molecular Evolution, Vol. 40, Issue 3 https://doi.org/10.1007/BF00163230	journal	March 1995
Quantitative determination of SH groups in low- and high-molecular-weight compounds by an electron spin resonance method Khramtsov, V. V.; Yelinova (Popova), V. I.; Weiner, L. M. Analytical Biochemistry, Vol. 182, Issue 1 https://doi.org/10.1016/0003-2697(89)90718-5	journal	October 1989
The β-Chemokine Receptors CCR3 and CCR5 Facilitate Infection by Primary HIV-1 Isolates Choe, Hyeryun; Farzan, Michael; Sun, Ying Cell, Vol. 85, Issue 7 https://doi.org/10.1016/S0092-8674(00)81313-6	journal	June 1996
Structural Insights on the Role of Antibodies in HIV-1 Vaccine and Therapy West, Anthony P.; Scharf, Louise; Scheid, Johannes F. Cell, Vol. 156, Issue 4 https://doi.org/10.1016/j.cell.2014.01.052	journal	February 2014
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
Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies McCoy, Laura E.; van Gils, Marit J.; Ozorowski, Gabriel Cell Reports, Vol. 16, Issue 9 https://doi.org/10.1016/j.celrep.2016.07.074	journal	August 2016
Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion Wang, Haoqing; Barnes, Christopher O.; Yang, Zhi Cell Host & Microbe, Vol. 24, Issue 4 https://doi.org/10.1016/j.chom.2018.09.003	journal	October 2018
Strategies for a multi-stage neutralizing antibody-based HIV vaccine Andrabi, Raiees; Bhiman, Jinal N.; Burton, Dennis R. Current Opinion in Immunology, Vol. 53 https://doi.org/10.1016/j.coi.2018.04.025	journal	August 2018
HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies Steichen, Jon M.; Kulp, Daniel W.; Tokatlian, Talar Immunity, Vol. 45, Issue 3 https://doi.org/10.1016/j.immuni.2016.08.016	journal	September 2016
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
DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions Stadtmueller, Beth M.; Bridges, Michael D.; Dam, Kim-Marie Immunity, Vol. 49, Issue 2 https://doi.org/10.1016/j.immuni.2018.06.017	journal	August 2018
Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies Duan, Hongying; Chen, Xuejun; Boyington, Jeffrey C. Immunity, Vol. 49, Issue 2 https://doi.org/10.1016/j.immuni.2018.07.005	journal	August 2018
Isolation of single HIV-1 Envelope specific B cells and antibody cloning from immunized rhesus macaques Wang, Zijun; Merkenschlager, Julia; Chen, Spencer T. Journal of Immunological Methods, Vol. 478 https://doi.org/10.1016/j.jim.2019.112734	journal	March 2020
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
Structure and dynamics of an imidazoline nitroxide side chain with strongly hindered internal motion in proteins Toledo Warshaviak, Dora; Khramtsov, Valery V.; Cascio, Duilio Journal of Magnetic Resonance, Vol. 232 https://doi.org/10.1016/j.jmr.2013.04.013	journal	July 2013
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
CTFFIND4: Fast and accurate defocus estimation from electron micrographs Rohou, Alexis; Grigorieff, Nikolaus Journal of Structural Biology, Vol. 192, Issue 2 https://doi.org/10.1016/j.jsb.2015.08.008	journal	November 2015
Technological advances in site-directed spin labeling of proteins Hubbell, Wayne L.; López, Carlos J.; Altenbach, Christian Current Opinion in Structural Biology, Vol. 23, Issue 5 https://doi.org/10.1016/j.sbi.2013.06.008	journal	October 2013
Viral membrane fusion Harrison, Stephen C. Virology, Vol. 479-480 https://doi.org/10.1016/j.virol.2015.03.043	journal	May 2015
Ligand Variation in the Transferrin Family: The Crystal Structure of the H249Q Mutant of the Human Transferrin N-lobe As a Model for Iron Binding in Insect Transferrins^, Baker, Heather M.; Mason, Anne B.; He, Qing-Yu Biochemistry, Vol. 40, Issue 39 https://doi.org/10.1021/bi010907p	journal	September 2001
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody Kwong, Peter D.; Wyatt, Richard; Robinson, James Nature, Vol. 393, Issue 6686 https://doi.org/10.1038/31405	journal	June 1998
Identifying conformational changes with site-directed spin labeling Hubbell, Wayne L.; Cafiso, David S.; Altenbach, Christian Nature Structural Biology, Vol. 7, Issue 9, p. 735-739 https://doi.org/10.1038/78956	journal	September 2000
Structural definition of a conserved neutralization epitope on HIV-1 gp120 Zhou, Tongqing; Xu, Ling; Dey, Barna Nature, Vol. 445, Issue 7129 https://doi.org/10.1038/nature05580	journal	February 2007
Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike Ozorowski, Gabriel; Pallesen, Jesper; de Val, Natalia Nature, Vol. 547, Issue 7663 https://doi.org/10.1038/nature23010	journal	July 2017
Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529 Pancera, Marie; Lai, Yen-Ting; Bylund, Tatsiana Nature Chemical Biology, Vol. 13, Issue 10 https://doi.org/10.1038/nchembio.2460	journal	August 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
Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site Gristick, Harry B.; von Boehmer, Lotta; West Jr, Anthony P. Nature Structural & Molecular Biology, Vol. 23, Issue 10 https://doi.org/10.1038/nsmb.3291	journal	September 2016
Improvement of antibody functionality by structure-guided paratope engraftment Liu, Qingbo; Lai, Yen-Ting; Zhang, Peng Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-08658-4	journal	February 2019
Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements Henderson, Rory; Lu, Maolin; Zhou, Ye Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-019-14196-w	journal	January 2020
Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation Jette, Claudia A.; Barnes, Christopher O.; Kirk, Sharon M. Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21816-x	journal	March 2021
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
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
Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization Brune, Karl D.; Leneghan, Darren B.; Brian, Iona J. Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep19234	journal	January 2016
Site-directed spin labeling of a genetically encoded unnatural amino acid Fleissner, M. R.; Brustad, E. M.; Kalai, T. Proceedings of the National Academy of Sciences, Vol. 106, Issue 51 https://doi.org/10.1073/pnas.0912009106	journal	December 2009
Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin Zakeri, B.; Fierer, J. O.; Celik, E. Proceedings of the National Academy of Sciences, Vol. 109, Issue 12 https://doi.org/10.1073/pnas.1115485109	journal	February 2012
Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120 West, Anthony P.; Diskin, Ron; Nussenzweig, Michel C. Proceedings of the National Academy of Sciences, Vol. 109, Issue 30 https://doi.org/10.1073/pnas.1208984109	journal	June 2012
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
Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop Wang, Haoqing; Cohen, Alexander A.; Galimidi, Rachel P. Proceedings of the National Academy of Sciences, Vol. 113, Issue 46 https://doi.org/10.1073/pnas.1615939113	journal	October 2016
A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Burton, D. R.; Barbas, C. F.; Persson, M. A. Proceedings of the National Academy of Sciences, Vol. 88, Issue 22 https://doi.org/10.1073/pnas.88.22.10134	journal	November 1991
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
PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations Dolinsky, T. J.; Czodrowski, P.; Li, H. Nucleic Acids Research, Vol. 35, Issue Web Server https://doi.org/10.1093/nar/gkm276	journal	May 2007
IMGT®, the international ImMunoGeneTics information system® 25 years on Lefranc, Marie-Paule; Giudicelli, Véronique; Duroux, Patrice Nucleic Acids Research, Vol. 43, Issue D1 https://doi.org/10.1093/nar/gku1056	journal	November 2014
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
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
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
Identification and specificity of broadly neutralizing antibodies against HIV McCoy, Laura E.; Burton, Dennis R. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12484	journal	January 2017
The HIV-1 envelope glycoprotein structure: nailing down a moving target Ward, Andrew B.; Wilson, Ian A. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12507	journal	January 2017
The quest for an antibody-based HIV vaccine Haynes, Barton F.; Mascola, John R. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12517	journal	January 2017
Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target Walker, L. M.; Phogat, S. K.; Chan-Hui, P. -Y. Science, Vol. 326, Issue 5950 https://doi.org/10.1126/science.1178746	journal	September 2009
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
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
HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor Feng, Y.; Broder, C. C.; Kennedy, P. E. Science, Vol. 272, Issue 5263 https://doi.org/10.1126/science.272.5263.872	journal	May 1996
Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody Kong, R.; Xu, K.; Zhou, T. Science, Vol. 352, Issue 6287 https://doi.org/10.1126/science.aae0474	journal	May 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
DEER Distance Measurements on Proteins Jeschke, Gunnar Annual Review of Physical Chemistry, Vol. 63, Issue 1 https://doi.org/10.1146/annurev-physchem-032511-143716	journal	May 2012
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
Epitopes for neutralizing antibodies induced by HIV-1 envelope glycoprotein BG505 SOSIP trimers in rabbits and macaques Klasse, P. J.; Ketas, Thomas J.; Cottrell, Christopher A. PLOS Pathogens, Vol. 14, Issue 2 https://doi.org/10.1371/journal.ppat.1006913	journal	February 2018
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

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