Structural basis of broad HIV neutralization by a vaccine-induced cow antibody

Stanfield, Robyn L.; Berndsen, Zachary T.; Huang, Ruiqi; Sok, Devin; Warner, Gabrielle; Torres, Jonathan L.; Burton, Dennis R.; Ward, Andrew B.; Wilson, Ian A.; Smider, Vaughn V.

doi:10.1126/sciadv.aba0468

Structural basis of broad HIV neutralization by a vaccine-induced cow antibody

Journal Article · Wed May 27 00:00:00 EDT 2020 · Science Advances

DOI:https://doi.org/10.1126/sciadv.aba0468· OSTI ID:1816401

^[1]; Berndsen, Zachary T. ^[2]; ^[3]; ^[4]; ^[5]; ^[2]; ^[6]; ^[2]; ^[7]; ^[5]

The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology. IAVI, Neutralizing Antibody Center. Scripps Consortium for HIV/AIDS Vaccine Development; OSTI
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology. IAVI, Neutralizing Antibody Center. Scripps Consortium for HIV/AIDS Vaccine Development
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular Medicine; Applied Biomedical Science Institute, San Diego, CA (United States); Taurus Biosciences LLC, San Diego, CA (United States)
The Scripps Research Inst., La Jolla, CA (United States). IAVI, Neutralizing Antibody Center; Scripps Consortium for HIV/AIDS Vaccine Development; Dept. of Immunology and Microbiology
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular Medicine; Applied Biomedical Science Institute, San Diego, CA (United States); Taurus Biosciences LLC, San Diego, CA (United States)
The Scripps Research Inst., La Jolla, CA (United States). IAVI, Neutralizing Antibody Center; Scripps Consortium for HIV/AIDS Vaccine Development; Dept. of Immunology and Microbiology; Massachusetts Institute of Technology and Harvard University, Cambridge, MA (United States). Ragon Inst. of Massachusetts General Hospital
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology. IAVI, Neutralizing Antibody Center. Scripps Consortium for HIV/AIDS Vaccine Development; Skaggs Institute for Chemical Biology

Potent broadly neutralizing antibodies (bnAbs) to HIV have been very challenging to elicit by vaccination in wild-type animals. Here, by x-ray crystallography, cryo–electron microscopy, and site-directed mutagenesis, we structurally and functionally elucidate the mode of binding of a potent bnAb (NC-Cow1) elicited in cows by immunization with the HIV envelope (Env) trimer BG505 SOSIP.664. The exceptionally long (60 residues) third complementarity-determining region of the heavy chain (CDR H3) of NC-Cow1 forms a mini domain (knob) on an extended stalk that navigates through the dense glycan shield on Env to target a small footprint on the gp120 CD4 receptor binding site with no contact of the other CDRs to the rest of the Env trimer. These findings illustrate, in molecular detail, how an unusual vaccine-induced cow bnAb to HIV Env can neutralize with high potency and breadth.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1816401

Alternate ID(s):: OSTI ID: 1833660
OSTI ID: 1837296

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 22 Vol. 6; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

References (60)

Exceptionally long CDR3H region with multiple cysteine residues in functional bovine IgM antibodies Saini, Surinder S.; Allore, Brian; Jacobs, Robert M. European Journal of Immunology, Vol. 29, Issue 8 https://doi.org/10.1002/(SICI)1521-4141(199908)29:08<2420::AID-IMMU2420>3.0.CO;2-A	journal	August 1999
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
The molecular surface package Connolly, Michael L. Journal of Molecular Graphics, Vol. 11, Issue 2 https://doi.org/10.1016/0263-7855(93)87010-3	journal	June 1993
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Reshaping Antibody Diversity Wang, Feng; Ekiert, Damian C.; Ahmad, Insha Cell, Vol. 153, Issue 6 https://doi.org/10.1016/j.cell.2013.04.049	journal	June 2013
Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection Wu, Xueling; Zhang, Zhenhai; Schramm, Chaim A. Cell, Vol. 161, Issue 3 https://doi.org/10.1016/j.cell.2015.03.004	journal	April 2015
Site-Specific Glycosylation of Virion-Derived HIV-1 Env Is Mimicked by a Soluble Trimeric Immunogen Struwe, Weston B.; Chertova, Elena; Allen, Joel D. Cell Reports, Vol. 24, Issue 8 https://doi.org/10.1016/j.celrep.2018.07.080	journal	August 2018
Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies Kwong, Peter D.; Mascola, John R. Immunity, Vol. 37, Issue 3 https://doi.org/10.1016/j.immuni.2012.08.012	journal	September 2012
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
HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure Kwong, Peter D.; Mascola, John R. Immunity, Vol. 48, Issue 5 https://doi.org/10.1016/j.immuni.2018.04.029	journal	May 2018
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
Locking the Elbow: Improved Antibody Fab Fragments as Chaperones for Structure Determination Bailey, Lucas J.; Sheehy, Kimberly M.; Dominik, Pawel K. Journal of Molecular Biology, Vol. 430, Issue 3 https://doi.org/10.1016/j.jmb.2017.12.012	journal	February 2018
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
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
The antigenic structure of the HIV gp120 envelope glycoprotein Wyatt, Richard; Kwong, Peter D.; Desjardins, Elizabeth Nature, Vol. 393, Issue 6686 https://doi.org/10.1038/31514	journal	June 1998
Immunogenetic factors driving formation of ultralong VH CDR3 in Bos taurus antibodies Deiss, Thaddeus C.; Vadnais, Melissa; Wang, Feng Cellular & Molecular Immunology, Vol. 16, Issue 1 https://doi.org/10.1038/cmi.2017.117	journal	December 2017
Activation-induced cytidine deaminase (AID) is strongly expressed in the fetal bovine ileal Peyer’s patch and spleen and is associated with expansion of the primary antibody repertoire in the absence of exogenous antigens Liljavirta, J.; Ekman, A.; Knight, J. S. Mucosal Immunology, Vol. 6, Issue 5 https://doi.org/10.1038/mi.2012.132	journal	January 2013
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
Cross-neutralization of influenza A viruses mediated by a single antibody loop Ekiert, Damian C.; Kashyap, Arun K.; Steel, John Nature, Vol. 489, Issue 7417 https://doi.org/10.1038/nature11414	journal	September 2012
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
Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies Doria-Rose, Nicole A.; Schramm, Chaim A.; Gorman, Jason Nature, Vol. 509, Issue 7498 https://doi.org/10.1038/nature13036	journal	March 2014
Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface Huang, Jinghe; Kang, Byong H.; Pancera, Marie Nature, Vol. 515, Issue 7525 https://doi.org/10.1038/nature13601	journal	September 2014
Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows Sok, Devin; Le, Khoa M.; Vadnais, Melissa Nature, Vol. 548, Issue 7665 https://doi.org/10.1038/nature23301	journal	July 2017
Antibody responses to envelope glycoproteins in HIV-1 infection Burton, Dennis R.; Mascola, John R. Nature Immunology, Vol. 16, Issue 6 https://doi.org/10.1038/ni.3158	journal	May 2015
HIV vaccine design and the neutralizing antibody problem Burton, Dennis R.; Desrosiers, Ronald C.; Doms, Robert W. Nature Immunology, Vol. 5, Issue 3 https://doi.org/10.1038/ni0304-233	journal	March 2004
EMRinger: side chain–directed model and map validation for 3D cryo-electron microscopy Barad, Benjamin A.; Echols, Nathaniel; Wang, Ray Yu-Ruei Nature Methods, Vol. 12, Issue 10 https://doi.org/10.1038/nmeth.3541	journal	August 2015
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
Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120 Kong, Leopold; Lee, Jeong Hyun; Doores, Katie J. Nature Structural & Molecular Biology, Vol. 20, Issue 7 https://doi.org/10.1038/nsmb.2594	journal	May 2013
Privateer: software for the conformational validation of carbohydrate structures Agirre, Jon; Iglesias-Fernández, Javier; Rovira, Carme Nature Structural & Molecular Biology, Vol. 22, Issue 11 https://doi.org/10.1038/nsmb.3115	journal	November 2015
A cold-blooded view of adaptive immunity Flajnik, Martin F. Nature Reviews Immunology, Vol. 18, Issue 7 https://doi.org/10.1038/s41577-018-0003-9	journal	March 2018
Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET Lu, Maolin; Ma, Xiaochu; Castillo-Menendez, Luis R. Nature, Vol. 568, Issue 7752 https://doi.org/10.1038/s41586-019-1101-y	journal	April 2019
Recent progress in broadly neutralizing antibodies to HIV Sok, Devin; Burton, Dennis R. Nature Immunology, Vol. 19, Issue 11 https://doi.org/10.1038/s41590-018-0235-7	journal	October 2018
An Analysis of the Sequences of the Variable Regions of Bence Jones Proteins and Myeloma Light Chains and Their Implications for Antibody Complementarity Wu, T. T. Journal of Experimental Medicine, Vol. 132, Issue 2 https://doi.org/10.1084/jem.132.2.211	journal	August 1970
Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies McGuire, Andrew T.; Hoot, Sam; Dreyer, Anita M. The Journal of Experimental Medicine, Vol. 210, Issue 4 https://doi.org/10.1084/jem.20122824	journal	March 2013
Humans and Cattle: A Review of Bovine Zoonoses McDaniel, Clinton J.; Cardwell, Diana M.; Moeller, Robert B. Vector-Borne and Zoonotic Diseases, Vol. 14, Issue 1 https://doi.org/10.1089/vbz.2012.1164	journal	January 2014
EMHP: an accurate automated hole masking algorithm for single-particle cryo-EM image processing Berndsen, Zachary; Bowman, Charles; Jang, Haerin Bioinformatics, Vol. 33, Issue 23 https://doi.org/10.1093/bioinformatics/btx500	journal	August 2017
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
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	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
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
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
A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield Pejchal, R.; Doores, K. J.; Walker, L. M. Science, Vol. 334, Issue 6059 https://doi.org/10.1126/science.1213256	journal	October 2011
HIV-1 neutralizing antibodies induced by native-like envelope trimers Sanders, R. W.; van Gils, M. J.; Derking, R. Science, Vol. 349, Issue 6244 https://doi.org/10.1126/science.aac4223	journal	June 2015
Conservation and diversity in the ultralong third heavy-chain complementarity-determining region of bovine antibodies Stanfield, Robyn L.; Wilson, Ian A.; Smider, Vaughn V. Science Immunology, Vol. 1, Issue 1 https://doi.org/10.1126/sciimmunol.aaf7962	journal	June 2016
Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies Li, M.; Gao, F.; Mascola, J. R. Journal of Virology, Vol. 79, Issue 16 https://doi.org/10.1128/JVI.79.16.10108-10125.2005	journal	July 2005
Structure and Immune Recognition of the HIV Glycan Shield Crispin, Max; Ward, Andrew B.; Wilson, Ian A. Annual Review of Biophysics, Vol. 47, Issue 1 https://doi.org/10.1146/annurev-biophys-060414-034156	journal	May 2018
Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers Landais, Elise; Moore, Penny L. Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0443-0	journal	September 2018
HIV-1 immunogens and strategies to drive antibody responses towards neutralization breadth van Schooten, Jelle; van Gils, Marit J. Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0457-7	journal	November 2018
Analysis of Memory B Cell Responses and Isolation of Novel Monoclonal Antibodies with Neutralizing Breadth from HIV-1-Infected Individuals Corti, Davide; Langedijk, Johannes P. M.; Hinz, Andreas PLoS ONE, Vol. 5, Issue 1 https://doi.org/10.1371/journal.pone.0008805	journal	January 2010
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
Molecular Evolution of Broadly Neutralizing Llama Antibodies to the CD4-Binding Site of HIV-1 McCoy, Laura E.; Rutten, Lucy; Frampton, Dan PLoS Pathogens, Vol. 10, Issue 12 https://doi.org/10.1371/journal.ppat.1004552	journal	December 2014
Host Range and Emerging and Reemerging Pathogens Woolhouse, Mark E. J.; Gowtage-Sequeria, Sonya Emerging Infectious Diseases, Vol. 11, Issue 12 https://doi.org/10.3201/eid1112.050997	journal	December 2005
Diversity in the Cow Ultralong CDR H3 Antibody Repertoire Haakenson, Jeremy K.; Huang, Ruiqi; Smider, Vaughn V. Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.01262	journal	June 2018
Structural Diversity of Ultralong CDRH3s in Seven Bovine Antibody Heavy Chains Dong, Jinhui; Finn, Jessica A.; Larsen, Peter A. Frontiers in Immunology, Vol. 10 https://doi.org/10.3389/fimmu.2019.00558	journal	March 2019
Automated structure refinement of macromolecular assemblies from cryo-EM maps using Rosetta Wang, Ray Yu-Ruei; Song, Yifan; Barad, Benjamin A. eLife, Vol. 5 https://doi.org/10.7554/eLife.17219	journal	September 2016
Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2 Kimanius, Dari; Forsberg, Björn O.; Scheres, Sjors HW eLife, Vol. 5 https://doi.org/10.7554/eLife.18722	journal	November 2016
Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core Borst, Andrew J.; Weidle, Connor E.; Gray, Matthew D. eLife, Vol. 7 https://doi.org/10.7554/eLife.37688	journal	November 2018

Similar Records

Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization

Journal Article · Mon Aug 21 20:00:00 EDT 2017 · Cell Reports · OSTI ID:1499807

Human CD4-binding site antibody elicited by polyvalent DNA prime-protein boost vaccine neutralizes cross-clade tier-2-HIV strains

Journal Article · Mon May 20 20:00:00 EDT 2024 · Nature Communications · OSTI ID:2470333

Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity

Journal Article · Tue Mar 07 19:00:00 EST 2017 · Journal of Virology · OSTI ID:1357627

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Structural basis of broad HIV neutralization by a vaccine-induced cow antibody

Citation Formats

References (60)

Similar Records

Related Subjects