HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope

Fera, Daniela; Lee, Matthew S.; Wiehe, Kevin; Meyerhoff, R. Ryan; Piai, Alessandro; Bonsignori, Mattia; Aussedat, Baptiste; Walkowicz, William E.; Ton, Therese; Zhou, Jeffrey O.; Danishefsky, Samuel; Haynes, Barton F.; Harrison, Stephen C.

doi:10.1038/s41467-018-03565-6

Title: HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope

Journal Article · Fri Mar 16 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-03565-6· OSTI ID:1431358

^[1]; Lee, Matthew S. ^[1]; Wiehe, Kevin ^[2]; Meyerhoff, R. Ryan ^[3];

^[1]; Bonsignori, Mattia ^[2]; Aussedat, Baptiste ^[4]; Walkowicz, William E. ^[4]; Ton, Therese ^[5]; Zhou, Jeffrey O. ^[5]; Danishefsky, Samuel ^[4]; Haynes, Barton F. ^[2]; Harrison, Stephen C. ^[1]

Harvard Medical School, Boston, MA (United States)
Duke Univ. Medical Center, Durham, NC (United States); Duke Human Vaccine Inst., Durham, NC (United States)
Duke Human Vaccine Inst., Durham, NC (United States); Duke Univ. Medical Center, Durham, NC (United States)
Sloan Kettering Institute, New York, NY (United States)
Swarthmore College, PA (United States)

HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide (“Man9-V3”) for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage (“DH270”), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9-V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs—the conserved GDIR motif and the N332 glycan. In our structure of an antibody fragment of a lineage member, DH270.6, in complex with the V3 glycopeptide, the conformation of the antibody-bound glycopeptide conforms closely to that of the corresponding segment in an intact HIV-1 Env trimer. An additional structure identifies roles for two critical mutations in the development of breadth. The results suggest a strategy for use of a V3 glycopeptide as a vaccine immunogen.

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

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH); NIH-ORIP HEI; National Inst. of Allergy and Infectious Diseases; Medical Scientist Training Program (MSTP)

Grant/Contract Number:: AC02-06CH11357; P41 GM103403; S10 RR029205; AI100645; T32GM007171; Al127193

OSTI ID:: 1431358

Journal Information:: Nature Communications, Vol. 9, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 21 works

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References (59)

Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans Garces, Fernando; Lee, Jeong Hyun; de Val, Natalia Immunity, Vol. 43, Issue 6 https://doi.org/10.1016/j.immuni.2015.11.007	journal	December 2015
Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env Do Kwon, Young; Pancera, Marie; Acharya, Priyamvada Nature Structural & Molecular Biology, Vol. 22, Issue 7 https://doi.org/10.1038/nsmb.3051	journal	June 2015
Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning Kwong, Peter D.; Mascola, John R.; Nabel, Gary J. Nature Reviews Immunology, Vol. 13, Issue 9 https://doi.org/10.1038/nri3516	journal	August 2013
Solving structures of protein complexes by molecular replacement with Phaser McCoy, Airlie J. Acta Crystallographica Section D Biological Crystallography, Vol. 63, Issue 1 https://doi.org/10.1107/S0907444906045975	journal	December 2006
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
Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains Fera, D.; Schmidt, A. G.; Haynes, B. F. Proceedings of the National Academy of Sciences, Vol. 111, Issue 28 https://doi.org/10.1073/pnas.1409954111	journal	June 2014
Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design Burton, Dennis R.; Hangartner, Lars Annual Review of Immunology, Vol. 34, Issue 1 https://doi.org/10.1146/annurev-immunol-041015-055515	journal	May 2016
Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies Bonsignori, Mattia; Kreider, Edward F.; Fera, Daniela Science Translational Medicine, Vol. 9, Issue 381 https://doi.org/10.1126/scitranslmed.aai7514	journal	March 2017
An Advance in the Chemical Synthesis of Homogeneous N-Linked Glycopolypeptides by Convergent Aspartylation Wang, Ping; Aussedat, Baptiste; Vohra, Yusufbhai Angewandte Chemie International Edition, Vol. 51, Issue 46 https://doi.org/10.1002/anie.201205038	journal	September 2012
Intraprotomer masking of third variable loop (V3) epitopes by the first and second variable loops (V1V2) within the native HIV-1 envelope glycoprotein trimer Liu, L.; Cimbro, R.; Lusso, P. Proceedings of the National Academy of Sciences, Vol. 108, Issue 50 https://doi.org/10.1073/pnas.1104840108	journal	November 2011
Glycosylation in cancer: mechanisms and clinical implications Pinho, Salomé S.; Reis, Celso A. Nature Reviews Cancer, Vol. 15, Issue 9 https://doi.org/10.1038/nrc3982	journal	August 2015
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids Davis, I. W.; Leaver-Fay, A.; Chen, V. B. Nucleic Acids Research, Vol. 35, Issue Web Server https://doi.org/10.1093/nar/gkm216	journal	May 2007
Chemical Synthesis of Highly Congested gp120 V1V2 N -Glycopeptide Antigens for Potential HIV-1-Directed Vaccines Aussedat, Baptiste; Vohra, Yusuf; Park, Peter K. Journal of the American Chemical Society, Vol. 135, Issue 35 https://doi.org/10.1021/ja405990z	journal	August 2013
Structure-based design of a constrained peptide mimic of the HIV-1 V3 loop neutralization site 1 1 Edited by F.E. Cohen Ghiara, Jayant B.; Ferguson, David C.; Satterthwait, Arnold C. Journal of Molecular Biology, Vol. 266, Issue 1 https://doi.org/10.1006/jmbi.1996.0768	journal	February 1997
Max Bergmann lecture Protein epitope mimetics in the age of structural vaccinology: PROTEIN EPITOPE MIMETICS Robinson, John A. Journal of Peptide Science, Vol. 19, Issue 3 https://doi.org/10.1002/psc.2482	journal	January 2013
Molecular switch for alternative conformations of the HIV-1 V3 region: Implications for phenotype conversion Rosen, O.; Sharon, M.; Quadt-Akabayov, S. R. Proceedings of the National Academy of Sciences, Vol. 103, Issue 38 https://doi.org/10.1073/pnas.0606312103	journal	September 2006
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots. Betz, A. G.; Rada, C.; Pannell, R. Proceedings of the National Academy of Sciences, Vol. 90, Issue 6 https://doi.org/10.1073/pnas.90.6.2385	journal	March 1993
Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch MacLeod, Daniel T.; Choi, Nancy M.; Briney, Bryan Immunity, Vol. 44, Issue 5 https://doi.org/10.1016/j.immuni.2016.04.016	journal	May 2016
Model Building and Refinement of a Natively Glycosylated HIV-1 Env Protein by High-Resolution Cryoelectron Microscopy Lee, Jeong Hyun; de Val, Natalia; Lyumkis, Dmitry Structure, Vol. 23, Issue 10 https://doi.org/10.1016/j.str.2015.07.020	journal	October 2015
Analysis of the structural correlates for antibody polyreactivity by multiple reassortments of chimeric human immunoglobulin heavy and light chain V segments Ichiyoshi, Y. Journal of Experimental Medicine, Vol. 180, Issue 3 https://doi.org/10.1084/jem.180.3.885	journal	September 1994
Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding Longo, Nancy S.; Sutton, Matthew S.; Shiakolas, Andrea R. Journal of Virology, Vol. 90, Issue 23 https://doi.org/10.1128/JVI.01012-16	journal	September 2016
Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G Stewart-Jones, Guillaume B. E.; Soto, Cinque; Lemmin, Thomas Cell, Vol. 165, Issue 4 https://doi.org/10.1016/j.cell.2016.04.010	journal	May 2016
Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies Rusert, Peter; Krarup, Anders; Magnus, Carsten The Journal of Experimental Medicine, Vol. 208, Issue 7 https://doi.org/10.1084/jem.20110196	journal	June 2011
Structural Rationale for the Broad Neutralization of HIV-1 by Human Monoclonal Antibody 447-52D Stanfield, Robyn L.; Gorny, Miroslaw K.; Williams, Constance Structure, Vol. 12, Issue 2 https://doi.org/10.1016/j.str.2004.01.003	journal	February 2004
Linear PADRE T Helper Epitope and Carbohydrate B Cell Epitope Conjugates Induce Specific High Titer IgG Antibody Responses Alexander, Jeff; del Guercio, Marie-France; Maewal, Ajesh The Journal of Immunology, Vol. 164, Issue 3 https://doi.org/10.4049/jimmunol.164.3.1625	journal	February 2000
Global site-specific N-glycosylation analysis of HIV envelope glycoprotein Cao, Liwei; Diedrich, Jolene K.; Kulp, Daniel W. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms14954	journal	March 2017
Models of Somatic Hypermutation Targeting and Substitution Based on Synonymous Mutations from High-Throughput Immunoglobulin Sequencing Data Yaari, Gur; Vander Heiden, Jason A.; Uduman, Mohamed Frontiers in Immunology, Vol. 4 https://doi.org/10.3389/fimmu.2013.00358	journal	January 2013
Structural principles controlling HIV envelope glycosylation Behrens, Anna-Janina; Crispin, Max Current Opinion in Structural Biology, Vol. 44 https://doi.org/10.1016/j.sbi.2017.03.008	journal	June 2017
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
Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation Kepler, Thomas B.; Munshaw, Supriya; Wiehe, Kevin Frontiers in Immunology, Vol. 5 https://doi.org/10.3389/fimmu.2014.00170	journal	April 2014
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
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
Structural Evolution of Glycan Recognition by a Family of Potent HIV Antibodies Garces, Fernando; Sok, Devin; Kong, Leopold Cell, Vol. 159, Issue 1 https://doi.org/10.1016/j.cell.2014.09.009	journal	September 2014
NMRPipe: A multidimensional spectral processing system based on UNIX pipes Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW. Journal of Biomolecular NMR, Vol. 6, Issue 3 https://doi.org/10.1007/BF00197809	journal	November 1995
B-cell–lineage immunogen design in vaccine development with HIV-1 as a case study Haynes, Barton F.; Kelsoe, Garnett; Harrison, Stephen C. Nature Biotechnology, Vol. 30, Issue 5 https://doi.org/10.1038/nbt.2197	journal	May 2012
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
Reconstructing a B-cell clonal lineage. I. Statistical inference of unobserved ancestors Kepler, Thomas B. F1000Research, Vol. 2 https://doi.org/10.12688/f1000research.2-103.v1	journal	January 2013
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
Conserved structural elements in the V3 crown of HIV-1 gp120 Jiang, Xunqing; Burke, Valicia; Totrov, Maxim Nature Structural & Molecular Biology, Vol. 17, Issue 8 https://doi.org/10.1038/nsmb.1861	journal	July 2010
A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans Sok, Devin; Pauthner, Matthias; Briney, Bryan Immunity, Vol. 45, Issue 1 https://doi.org/10.1016/j.immuni.2016.06.026	journal	July 2016
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
Molecular structure of eight human autoreactive monoclonal antibodies Aguilera, I.; Melero, J.; Nunez-Roldan, A. Immunology, Vol. 102, Issue 3 https://doi.org/10.1046/j.1365-2567.2001.01159.x	journal	March 2001
Structural Basis of the Cross-Reactivity of Genetically Related Human Anti-HIV-1 mAbs: Implications for Design of V3-Based Immunogens Burke, Valicia; Williams, Constance; Sukumaran, Madhav Structure, Vol. 17, Issue 11 https://doi.org/10.1016/j.str.2009.09.012	journal	November 2009
Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide Alam, S. Munir; Aussedat, Baptiste; Vohra, Yusuf Science Translational Medicine, Vol. 9, Issue 381 https://doi.org/10.1126/scitranslmed.aai7521	journal	March 2017
Glycosylation: Heterogeneity and the 3D Structure of Proteins Rudd, Pauline M.; Dwek, Raymond A. Critical Reviews in Biochemistry and Molecular Biology, Vol. 32, Issue 1 https://doi.org/10.3109/10409239709085144	journal	January 1997
An Advance in the Chemical Synthesis of Homogeneous N-Linked Glycopolypeptides by Convergent Aspartylation Wang, Ping; Aussedat, Baptiste; Vohra, Yusufbhai Angewandte Chemie, Vol. 124, Issue 46 https://doi.org/10.1002/ange.201205038	journal	September 2012
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
Multi-functionality of a tryptophan residue conserved in substrate-binding groove of GH19 chitinases Nagata, Takuya; Shinya, Shoko; Ohnuma, Takayuki Scientific Reports, Vol. 11, Issue 1 https://doi.org/10.1038/s41598-021-81903-3	journal	January 2021
Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide Hua-Xin, Liao,; R., Mascola, John; Amanda, Eaton, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/8pms-aw04	text	January 2017
Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies Rusert, P.; Krarup, A.; Magnus, C. Rockefeller University Press https://doi.org/10.5167/uzh-55477	text	January 2011
Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies Todd, Bradley,; Baptiste, Aussedat,; Amit, Kumar, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/a0m6-td59	text	January 2017
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids B., Chen, Vincent; C., Richardson, David; S., Richardson, Jane The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/m2an-p252	text	January 2007
Max Bergmann lecture protein epitope mimetics in the age of structural vaccinology Robinson, John A. Wiley-Blackwell https://doi.org/10.5167/uzh-87741	text	January 2013
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Author Correction: Structure of the yeast Swi/Snf complex in a nucleosome free state Wang, Chengcheng; Guo, Zhouyan; Zhan, Xiechao Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-19707-8	journal	November 2020
Biochemical Analysis of Hypermutational Targeting by Wild Type and Mutant Activation-induced Cytidine Deaminase Bransteitter, Ronda; Pham, Phuong; Calabrese, Peter Journal of Biological Chemistry, Vol. 279, Issue 49 https://doi.org/10.1074/jbc.m408135200	journal	September 2004
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/s0907444904019158	journal	November 2004
Crystal Structures of Human Immunodeficiency Virus Type 1 (HIV-1) Neutralizing Antibody 2219 in Complex with Three Different V3 Peptides Reveal a New Binding Mode for HIV-1 Cross-Reactivity Stanfield, R. L.; Gorny, M. K.; Zolla-Pazner, S. Journal of Virology, Vol. 80, Issue 12 https://doi.org/10.1128/jvi.00205-06	journal	May 2006

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Title: HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope

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