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Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope

Barnes, Christopher O. and Gristick, Harry B. and Freund, Natalia T. and Escolano, Amelia and Lyubimov, Artem Y. and Hartweger, Harald and West, Anthony P., Jr. and Cohen, Aina E. and Nussenzweig, Michel C. and Bjorkman, Pamela J. (2018) Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope. Nature Communications, 9 . Art. No. 1251. ISSN 2041-1723. PMCID PMC5871869.

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Broadly neutralizing antibodies (bNAbs) isolated from HIV-1-infected individuals inform HIV-1 vaccine design efforts. Developing bNAbs with increased efficacy requires understanding how antibodies interact with the native oligomannose and complex-type N-glycan shield that hides most protein epitopes on HIV-1 envelope (Env). Here we present crystal structures, including a 3.8-Å X-ray free electron laser dataset, of natively glycosylated Env trimers complexed with BG18, the most potent V3/N332_(gp120) glycan-targeting bNAb reported to date. Our structures show conserved contacts mediated by common D gene-encoded residues with the N332_(gp120) glycan and the gp120 GDIR peptide motif, but a distinct Env-binding orientation relative to PGT121/10-1074 bNAbs. BG18’s binding orientation provides additional contacts with N392_(gp120) and N386_(gp120) glycans near the V3-loop base and engages protein components of the V1-loop. The BG18-natively-glycosylated Env structures facilitate understanding of bNAb–glycan interactions critical for using V3/N332_(gp120) bNAbs therapeutically and targeting their epitope for immunogen design.

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URLURL TypeDescription CentralArticle
Freund, Natalia T.0000-0002-5386-502X
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received: 01 December 2017; Accepted: 01 March 2018; Published online: 28 March 2018. Data availability: Coordinates and structure factors reported in this manuscript have been deposited in the Protein Data Bank with accession codes 6CH7, 6CH8, 6CH9, and 6CHB. Other data are available from the corresponding author upon reasonable request. We thank J. Vielmetter, S. Khomandiak, and the Caltech Protein Expression Center for producing proteins, J. Kaiser and the beamline staff at SSRL for data collection assistance, and members of the Bjorkman and Nussenzweig laboratories for critical reading of the manuscript. We also thank Silvia Russi, Clyde Smith, Jinhu Song, and Alexander Batyuk for user support during our MFX experiment and the lab of Guillermo Calero (University of Pittsburgh) for providing loop supports to mount multiple crystals during XFEL experiments. C.O.B holds a Hanna Gray Fellowship from the Howard Hughes Medical Institute and a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund. This research was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health Grant HIVRAD P01 AI100148 (P.J.B.); (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health), the Bill and Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery Grant OPP1124068 (M.C.N./P.J.B.)), and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation. Use of the Linac Coherent Light Source (LCLS) and use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the US Department of Energy Office of Biological and Environmental Research, and by the National Institutes of Health (NIH), National Institute of General Medical Sciences (including P41GM103393). Author Contributions: C.O.B., A.P.W. Jr., M.C.N., and P.J.B. conceived the experiments; C.O.B. optimized the crystallography conditions, solved and analyzed the crystal structures; C.O.B., H.B.G., and A.P.W. Jr. performed computational and structural analyses of BG18-class and PGT121/10-1074-class antibodies; C.O.B. and H.B.G. purified the proteins, performed and analyzed SPR binding experiments; C.O.B., A.Y.L., and A.E.C. performed the XFEL data collection and analyses; N.T.F. was responsible for isolating BG18 monoclonal antibodies; A.E. and H.H. performed ELISA experiments; C.O.B., A.P.W., M.C.N., and P.J.B. wrote the paper, on which all principal investigators and authors commented. The authors declare no competing interests.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
NIHP01 AI100148
Bill and Melinda Gates FoundationOPP1124068
Gordon and Betty Moore FoundationUNSPECIFIED
Department of Energy (DOE)DE-AC02-76SF00515
PubMed Central ID:PMC5871869
Record Number:CaltechAUTHORS:20180330-082805151
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85520
Deposited By: Tony Diaz
Deposited On:30 Mar 2018 15:45
Last Modified:05 Dec 2019 21:38

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