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

Dam, Kim-Marie A. and Barnes, Christopher O. and Gristick, Harry B. and Schoofs, Till and Gnanapragasam, Priyanthi N. P. and Nussenzweig, Michel C. and Bjorkman, Pamela J. (2022) HIV-1 CD4-binding site germline antibody-Env structures inform vaccine design. Nature Communications, 13 . Art. No. 6123. ISSN 2041-1723. PMCID PMC9576718. doi:10.1038/s41467-022-33860-2.

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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.

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URLURL TypeDescription ItemDiscussion Paper CentralArticle
Dam, Kim-Marie A.0000-0002-1416-4757
Barnes, Christopher O.0000-0003-2754-5951
Gristick, Harry B.0000-0002-1957-2821
Schoofs, Till0000-0002-3584-8736
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:We thank J. Vielmetter, P. Hoffman, and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance. Electron microscopy was performed in the Caltech Cryo-EM Center with assistance from S. Chen and A. Malyutin. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory (Dr. Jens Kaiser, Director) and the beamline staff at SSRL for data collection assistance. Use of the Stanford Synchrotron Radiation Lightsource, 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-c76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. C.O.B. was supported by a Burroughs Wellcome PDEP fellowship and HHMI Hanna Gray Fellowship. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) Grant HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant INV-002143 (P.J.B. and M.C.N.), and NIH P50 AI150464 (P.J.B.).
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
Department of Energy (DOE)DE-AC02-C76SF00515
Burroughs Wellcome FundUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIHP01 AI100148
Bill and Melinda Gates FoundationINV-002143
NIHP50 AI150464
PubMed Central ID:PMC9576718
Record Number:CaltechAUTHORS:20221107-998310200.7
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:117743
Deposited By: Research Services Depository
Deposited On:18 Nov 2022 18:12
Last Modified:18 Nov 2022 23:15

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