Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core
VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1-3 in the presence or absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design.
Mass spectrometry data have been deposited to the PRIDE archive under accession number PXD011494. CryoEM maps are available for download from the EMDB under accession numbers EMD-9294 (426cDS-SOSIP D3†-VRC01GL, 3 Fabs, sharpened), EMD-9295 (426cDS-SOSIP D3†-VRC01GL, 3 Fabs, unsharpened), EMD-9304 (426cDS-SOSIP D3†-VRC01GL, 2 fabs, unsharpened), and EMD-9303 (426cDS-SOSIP D3†-VRC01GL, 2 fabs, sharpened). Structures have been deposited to the PDB under accession numbers PDB-6MYY (426cDS-SOSIP D3†-VRC01GL, 3 Fabs]), PDB-6MZJ (426cDS-SOSIP D3†-VRC01GL, 2 fabs), and PDB-6MFT (426c core†-VRC01GL).
Article and author information
National Institute of General Medical Sciences (R01GM120553)
- David Veesler
National Institute of Allergy and Infectious Diseases (R01AI081625)
- Leonidas Stamatatos
Pew Charitable Trusts
- David Veesler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Pamela J Bjorkman, California Institute of Technology, United States
- Received: April 18, 2018
- Accepted: October 11, 2018
- Accepted Manuscript published: November 7, 2018 (version 1)
- Version of Record published: November 15, 2018 (version 2)
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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