Antibody 8ANC195 Reveals a Site of Broad Vulnerability on the HIV-1 Envelope Spike
Abstract
Broadly neutralizing antibodies (bNAbs) to HIV-1 envelope glycoprotein (Env) can prevent infection in animal models. Characterized bNAb targets, although key to vaccine and therapeutic strategies, are currently limited. We defined a new site of vulnerability by solving structures of bNAb 8ANC195 complexed with monomeric gp120 by X-ray crystallography and trimeric Env by electron microscopy. The site includes portions of gp41 and N-linked glycans adjacent to the CD4-binding site on gp120, making 8ANC195 the first donor-derived anti-HIV-1 bNAb with an epitope spanning both Env subunits. Rather than penetrating the glycan shield by using a single variable-region CDR loop, 8ANC195 inserted its entire heavy-chain variable domain into a gap to form a large interface with gp120 glycans and regions of the gp120 inner domain not contacted by other bNAbs. By isolating additional 8ANC195 clonal variants, we identified a more potent variant, which may be valuable for therapeutic approaches using bNAb combinations with nonoverlapping epitopes.
Additional Information
© 2014 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). Available online 24 April 2014. Received: March 4, 2014. Revised: April 1, 2014. Accepted: April 4, 2014. Published: April 24, 2014. This research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grants HIVRAD P01 AI100148 (to P.J.B. and M.C.N.) and HIVRAD P01 AI082362 (to A.B.W.) (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 Grants 1040753 [to P.J.B.] and 38619s [to M.C.N.] and Comprehensive Antibody-Vaccine Immune Monitoring Consortium Grant 1032144 [to M.S.S.]); NIH Center for HIV/AID Vaccine Immunology and Immunogen Discovery 1UM1 AI100663-01 (to M.C.N.); American Cancer Society Grant PF-13-076-01-MPC (to L.S.); a Dissertation Fellowship from the California HIV/AIDS Research Program (to JH.L); and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation. The EM work was conducted at the National Resource for Automated Molecular Microscopy at The Scripps Research Institute, which is supported by the Biomedical Technology Research Center program (GM103310) of the National Institute of General Medical Sciences. We thank John P. Moore and Albert Cupo (Weill Cornell Medical College) for purified SOSIP trimers, Anna Gazumyan and Cassie Liu (Rockefeller University) for help with antibody expression, Brittany Lewis (Cornell Medical School) for help with cloning of 8ANC195 variants, and the Caltech Protein Expression Center for producing antibody and gp120 proteins, generation of suspension-adapted HEK293-S cells, and use of the Biacore T100. Operations at the Stanford Synchrotron Radiation Lightsource are supported by the US Department of Energy and the National Institutes of Health. We thank the beamline staff at the Advanced Photon Source GM/CA-CAT for use and support for beamline 23ID-D. M.C.N. and P.J.B. are Howard Hughes Medical Institute Investigators.Attached Files
Published - 1-s2.0-S2211124714002848-main.pdf
Supplemental Material - mmc1.pdf
Supplemental Material - mmc2.xls
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Additional details
- PMCID
- PMC4109818
- Eprint ID
- 45493
- Resolver ID
- CaltechAUTHORS:20140505-103212905
- HIVRAD P01 AI100148
- NIH
- HIVRAD P01 AI082362
- NIH
- 1040753
- AIDS Vaccine Discovery Grants
- 38619s
- AIDS Vaccine Discovery Grants
- 1032144
- Comprehensive Antibody-Vaccine Immune Monitoring Consortium
- 1UM1 AI100663-01
- NIH
- PF-13-076-01-MPC
- American Cancer Society
- Gordon and Betty Moore Foundation
- GM103310
- NIH
- Department of Energy (DOE)
- Howard Hughes Medical Institute (HHMI)
- Created
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2014-05-05Created from EPrint's datestamp field
- Updated
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2021-11-10Created from EPrint's last_modified field