Journal
CELL REPORTS
Volume 7, Issue 3, Pages 785-795Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.04.001
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Funding
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grants [HIVRAD P01 AI100148, HIVRAD P01 AI082362]
- Bill and Melinda Gates Foundation [1040753, 38619s]
- Comprehensive Antibody-Vaccine Immune Monitoring Consortium Grant [1032144]
- NIH Center for HIV/AID Vaccine Immunology and Immunogen Discovery [1UM1 AI100663-01]
- American Cancer Society Grant [PF-13-076-01-MPC]
- California HIV/AIDS Research Program
- Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation
- Biomedical Technology Research Center program [GM103310]
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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.
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