期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 47, 页码 E3268-E3277出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1217207109
关键词
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资金
- Rockefeller University, National Institutes of Health [1 P01 AI081677]
- International AIDS Vaccine Initiative
- Bill and Melinda Gates Foundation [Comprehensive Antibody-Vaccine Immune Monitoring Consortium] [1032144]
- Bill and Melinda Gates Foundation [Collaboration for AIDS Vaccine Discovery Grants] [38660, 38619s]
- UK Research Councils' Basic Technology Initiative Glycoarrays [GRS/79268]
- Engineering and Physical Sciences Research Council [EP/G037604/1]
- Wellcome Trust [WT093378MA]
- National Cancer Institute Alliance of Glycobiologists for Detection of Cancer and Cancer Risk [U01 CA128416]
- Gordon and Betty Moore Foundation
- US Department of Energy
- National Institutes of Health
- EPSRC [EP/G037604/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [GR/S79268/02, EP/G037604/1] Funding Source: researchfish
Broadly neutralizing HIV antibodies (bNAbs) can recognize carbohydrate-dependent epitopes on gp120. In contrast to previously characterized glycan-dependent bNAbs that recognize high-mannose N-glycans, PGT121 binds complex-type N-glycans in glycan microarrays. We isolated the B-cell clone encoding PGT121, which segregates into PGT121-like and 10-1074-like groups distinguished by sequence, binding affinity, carbohydrate recognition, and neutralizing activity. Group 10-1074 exhibits remarkable potency and breadth but no detectable binding to protein-free glycans. Crystal structures of unliganded PGT121, 10-1074, and their likely germ-line precursor reveal that differential carbohydrate recognition maps to a cleft between complementarity determining region (CDR)H2 and CDRH3. This cleft was occupied by a complex-type N-glycan in a liganded PGT121 structure. Swapping glycan contact residues between PGT121 and 10-1074 confirmed their importance for neutralization. Although PGT121 binds complex-type N-glycans, PGT121 recognized high-mannose-only HIV envelopes in isolation and on virions. As HIV envelopes exhibit varying proportions of high-mannose-and complex-type N-glycans, these results suggest promiscuous carbohydrate interactions, an advantageous adaptation ensuring neutralization of all viruses within a given strain.
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