Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies.

TitleComplex-type N-glycan recognition by potent broadly neutralizing HIV antibodies.
Publication TypeJournal Article
Year of Publication2012
AuthorsMouquet H, Scharf L, Euler Z, Liu Y, Eden C, Scheid JF, Halper-Stromberg A, Gnanapragasam PNP, Spencer DIR, Seaman MS, Schuitemaker H, Feizi T, Nussenzweig MC, Bjorkman PJ
JournalProc Natl Acad Sci U S A
Volume109
Issue47
PaginationE3268-77
Date Published11/20/2012
ISSN1091-6490
KeywordsAmino Acid Sequence, Amino Acid Substitution, Antibodies, Neutralizing, Clone Cells, Crystallography, X-Ray, Epitopes, HIV Antibodies, HIV-1, Humans, Immunoglobulin Fab Fragments, Leukocytes, Mononuclear, Ligands, Models, Molecular, Molecular Sequence Data, Mutant Proteins, Neutralization Tests, Polysaccharides, Protein Binding
Abstract

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.

DOI10.1073/pnas.1217207109
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23115339
PubMed Central IDPMC3511153
Grant List1 P01 AI081677 / AI / NIAID NIH HHS / United States
U01 CA128416 / CA / NCI NIH HHS / United States
WT093378MA / / PEPFAR / United States
/ / Wellcome Trust / United Kingdom
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