title: Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies.
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.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA. hmouquet@rockefeller.edu
authors.forename: Hugo
authors.initials: H
authors.lastname: Mouquet
authors.forename: Louise
authors.initials: L
authors.lastname: Scharf
authors.forename: Zelda
authors.initials: Z
authors.lastname: Euler
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Caroline
authors.initials: C
authors.lastname: Eden
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Scheid
authors.forename: Ariel
authors.initials: A
authors.lastname: Halper-Stromberg
authors.forename: Priyanthi N P
authors.initials: PN
authors.lastname: Gnanapragasam
authors.forename: Daniel I R
authors.initials: DI
authors.lastname: Spencer
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
authors.forename: Ten
authors.initials: T
authors.lastname: Feizi
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Bjorkman
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D002999:Clone Cells; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009500:Neutralization Tests; D011134:Polysaccharides / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D050505:Mutant Proteins; D011134:Polysaccharides