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

H Mouquet, L Scharf, Z Euler, Y Liu… - Proceedings of the …, 2012 - National Acad Sciences
H Mouquet, L Scharf, Z Euler, Y Liu, C Eden, JF Scheid, A Halper-Stromberg…
Proceedings of the National Academy of Sciences, 2012National Acad Sciences
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 …
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.
National Acad Sciences