Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16.

TitleStructural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16.
Publication TypeJournal Article
Year of Publication2013
AuthorsPancera M, Shahzad-ul-Hussan S, Doria-Rose NA, McLellan JS, Bailer RT, Dai K, Loesgen S, Louder MK, Staupe RP, Yang Y, Zhang B, Parks R, Eudailey J, Lloyd KE, Blinn J, Alam MS, Haynes BF, Amin MN, Wang L-X, Burton DR, Koff WC, Nabel GJ, Mascola JR, Bewley CA, Kwong PD
JournalNat Struct Mol Biol
Date Published07/01/2013
KeywordsAmino Acid Motifs, Amino Acid Sequence, Antibodies, Neutralizing, Antibody Specificity, Antigen-Antibody Reactions, Binding Sites, Antibody, Carbohydrate Conformation, Carbohydrate Sequence, Crystallography, X-Ray, Epitopes, Glycosylation, HEK293 Cells, HIV Antibodies, HIV Envelope Protein gp120, Humans, Immunoglobulin Fab Fragments, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Polysaccharides, Protein Conformation, Protein Processing, Post-Translational, Structure-Activity Relationship, Swainsonine

HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1-V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1-V2, showing an epitope comprising both high mannose-type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, and introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1-glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization.

Alternate JournalNat. Struct. Mol. Biol.
PubMed ID23708607
Grant List1R21 AI101035 / AI / NIAID NIH HHS / United States
AI 5U19 AI 067854-06 / AI / NIAID NIH HHS / United States
P41 RR018502-01 / RR / NCRR NIH HHS / United States
U19 AI067854 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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