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

Nat Struct Mol Biol. 2013 Jul;20(7):804-13. doi: 10.1038/nsmb.2600. Epub 2013 May 26.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / metabolism
  • Antibody Specificity
  • Antigen-Antibody Reactions
  • Binding Sites, Antibody
  • Carbohydrate Conformation
  • Carbohydrate Sequence
  • Crystallography, X-Ray
  • Epitopes / chemistry
  • Epitopes / immunology
  • Epitopes / metabolism
  • Glycosylation / drug effects
  • HEK293 Cells
  • HIV Antibodies / chemistry
  • HIV Antibodies / immunology*
  • HIV Antibodies / metabolism
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp120 / metabolism
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fab Fragments / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology*
  • Peptide Fragments / metabolism
  • Polysaccharides / chemistry
  • Polysaccharides / immunology*
  • Polysaccharides / metabolism
  • Protein Conformation
  • Protein Processing, Post-Translational / drug effects
  • Structure-Activity Relationship
  • Swainsonine / pharmacology

Substances

  • Antibodies, Neutralizing
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV envelope protein gp120 (135-148)
  • Immunoglobulin Fab Fragments
  • Peptide Fragments
  • Polysaccharides
  • gp120 protein, Human immunodeficiency virus 1
  • Swainsonine