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

M Pancera, S Shahzad-ul-Hussan… - Nature structural & …, 2013 - nature.com
M Pancera, S Shahzad-ul-Hussan, NA Doria-Rose, JS McLellan, RT Bailer, K Dai…
Nature structural & molecular biology, 2013nature.com
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 …
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.
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