Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16.
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.
Pancera, 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, SM; Haynes, BF; Amin, MN; Wang, L-X; Burton, DR; Koff, WC; Nabel, GJ; Mascola, JR; Bewley, CA; Kwong, PD
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