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

• Published in: Nature structural & molecular biology Vol. 20; no. 7; pp. 804 - 813
• Main Authors: Pancera, Marie, Shahzad-ul-Hussan, Syed, Doria-Rose, Nicole A, McLellan, Jason S, Bailer, Robert T, Dai, Kaifan, Loesgen, Sandra, Louder, Mark K, Staupe, Ryan P, Yang, Yongping, Zhang, Baoshan, Parks, Robert, Eudailey, Joshua, Lloyd, Krissey E, Blinn, Julie, Alam, S Munir, Haynes, Barton F, Amin, Mohammed N, Wang, Lai-Xi, Burton, Dennis R, Koff, Wayne C, Nabel, Gary J, Mascola, John R, Bewley, Carole A, Kwong, Peter D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2013; Nature Publishing Group
• Subjects: 631/250; 631/326/596; 631/535/1266; Amino Acid Motifs; Amino Acid Sequence; Analysis; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Antibody Specificity; Antigen-Antibody Reactions; Antigenic determinants; Binding Sites, Antibody; Biochemistry; Biological Microscopy; Carbohydrate Conformation; Carbohydrate Sequence; Crystallography, X-Ray; Epitopes - chemistry; Epitopes - immunology; Epitopes - metabolism; Genetic aspects; Glycosylation - drug effects; Health aspects; HEK293 Cells; HIV; HIV (Viruses); HIV Antibodies - chemistry; HIV Antibodies - immunology; HIV Antibodies - metabolism; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - immunology; HIV Envelope Protein gp120 - metabolism; Human immunodeficiency virus; Humans; Immunoglobulin Fab Fragments - immunology; Immunoglobulin Fab Fragments - metabolism; Life Sciences; Membrane Biology; Models, Molecular; Molecular biology; Molecular Sequence Data; Mutagenesis; Neutralization; Peptide Fragments - chemistry; Peptide Fragments - immunology; Peptide Fragments - metabolism; Physiological aspects; Polyclonal antibodies; Polysaccharides - chemistry; Polysaccharides - immunology; Polysaccharides - metabolism; Protein Conformation; Protein Processing, Post-Translational - drug effects; Protein Structure; Residues; Structure; Structure-Activity Relationship; Swainsonine - pharmacology; United States; United States > US
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2600

Some broadly neutralizing antibodies against HIV-1 recognize glycopeptide epitopes in the gp120 V1–V2 region. Now X-ray crystallography and NMR approaches, together with functional analyses of two such antibodies (PG9 and PG16), reveal how glycan binding specificity is achieved. The authors also created a chimeric Fab that showed improved neutralization activity. 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.