title: Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16.
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.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Pancera
authors.forename: Syed
authors.initials: S
authors.lastname: Shahzad-Ul-Hussan
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doria-Rose
authors.forename: Jason S
authors.initials: JS
authors.lastname: McLellan
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.forename: Kaifan
authors.initials: K
authors.lastname: Dai
authors.forename: Sandra
authors.initials: S
authors.lastname: Loesgen
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Staupe
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Parks
authors.forename: Joshua
authors.initials: J
authors.lastname: Eudailey
authors.forename: Krissey E
authors.initials: KE
authors.lastname: Lloyd
authors.forename: Julie
authors.initials: J
authors.lastname: Blinn
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Amin
authors.forename: Lai-Xi
authors.initials: LX
authors.lastname: Wang
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Koff
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Carole A
authors.initials: CA
authors.lastname: Bewley
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions; D001666:Binding Sites, Antibody; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013329:Structure-Activity Relationship; D017026:Swainsonine / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059761:HIV envelope protein gp120 (135-148); D007140:Immunoglobulin Fab Fragments; D010446:Peptide Fragments; D011134:Polysaccharides; C514793:gp120 protein, Human immunodeficiency virus 1; D017026:Swainsonine