Binding of high-mannose-type oligosaccharides and synthetic oligomannose clusters to human antibody 2G12: implications for HIV-1 vaccine design.
Human antibody 2G12 broadly neutralizes human immunodeficiency virus type 1 (HIV-1) isolates and shows protective activity against viral challenge in animal models. Previous mutational analysis suggested that 2G12 recognized a novel cluster of high-mannose type oligosaccharides on HIV-1 gp120. To explore the carbohydrate antigen for HIV-1 vaccine design, we have studied the binding of 2G12 to an array of HIV-1 high-mannose type oligosaccharides by competitive ELISAs and found that Man9GlcNAc is 210- and 74-fold more effective than Man5GlcNAc and Man6GlcNAc in binding to 2G12. The results establish that the larger high-mannose oligosaccharide on HIV-1 is the favorable subunit for 2G12 recognition. To mimic the putative epitope of 2G12, we have created scaffold-based multivalent Man9 clusters and found that the galactose-scaffolded bi-, tri-, and tetra-valent Man9 clusters are 7-, 22-, and 73-fold more effective in binding to 2G12 than the monomeric Man9GlcNAc2Asn. The experimental data shed light on further structural optimization of epitope mimics for developing a carbohydrate-based HIV-1 vaccine.
Wang
Lai-Xi
LX
Institute of Human Virology, University of Maryland Biotechnology Institute, University of Maryland, Baltimore, Maryland 21201, USA. wangx@umbi.umd.edu
Ni
Jiahong
J
Singh
Suddham
S
Li
Hengguang
H
D016915:AIDS Vaccines / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D001665:Binding Sites; D002240:Carbohydrate Sequence; D003001:Cloning, Molecular; D015195:Drug Design; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008358:Mannose / Q000031:analogs & derivatives* / Q000276:immunology; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D009844:Oligosaccharides / Q000737:chemistry / Q000276:immunology*
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D009844:Oligosaccharides; D008358:Mannose