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Differences in the mannose oligomer specificities of the closely related lectins from Galanthus nivalis and Zea maysstrongly determine their eventual anti-HIV activity

2011; BioMed Central; Volume: 8; Issue: 1 Linguagem: Inglês

10.1186/1742-4690-8-10

1742-4690

Bart Hoorelbeke, Els J. M. Van Damme, Pierre Rougé, Dominique Schols, Kristel Van Laethem, Elke Fouquaert, Jan Balzarini,

Transgenic Plants and Applications

Abstract Background In a recent report, the carbohydrate-binding specificities of the plant lectins Galanthus nivalis (GNA) and the closely related lectin from Zea mays (GNA maize ) were determined by glycan array analysis and indicated that GNA maize recognizes complex-type N-glycans whereas GNA has specificity towards high-mannose-type glycans. Both lectins are tetrameric proteins sharing 64% sequence similarity. Results GNA maize appeared to be ~20- to 100-fold less inhibitory than GNA against HIV infection, syncytia formation between persistently HIV-1-infected HuT-78 cells and uninfected CD4 + T-lymphocyte SupT1 cells, HIV-1 capture by DC-SIGN and subsequent transmission of DC-SIGN-captured virions to uninfected CD4 + T-lymphocyte cells. In contrast to GNA, which preferentially selects for virus strains with deleted high-mannose-type glycans on gp120, prolonged exposure of HIV-1 to dose-escalating concentrations of GNA maize selected for mutant virus strains in which one complex-type glycan of gp120 was deleted. Surface Plasmon Resonance (SPR) analysis revealed that GNA and GNA maize interact with HIV III B gp120 with affinity constants (K D ) of 0.33 nM and 34 nM, respectively. Whereas immobilized GNA specifically binds mannose oligomers, GNA maize selectively binds complex-type GlcNAcβ1,2Man oligomers. Also, epitope mapping experiments revealed that GNA and the mannose-specific mAb 2G12 can independently bind from GNA maize to gp120, whereas GNA maize cannot efficiently bind to gp120 that contained prebound PHA-E (GlcNAcβ1,2man specific) or SNA (NeuAcα2,6X specific). Conclusion The markedly reduced anti-HIV activity of GNA maize compared to GNA can be explained by the profound shift in glycan recognition and the disappearance of carbohydrate-binding sites in GNA maize that have high affinity for mannose oligomers. These findings underscore the need for mannose oligomer recognition of therapeutics to be endowed with anti-HIV activity and that mannose, but not complex-type glycan binding of chemotherapeutics to gp120, may result in a pronounced neutralizing activity against the virus.