Differences in the mannose oligomer specificities of the closely related lectins from Galanthus nivalisand Zea maysstrongly determine their eventual anti-HIV activity
16 pages
English

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

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16 pages
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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.

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Publié par
Publié le 01 janvier 2011
Nombre de lectures 11
Langue English
Poids de l'ouvrage 2 Mo

Extrait

Hoorelbekeet al.Retrovirology2011,8:10 http://www.retrovirology.com/content/8/1/10
R E S E A R C H
Open Access
Differences in the mannose oligomer specificities of the closely related lectins fromGalanthus nivalisandZea maysstrongly determine their eventual antiHIV activity 1 2 3 1 1 2 Bart Hoorelbeke , Els JM Van Damme , Pierre Rougé , Dominique Schols , Kristel Van Laethem , Elke Fouquaert , 1* Jan Balzarini
Abstract Background:In a recent report, the carbohydratebinding specificities of the plant lectinsGalanthus nivalis(GNA) and the closely related lectin fromZea mays(GNAmaize) were determined by glycan array analysis and indicated that GNAmaizerecognizes complextype Nglycans whereas GNA has specificity towards highmannosetype glycans. Both lectins are tetrameric proteins sharing 64% sequence similarity. Results:GNAmaizeappeared 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 GNAmaizeselected for mutant virus strains in which one complextype glycan of gp120 was deleted. Surface Plasmon Resonance (SPR) analysis revealed that GNA and GNAmaizeinteract with HIV IIIBgp120 with affinity constants (KD) of 0.33 nM and 34 nM, respectively. Whereas immobilized GNA specifically binds mannose oligomers, GNAmaizeselectively binds complextype GlcNAcb1,2Man oligomers. Also, epitope mapping experiments revealed that GNA and the mannosespecific mAb 2G12 can independently bind from GNAmaizeto gp120, whereas GNAmaizecannot efficiently bind to gp120 that contained prebound PHAE (GlcNAcb1,2man specific) or SNA (NeuAca2,6X specific). Conclusion:The markedly reduced antiHIV activity of GNAmaizecompared to GNA can be explained by the profound shift in glycan recognition and the disappearance of carbohydratebinding sites in GNAmaizethat 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.
Background Lectins represent a heterogeneous group of carbohy dratebinding proteins that are present in different spe cies (e.g. prokaryotes, plants, invertebrates and vertebrates) and vary in size, structure and ability (affi nity for different glycan determinants) to bind carbohy drates. Plant lectins represent a large group of proteins
* Correspondence: jan.balzarini@rega.kuleuven.be 1 Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B 3000 Leuven, Belgium Full list of author information is available at the end of the article
classified into twelve families, each typified by a particu lar carbohydrate binding motif [1]. At present, most stu dies have dealt with plant lectins classified as legume lectins, chitinbinding lectins, type 2 ribosome inactivat ing proteins and monocot mannosebinding lectins (MMBLs). After the identification of the first reported MMBL from snowdrop bulbs, namelyGalanthus nivalis agglutinin (GNA) [2], lectins were isolated and charac terized from other closely related plant species. Similar lectins were also identified outside plants, for example in the fishFugu rubripes[3] and in several
© 2011 Hoorelbeke et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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