title: Inhibition of mammalian glycan biosynthesis produces non-self antigens for a broadly neutralising, HIV-1 specific antibody.
abstract: The HIV envelope has evolved a dense array of immunologically "self" carbohydrates that efficiently protect the virus from antibody recognition. Nonetheless, one broadly neutralising antibody, IgG1 2G12, has been shown to recognise a cluster of oligomannose glycans on the HIV-1 surface antigen gp120. Thus the self carbohydrates of HIV are now regarded as potential targets for viral neutralisation and vaccine design. Here, we show that chemical inhibition of mammalian glycoprotein synthesis, with the plant alkaloid kifunensine, creates multiple HIV (2G12) epitopes on the surface of previously non-antigenic self proteins and cells, including HIV gp120. This formally demonstrates the structural basis for self/non-self discrimination between viral and host glycans, by a neutralising antibody. Moreover, this study provides an alternative protein engineering approach to the design of a carbohydrate vaccine for HIV-1 by chemical synthesis.
authors.affiliation: Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford. chris.scanlan@bioch.ox.ac.uk
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Scanlan
authors.forename: Gayle E
authors.initials: GE
authors.lastname: Ritchie
authors.forename: Kavitha
authors.initials: K
authors.lastname: Baruah
authors.forename: Max
authors.initials: M
authors.lastname: Crispin
authors.forename: David J
authors.initials: DJ
authors.lastname: Harvey
authors.forename: Bernhard B
authors.initials: BB
authors.lastname: Singer
authors.forename: Lothar
authors.initials: L
authors.lastname: Lucka
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wormald
authors.forename: Paul
authors.initials: P
authors.lastname: Wentworth
authors.forename: Nicole
authors.initials: N
authors.lastname: Zitzmann
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Rudd
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000187:drug effects* / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000378:metabolism*; D015488:HIV Antigens / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008361:Mannosidases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D008958:Models, Molecular; D009500:Neutralization Tests; D011134:Polysaccharides / Q000096:biosynthesis* / Q000276:immunology*
chemical_list: D000470:Alkaloids; D019380:Anti-HIV Agents; D000939:Epitopes; D015483:HIV Antibodies; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides; C065629:kifunensine; D008361:Mannosidases