title: Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies.
abstract: The envelope spike of HIV-1 employs a 'glycan shield' to protect itself from antibody-mediated neutralization. Paradoxically, however, potent broadly neutralizing antibodies (bnAbs) that target this shield have been isolated. The unusually high glycan density on the gp120 subunit limits processing during biosynthesis, leaving a region of under-processed oligomannose-type structures, which is a primary target of these bnAbs. Here we investigate the contribution of individual glycosylation sites in the formation of this so-called intrinsic mannose patch. Deletion of individual sites has a limited effect on the overall size of the intrinsic mannose patch but leads to changes in the processing of neighbouring glycans. These structural changes are largely tolerated by a panel of glycan-dependent bnAbs targeting these regions, indicating a degree of plasticity in their recognition. These results support the intrinsic mannose patch as a stable target for vaccine design.
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Pritchard
authors.affiliation: Ludger Ltd., Culham Science Centre, Abingdon, Oxfordshire OX14 3EB, UK.
authors.forename: Daniel I R
authors.initials: DI
authors.lastname: Spencer
authors.affiliation: Ludger Ltd., Culham Science Centre, Abingdon, Oxfordshire OX14 3EB, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Royle
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Camille
authors.initials: C
authors.lastname: Bonomelli
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Gemma E
authors.initials: GE
authors.lastname: Seabright
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Anna-Janina
authors.initials: AJ
authors.lastname: Behrens
authors.affiliation: 1] Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kulp
authors.affiliation: 1] Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Menis
authors.affiliation: King's College London School of Medicine at Guy's, King's and St Thomas' Hospitals, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Krumm
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: D Cameron
authors.initials: DC
authors.lastname: Dunlop
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Crispin
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bowden
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Scanlan
authors.affiliation: Department of Integrative Structural and Computational Biology, IAVI Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: 1] Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [3] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
authors.affiliation: King's College London School of Medicine at Guy's, King's and St Thomas' Hospitals, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Doores
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Max
authors.initials: M
authors.lastname: Crispin
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006031:Glycosylation; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008358:Mannose / Q000276:immunology* / Q000378:metabolism; D013058:Mass Spectrometry; D016297:Mutagenesis, Site-Directed; D011134:Polysaccharides / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides; D008358:Mannose