title: Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers.
abstract: A highly glycosylated, trimeric envelope glycoprotein (Env) mediates HIV-1 cell entry. The high density and heterogeneity of the glycans shield Env from recognition by the immune system, but paradoxically, many potent broadly neutralizing antibodies (bNAbs) recognize epitopes involving this glycan shield. To better understand Env glycosylation and its role in bNAb recognition, we characterized a soluble, cleaved recombinant trimer (BG505 SOSIP.664) that is a close structural and antigenic mimic of native Env. Large, unprocessed oligomannose-type structures (Man8-9GlcNAc2) are notably prevalent on the gp120 components of the trimer, irrespective of the mammalian cell expression system or the bNAb used for affinity purification. In contrast, gp41 subunits carry more highly processed glycans. The glycans on uncleaved, non-native oligomeric gp140 proteins are also highly processed. A homogeneous, oligomannose-dominated glycan profile is therefore a hallmark of a native Env conformation and a potential Achilles' heel that can be exploited for bNAb recognition and 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: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Snezana
authors.initials: S
authors.lastname: Vasiljevic
authors.affiliation: Department of Integrative Structural and Computational Biology, IAVI Neutralizing Antibody Center and the collaboration for AIDS Vaccine Discovery, 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, CA 92037, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ozorowski
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: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, NY 10021, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Cupo
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, NY 10021, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ringe
authors.affiliation: Department of Integrative Structural and Computational Biology, IAVI Neutralizing Antibody Center and the collaboration for AIDS Vaccine Discovery, 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, CA 92037, USA.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, NY 10021, USA; Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
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: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02142, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.affiliation: Department of Integrative Structural and Computational Biology, IAVI Neutralizing Antibody Center and the collaboration for AIDS Vaccine Discovery, 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, CA 92037, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.affiliation: Department of Integrative Structural and Computational Biology, IAVI Neutralizing Antibody Center and the collaboration for AIDS Vaccine Discovery, 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, CA 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, NY 10021, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: max.crispin@bioch.ox.ac.uk.
authors.forename: Max
authors.initials: M
authors.lastname: Crispin
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D016466:CHO Cells; D003412:Cricetulus; D006031:Glycosylation; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011134:Polysaccharides / Q000378:metabolism; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship
chemical_list: D057134:Antibodies, Neutralizing; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D011134:Polysaccharides