title: Recognition determinants of broadly neutralizing human antibodies against dengue viruses.
abstract: Dengue disease is caused by four different flavivirus serotypes, which infect 390 million people yearly with 25% symptomatic cases and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies. We recently isolated human antibodies potently neutralizing all four dengue virus serotypes. Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell, explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.
authors.affiliation: 1] Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France [2] CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rouvinski
authors.affiliation: 1] Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France [2] CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France.
authors.forename: Pablo
authors.initials: P
authors.lastname: Guardado-Calvo
authors.affiliation: 1] Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France [2] CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Barba-Spaeth
authors.affiliation: 1] Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France [2] CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France [3] Université Paris-Sud, Faculté des Sciences, 91405 Orsay, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Duquerroy
authors.affiliation: 1] Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France [2] CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vaney
authors.affiliation: 1] Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France [2] CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Kikuti
authors.affiliation: 1] Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France [2] CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France.
authors.forename: M Erika
authors.initials: ME
authors.lastname: Navarro Sanchez
authors.affiliation: Division of Immunology and Inflammation, Department of Medicine, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK.
authors.forename: Wanwisa
authors.initials: W
authors.lastname: Dejnirattisai
authors.affiliation: Division of Immunology and Inflammation, Department of Medicine, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK.
authors.forename: Wiyada
authors.initials: W
authors.lastname: Wongwiwat
authors.affiliation: Institut Pasteur, Protéopôle, CNRS UMR 3528, 75724 Paris Cedex 15, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Haouz
authors.affiliation: Institut Pasteur, Protéopôle, CNRS UMR 3528, 75724 Paris Cedex 15, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Girard-Blanc
authors.affiliation: Institut Pasteur, Protéopôle, CNRS UMR 3528, 75724 Paris Cedex 15, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Petres
authors.affiliation: Synchrotron SOLEIL, L'Orme des Merisiers, Saint Aubin, BP48, 91192 Gif-sur-Yvette, France.
authors.forename: William E
authors.initials: WE
authors.lastname: Shepard
authors.affiliation: Institut Pasteur, Département de Virologie, Unité des Interactions Moléculaires Flavivirus-Hôtes, 75724 Paris Cedex 15, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Desprès
authors.affiliation: Institut Pasteur, Département de Virologie, Unité de Pathogénie Virale, INSERM U1108, 75724 Paris Cedex 15, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.affiliation: Institut Pasteur de Guyane, BP 6010, 97306 Cayenne, French Guiana.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dussart
authors.affiliation: 1] Division of Immunology and Inflammation, Department of Medicine, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK [2] Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Juthathip
authors.initials: J
authors.lastname: Mongkolsapaya
authors.affiliation: Division of Immunology and Inflammation, Department of Medicine, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK.
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Screaton
authors.affiliation: 1] Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France [2] CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France [3] Institut Pasteur, Protéopôle, CNRS UMR 3528, 75724 Paris Cedex 15, France.
authors.forename: Félix A
authors.initials: FA
authors.lastname: Rey
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D018360:Crystallography, X-Ray; D003716:Dengue Virus / Q000737:chemistry* / Q000145:classification / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D055503:Protein Multimerization; D012995:Solubility; D013045:Species Specificity; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D014759:Viral Envelope Proteins