title: Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody.
abstract: The dengue virus (DENV) complex is composed of four distinct but serologically related flaviviruses, which together cause the present-day most important emerging viral disease. Although DENV infection induces lifelong immunity against viruses of the same serotype, the antibodies raised appear to contribute to severe disease in cases of heterotypic infections. Understanding the mechanisms of DENV neutralization by antibodies is, therefore, crucial for the design of vaccines that simultaneously protect against all four viruses. Here, we report a comparative, high-resolution crystallographic analysis of an "A-strand" murine monoclonal antibody, Mab 4E11, in complex with its target domain of the envelope protein from the four DENVs. Mab 4E11 is capable of neutralizing all four serotypes, and our study reveals the determinants of this cross-reactivity. The structures also highlight the mechanism by which A-strand Mabs disrupt the architecture of the mature virion, inducing premature fusion loop exposure and concomitant particle inactivation.
authors.affiliation: Unité de Virologie Structurale, Département de Virologie, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Joseph J B
authors.initials: JJ
authors.lastname: Cockburn
authors.forename: M Erika
authors.initials: ME
authors.lastname: Navarro Sanchez
authors.forename: Nickolas
authors.initials: N
authors.lastname: Fretes
authors.forename: Agathe
authors.initials: A
authors.lastname: Urvoas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Staropoli
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Kikuti
authors.forename: Lark L
authors.initials: LL
authors.lastname: Coffey
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana Seisdedos
authors.forename: Hugues
authors.initials: H
authors.lastname: Bedouelle
authors.forename: Felix A
authors.initials: FA
authors.lastname: Rey
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry* / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003716:Dengue Virus / Q000276:immunology* / Q000502:physiology; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D013499:Surface Properties; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000276:immunology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D000939:Epitopes; D014759:Viral Envelope Proteins