Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody

Joseph J B Cockburn, M. Erika Navarro Sanchez, Nickolas Fretes, Agathe Urvoas, Isabelle Staropoli, Carlos M. Kikuti, Lark L Schneider, Fernando Arenzana Seisdedos, Hugues Bedouelle, Felix A. Rey

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97 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)303-314
Number of pages12
JournalStructure
Volume20
Issue number2
DOIs
StatePublished - Feb 8 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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    Cockburn, J. J. B., Navarro Sanchez, M. E., Fretes, N., Urvoas, A., Staropoli, I., Kikuti, C. M., Schneider, L. L., Arenzana Seisdedos, F., Bedouelle, H., & Rey, F. A. (2012). Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody. Structure, 20(2), 303-314. https://doi.org/10.1016/j.str.2012.01.001