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  • The EMBO Journal (2009) 28, 3269 - 3276
  • doi:10.1038/emboj.2009.245

Published online: 27 August 2009

Structural basis for the preferential recognition of immature flaviviruses by a fusion-loop antibody

Mickaël V Cherrier1, Bärbel Kaufmann1, Grant E Nybakken2, Shee-Mei Lok1,4, Julia T Warren2, Beverly R Chen2, Christopher A Nelson2, Victor A Kostyuchenko1, Heather A Holdaway1, Paul R Chipman1, Richard J Kuhn1, Michael S Diamond3, Michael G Rossmann1 and Daved H Fremont2

  1. Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
  2. Departments of Pathology and Immunology, Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA
  3. Departments of Medicine, Molecular Microbiology, Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

Correspondence to:

Michael G Rossmann, Department of Biological Sciences, Purdue University, 915 W. State Street, West Lafayette, IN 47907-2054, USA. Tel.: +1 765 494 4911; Fax: +1 765 496 1189; E-mail: mr@purdue.edu

Daved H Fremont, Departments of Pathology and Immunology, Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA. Tel.: +1 314 747 6547; Fax: +1 314 362 8888; E-mail: fremont@wustl.edu

4Present address: Duke-NUS Graduate Medical School, 30 Medical Drive, Brenner Centre for Molecular Medicine, 117609, Singapore

Received 6 May 2009; Accepted 30 July 2009

Flaviviruses are a group of human pathogens causing severe encephalitic or hemorrhagic diseases that include West Nile, dengue and yellow fever viruses. Here, using X-ray crystallography we have defined the structure of the flavivirus cross-reactive antibody E53 that engages the highly conserved fusion loop of the West Nile virus envelope glycoprotein. Using cryo-electron microscopy, we also determined that E53 Fab binds preferentially to spikes in noninfectious, immature flavivirions but is unable to bind significantly to mature virions, consistent with the limited solvent exposure of the epitope. We conclude that the neutralizing impact of E53 and likely similar fusion-loop-specific antibodies depends on its binding to the frequently observed immature component of flavivirus particles. Our results elucidate how fusion-loop antibodies, which comprise a significant fraction of the humoral response against flaviviruses, can function to control infection without appreciably recognizing mature virions. As these highly cross-reactive antibodies are often weakly neutralizing they also may contribute to antibody-dependent enhancement and flavi virus pathogenesis thereby complicating development of safe and effective vaccines.

  • Keywords:

    • antibodies,
    • flaviviruses,
    • fusion loop,
    • partially immature virus,
    • structure