Structure of adeno-associated virus-2 in complex with neutralizing monoclonal antibody A20

Dustin M. McCraw, Jason K. O'Donnell, Kenneth A. Taylor, Scott M. Stagg, Michael S. Chapman

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

The use of adeno-associated virus (AAV) as a gene therapy vector is limited by the host neutralizing immune response. The cryo-electron microscopy (EM) structure at 8.5. Å resolution is determined for a complex of AAV-2 with the Fab' fragment of monoclonal antibody (MAb) A20, the most extensively characterized AAV MAb. The binding footprint is determined through fitting the cryo-EM reconstruction with a homology model following sequencing of the variable domain, and provides a structural basis for integrating diverse prior epitope mappings. The footprint extends from the previously implicated plateau to the side of the spike, and into the conserved canyon, covering a larger area than anticipated. Comparison with structures of binding and non-binding serotypes indicates that recognition depends on a combination of subtle serotype-specific features. Separation of the neutralizing epitope from the heparan sulfate cell attachment site encourages attempts to develop immune-resistant vectors that can still bind to target cells.

Original languageEnglish (US)
Pages (from-to)40-49
Number of pages10
JournalVirology
Volume431
Issue number1-2
DOIs
StatePublished - Sep 15 2012

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Keywords

  • A20
  • Adeno-associated virus
  • Antibody
  • Epitope
  • Fab'
  • Gene therapy
  • Monoclonal

ASJC Scopus subject areas

  • Virology

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