Structure of the gene therapy vector, adeno-associated virus with its cell receptor, aavr

Nancy L. Meyer, Guiqing Hu, Omar Davulcu, Qing Xie, Alex J. Noble, Craig Yoshioka, Drew S. Gingerich, Andrew Trzynka, Larry David, Scott M. Stagg, Michael Stewart Chapman

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Adeno-associated virus (AAV) vectors are preeminent in emerging clinical gene therapies. Generalizing beyond the most tractable genetic diseases will require modulation of cell specificity and immune neutralization. Interactions of AAV with its cellular receptor, AAVR, are key to understanding cell-entry and trafficking with the rigor needed to engineer tissue-specific vectors. Cryo-electron tomography shows ordered binding of part of the flexible receptor to the viral surface, with distal domains in multiple conformations. Regions of the virus and receptor in close physical proximity can be identified by cross-linking/mass spectrometry. Cryo-electron microscopy with a two-domain receptor fragment reveals the interactions at 2.4 A° resolution. AAVR binds between AAV’s spikes on a plateau that is conserved, except in one clade whose structure is AAVR-incompatible. AAVR’s footprint overlaps the epitopes of several neutralizing antibodies, prompting a re-evaluation of neutralization mechanisms. The structure provides a roadmap for experimental probing and manipulation of viral-receptor interactions.

Original languageEnglish (US)
Article numbere44707
JournaleLife
Volume8
DOIs
StatePublished - May 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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