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 Chapman

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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 Å 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)
JournaleLife
Volume8
DOIs
StatePublished - May 22 2019

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Keywords

  • atomic
  • electron microscopy
  • entry
  • human
  • infectious disease
  • microbiology
  • molecular biophysics
  • structural biology
  • trafficking
  • viral vector
  • virus

ASJC Scopus subject areas

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

Cite this

Meyer, N. L., Hu, G., Davulcu, O., Xie, Q., Noble, A. J., Yoshioka, C., Gingerich, D. S., Trzynka, A., David, L., Stagg, S. M., & Chapman, M. (2019). Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR. eLife, 8. https://doi.org/10.7554/eLife.44707