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 language | English (US) |
---|---|
Pages (from-to) | 40-49 |
Number of pages | 10 |
Journal | Virology |
Volume | 431 |
Issue number | 1-2 |
DOIs | |
State | Published - Sep 15 2012 |
Externally published | Yes |
Keywords
- A20
- Adeno-associated virus
- Antibody
- Epitope
- Fab'
- Gene therapy
- Monoclonal
ASJC Scopus subject areas
- Virology