Capsid Antibodies to Different Adeno-Associated Virus Serotypes Bind Common Regions
Open Access
- 15 August 2013
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 87 (16), 9111-9124
- https://doi.org/10.1128/jvi.00622-13
Abstract
Interactions between viruses and the host antibody immune response are critical in the development and control of disease, and antibodies are also known to interfere with the efficacy of viral vector-based gene delivery. The adeno-associated viruses (AAVs) being developed as vectors for corrective human gene delivery have shown promise in clinical trials, but preexisting antibodies are detrimental to successful outcomes. However, the antigenic epitopes on AAV capsids remain poorly characterized. Cryo-electron microscopy and three-dimensional image reconstruction were used to define the locations of epitopes to which monoclonal fragment antibodies (Fabs) against AAV1, AAV2, AAV5, and AAV6 bind. Pseudoatomic modeling showed that, in each serotype, Fabs bound to a limited number of sites near the protrusions surrounding the 3-fold axes of the T=1 icosahedral capsids. For the closely related AAV1 and AAV6, a common Fab exhibited substoichiometric binding, with one Fab bound, on average, between two of the three protrusions as a consequence of steric crowding. The other AAV Fabs saturated the capsid and bound to the walls of all 60 protrusions, with the footprint for the AAV5 antibody extending toward the 5-fold axis. The angle of incidence for each bound Fab on the AAVs varied and resulted in significant differences in how much of each viral capsid surface was occluded beyond the Fab footprints. The AAV-antibody interactions showed a common set of footprints that overlapped some known receptor-binding sites and transduction determinants, thus suggesting potential mechanisms for virus neutralization by the antibodies.Keywords
This publication has 96 references indexed in Scilit:
- The structure of adeno-associated virus serotype 3B (AAV-3B): Insights into receptor binding and immune evasionVirology, 2010
- Adeno-associated virus-2 and its primary cellular receptor—Cryo-EM structure of a heparin complexVirology, 2009
- Antibodies against viruses: passive and active immunizationCurrent Opinion in Immunology, 2008
- Inference of Macromolecular Assemblies from Crystalline StateJournal of Molecular Biology, 2007
- Interpretation of electron density with stereographic roadmap projectionsJournal of Structural Biology, 2007
- AUTO3DEM—an automated and high throughput program for image reconstruction of icosahedral particlesJournal of Structural Biology, 2007
- Ab initio random model method facilitates 3D reconstruction of icosahedral particlesJournal of Structural Biology, 2007
- Visualizing density maps with UCSF ChimeraJournal of Structural Biology, 2007
- Fourier shell correlation threshold criteriaJournal of Structural Biology, 2005
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004