title: Capsid antibodies to different adeno-associated virus serotypes bind common regions.
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.
authors.affiliation: Deptartment of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA.
authors.forename: Brittney L
authors.initials: BL
authors.lastname: Gurda
authors.forename: Michael A
authors.initials: MA
authors.lastname: DiMattia
authors.forename: Edward B
authors.initials: EB
authors.lastname: Miller
authors.forename: Antonette
authors.initials: A
authors.lastname: Bennett
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Weichert
authors.forename: Christian D
authors.initials: CD
authors.lastname: Nelson
authors.forename: Wei-jun
authors.initials: WJ
authors.lastname: Chen
authors.forename: Nicholas
authors.initials: N
authors.lastname: Muzyczka
authors.forename: Norman H
authors.initials: NH
authors.lastname: Olson
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sinkovits
authors.forename: John A
authors.initials: JA
authors.lastname: Chiorini
authors.forename: Sergei
authors.initials: S
authors.lastname: Zolotutkhin
authors.forename: Olga G
authors.initials: OG
authors.lastname: Kozyreva
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Baker
authors.forename: Colin R
authors.initials: CR
authors.lastname: Parrish
authors.forename: Mavis
authors.initials: M
authors.lastname: Agbandje-McKenna
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D001665:Binding Sites; D002213:Capsid / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D020285:Cryoelectron Microscopy; D000229:Dependovirus / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional; D046911:Macromolecular Substances / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000939:Epitopes; D046911:Macromolecular Substances