Structure of adeno-associated virus-2 in complex with neutralizing monoclonal antibody A20.
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 8.5Å 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.
Department of Biochemistry and Molecular Biology, School of Medicine, Mail code L224, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239-3098, USA.
Dustin M
DM
McCraw
Jason K
JK
O'Donnell
Kenneth A
KA
Taylor
Scott M
SM
Stagg
Michael S
MS
Chapman
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology*; D000914:Antibodies, Viral / Q000737:chemistry* / Q000276:immunology*; D020285:Cryoelectron Microscopy; D000229:Dependovirus / Q000737:chemistry* / Q000276:immunology*; D018604:Epitope Mapping; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D046911:Macromolecular Substances / Q000648:ultrastructure*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D020836:Protein Structure, Quaternary
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D007140:Immunoglobulin Fab Fragments; D046911:Macromolecular Substances