期刊
VIROLOGY
卷 431, 期 1-2, 页码 40-49出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2012.05.004
关键词
Adeno-associated virus; Antibody; A20; Epitope; Fab'; Gene therapy; Monoclonal
类别
资金
- National Institutes of Health [R01GM66875, R01GM78538]
- Office of Naval Research [N000141010082]
- [S10-RR025080]
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 angstrom 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. (C) 2012 Elsevier Inc. All rights reserved.
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