Structure of adeno-associated virus-2 in complex with neutralizing monoclonal antibody A20

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• 作者：Dustin M. McCraw^a ; Jason K. O&rsquo ; Donnell^b ; ¹ ; Kenneth A. Taylor^c ; Scott M. Stagg^b ; ^d ; Michael S. Chapman^a ; ^{chapmami@ohsu.edu}
• 关键词：AAV ; adeno associated virus ; CPV ; canine parvovirus ; CTF ; contrast transfer function ; EM ; electron microscopy ; FPV ; feline panleukopenia virus ; HSPG ; heparan sulfate proteoglycan ; MVM ; minute virus of mouse ; mAb ; monoclonal antibody ; NCS ; non crystallogra
• 刊名：Virology
• 出版年：2012
• 期刊代码：108_00426822
• 类别：imm
• 出版时间：15-30 September, 2012
• 卷：431
• 期：1-2
• 页码：40-49
• 文件大小：1830 K

摘要

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 脜 resolution is determined for a complex of AAV-2 with the Fab鈥?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.