Retargeting FX binding-ablated HAdV-5 to vascular cells by inclusion of the RGD-4C peptide in hexon hypervariable region 7 and the HI loop

Robertson, S., Parker, A. L., Clarke, C., Duffy, M. R., Alba, R., Nicklin, S. A. and Baker, A. H. (2016) Retargeting FX binding-ablated HAdV-5 to vascular cells by inclusion of the RGD-4C peptide in hexon hypervariable region 7 and the HI loop. Journal of General Virology, 97(8), pp. 1911-1916. (doi:10.1099/jgv.0.000505) (PMID:27189759) (PMCID:PMC5156330)

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Abstract

Recent studies have generated interest in the function of human adenovirus serotype 5 (HAdV-5) hexon:  factor X (FX) binding and subsequent hepatocyte transduction and interaction with the immune system. Here, we retargeted adenovirus serotype 5 vectors, ablated for FX interaction, by replacing amino acids in hexon HVR7 with RGD-4C or inserting the peptide into the fibre HI loop. These genetic modifications in the capsid were compatible with virus assembly, and could efficiently retarget transduction of the vector via the αvβ3/5 integrin-mediated pathway, but did not alter immune recognition by pre-existing human neutralizing anti-HAdV-5 antibodies or by natural antibodies in mouse serum. Thus, FX-binding-ablated HAdV-5 can be retargeted but remain sensitive to immune-mediated attack. These findings further refine HAdV-5-based vectors for human gene therapy and inform future vector development.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Clarke, Dr Carolyn and Robertson, Dr Stacy and Duffy, Ms Margaret and Alba, Dr Raul and Baker, Professor Andrew
Authors: Robertson, S., Parker, A. L., Clarke, C., Duffy, M. R., Alba, R., Nicklin, S. A., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of General Virology
Publisher:Society for General Microbiology
ISSN:0022-1317
ISSN (Online):1465-2099
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Journal of General Virology 97(8): 1911-1916
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
563291Improved gene therapy via genetic modification of the adenovirus capsid to ablate interaction with blood coagulation factor XAndrew BakerBiotechnology and Biological Sciences Research Council (BBSRC)BB/I53297X/1RI CARDIOVASCULAR & MEDICAL SCIENCES