title: 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.
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.
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Stacy
authors.initials: S
authors.lastname: Robertson
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Parker
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Clarke
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Duffy
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Raul
authors.initials: R
authors.lastname: Alba
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics* / Q000378:metabolism*; D002238:Carbohydrate Epimerases / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007658:Ketone Oxidoreductases / Q000378:metabolism; D051379:Mice; D011991:Receptors, Virus / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D053585:Virus Attachment
chemical_list: D036022:Capsid Proteins; D039302:Integrin alphaVbeta3; D011991:Receptors, Virus; D019030:Receptors, Vitronectin; D011993:Recombinant Fusion Proteins; C018315:hexon capsid protein, Adenovirus; C064660:integrin alphaVbeta5; C028277:TSTA3 protein, human; D007658:Ketone Oxidoreductases; D002238:Carbohydrate Epimerases