title: Adenovirus serotype 5 hexon mediates liver gene transfer.
abstract: Adenoviruses are used extensively as gene transfer agents, both experimentally and clinically. However, targeting of liver cells by adenoviruses compromises their potential efficacy. In cell culture, the adenovirus serotype 5 fiber protein engages the coxsackievirus and adenovirus receptor (CAR) to bind cells. Paradoxically, following intravascular delivery, CAR is not used for liver transduction, implicating alternate pathways. Recently, we demonstrated that coagulation factor (F)X directly binds adenovirus leading to liver infection. Here, we show that FX binds to the Ad5 hexon, not fiber, via an interaction between the FX Gla domain and hypervariable regions of the hexon surface. Binding occurs in multiple human adenovirus serotypes. Liver infection by the FX-Ad5 complex is mediated through a heparin-binding exosite in the FX serine protease domain. This study reveals an unanticipated function for hexon in mediating liver gene transfer in vivo.
authors.affiliation: Department of Haematology, Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School, London NW3 2PF, UK.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.forename: John H
authors.initials: JH
authors.lastname: McVey
authors.forename: David
authors.initials: D
authors.lastname: Bhella
authors.forename: Alan L
authors.initials: AL
authors.lastname: Parker
authors.forename: Kristeen
authors.initials: K
authors.lastname: Barker
authors.forename: Hideko
authors.initials: H
authors.lastname: Atoda
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pink
authors.forename: Suzanne M K
authors.initials: SM
authors.lastname: Buckley
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Greig
authors.forename: Laura
authors.initials: L
authors.lastname: Denby
authors.forename: Jerome
authors.initials: J
authors.lastname: Custers
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.forename: Ivo M B
authors.initials: IM
authors.lastname: Francischetti
authors.forename: Robson Q
authors.initials: RQ
authors.lastname: Monteiro
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
authors.forename: Menzo J E
authors.initials: MJ
authors.lastname: Havenga
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000260:Adenoviruses, Human / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D020285:Cryoelectron Microscopy; D005170:Factor X / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D021621:Imaging, Three-Dimensional; D008099:Liver / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D010802:Phylogeny; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D020349:Surface Plasmon Resonance; D014161:Transduction, Genetic; D053586:Virus Internalization; D014859:Warfarin / Q000494:pharmacology
chemical_list: D036022:Capsid Proteins; D002352:Carrier Proteins; C431277:factor X-binding protein, Deinagkistrodon acutus; C018315:hexon capsid protein, Adenovirus; D014859:Warfarin; D005170:Factor X