Adenovirus serotype 5 hexon mediates liver gene transfer.
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.
Waddington
Simon N
SN
Department of Haematology, Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School, London NW3 2PF, UK.
McVey
John H
JH
Bhella
David
D
Parker
Alan L
AL
Barker
Kristeen
K
Atoda
Hideko
H
Pink
Rebecca
R
Buckley
Suzanne M K
SM
Greig
Jenny A
JA
Denby
Laura
L
Custers
Jerome
J
Morita
Takashi
T
Francischetti
Ivo M B
IM
Monteiro
Robson Q
RQ
Barouch
Dan H
DH
van Rooijen
Nico
N
Napoli
Claudio
C
Havenga
Menzo J E
MJ
Nicklin
Stuart A
SA
Baker
Andrew H
AH
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
D036022:Capsid Proteins; D002352:Carrier Proteins; C431277:factor X-binding protein, Deinagkistrodon acutus; C018315:hexon capsid protein, Adenovirus; D014859:Warfarin; D005170:Factor X