Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer

Simon N. Waddington; John H. McVey; David Bhella; Alan L. Parker; Kristeen Barker; Hideko Atoda; Rebecca Pink; Suzanne M.K. Buckley; Jenny A. Greig; Laura Denby; Jerome Custers; Takashi Morita; Ivo M.B. Francischetti; Robson Q. Monteiro; Dan H. Barouch; Nico van Rooijen; Claudio Napoli; Menzo J.E. Havenga; Stuart A. Nicklin; Andrew H. Baker

doi:10.1016/j.cell.2008.01.016

Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer

Simon N. Waddington, John H. McVey, David Bhella, Alan L. Parker, Kristeen Barker, Hideko Atoda, Rebecca Pink, Suzanne M.K. Buckley, Jenny A. Greig, Laura Denby, Jerome Custers, Takashi Morita, Ivo M.B. Francischetti, Robson Q. Monteiro, Dan H. Barouch, Nico van Rooijen, Claudio Napoli, Menzo J.E. Havenga, Stuart A. Nicklin, Andrew H. Baker

Research output: Contribution to journal › Article › peer-review

470 Scopus citations

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.

Original language	English (US)
Pages (from-to)	397-409
Number of pages	13
Journal	Cell
Volume	132
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2008.01.016
State	Published - Feb 8 2008
Externally published	Yes

Keywords

HUMDISEASE
MICROBIO

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2008.01.016

Cite this

Waddington, S. N., McVey, J. H., Bhella, D., Parker, A. L., Barker, K., Atoda, H., Pink, R., Buckley, S. M. K., Greig, J. A., Denby, L., Custers, J., Morita, T., Francischetti, I. M. B., Monteiro, R. Q., Barouch, D. H., van Rooijen, N., Napoli, C., Havenga, M. J. E., Nicklin, S. A., & Baker, A. H. (2008). Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer. Cell, 132(3), 397-409. https://doi.org/10.1016/j.cell.2008.01.016

Waddington, SN, McVey, JH, Bhella, D, Parker, AL, Barker, K, Atoda, H, Pink, R, Buckley, SMK, Greig, JA, Denby, L, Custers, J, Morita, T, Francischetti, IMB, Monteiro, RQ, Barouch, DH, van Rooijen, N, Napoli, C, Havenga, MJE, Nicklin, SA & Baker, AH 2008, 'Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer', Cell, vol. 132, no. 3, pp. 397-409. https://doi.org/10.1016/j.cell.2008.01.016

@article{1ccda9e8b7934cfdbb2247def5c027d3,

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.",

keywords = "HUMDISEASE, MICROBIO",

author = "Waddington, {Simon N.} and McVey, {John H.} and David Bhella and Parker, {Alan L.} and Kristeen Barker and Hideko Atoda and Rebecca Pink and Buckley, {Suzanne M.K.} and Greig, {Jenny A.} and Laura Denby and Jerome Custers and Takashi Morita and Francischetti, {Ivo M.B.} and Monteiro, {Robson Q.} and Barouch, {Dan H.} and {van Rooijen}, Nico and Claudio Napoli and Havenga, {Menzo J.E.} and Nicklin, {Stuart A.} and Baker, {Andrew H.}",

note = "Funding Information: We thank Erguang Li for the plasmids to make Ad5-21R and Ad5-7.5R, Linda Klavinskis for CD46 transgenic mice, and Dan Johnson for the EGF2-SP FX. We thank Professor Charles Coutelle for helpful discussions. We thank Nicola Britton and Gregor Aitchison for technical support and Lennart Holterman for virus production. Gary Childs and staff provided valuable technical support for in vivo studies. Professor Gadi Frankel and Siouxsie Wiles (Imperial College London) provided training and access to the Xenogen equipment. This work was supported by the European Commission, the Biotechnology and Biophysical Research Council, and British Heart Foundation. Haemostasis and Thrombosis are supported by the Medical Research Council. A.L.P. is funded by a Personal Research Fellowship from the Caledonian Research Foundation. S.W. is a recipient of the Philip Gray Fellowship, Katharine Dormandy Trust. ",

year = "2008",

month = feb,

day = "8",

doi = "10.1016/j.cell.2008.01.016",

language = "English (US)",

volume = "132",

pages = "397--409",

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TY - JOUR

T1 - Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer

AU - Waddington, Simon N.

AU - McVey, John H.

AU - Bhella, David

AU - Parker, Alan L.

AU - Barker, Kristeen

AU - Atoda, Hideko

AU - Pink, Rebecca

AU - Buckley, Suzanne M.K.

AU - Greig, Jenny A.

AU - Denby, Laura

AU - Custers, Jerome

AU - Morita, Takashi

AU - Francischetti, Ivo M.B.

AU - Monteiro, Robson Q.

AU - Barouch, Dan H.

AU - van Rooijen, Nico

AU - Napoli, Claudio

AU - Havenga, Menzo J.E.

AU - Nicklin, Stuart A.

AU - Baker, Andrew H.

N1 - Funding Information: We thank Erguang Li for the plasmids to make Ad5-21R and Ad5-7.5R, Linda Klavinskis for CD46 transgenic mice, and Dan Johnson for the EGF2-SP FX. We thank Professor Charles Coutelle for helpful discussions. We thank Nicola Britton and Gregor Aitchison for technical support and Lennart Holterman for virus production. Gary Childs and staff provided valuable technical support for in vivo studies. Professor Gadi Frankel and Siouxsie Wiles (Imperial College London) provided training and access to the Xenogen equipment. This work was supported by the European Commission, the Biotechnology and Biophysical Research Council, and British Heart Foundation. Haemostasis and Thrombosis are supported by the Medical Research Council. A.L.P. is funded by a Personal Research Fellowship from the Caledonian Research Foundation. S.W. is a recipient of the Philip Gray Fellowship, Katharine Dormandy Trust.

PY - 2008/2/8

Y1 - 2008/2/8

N2 - 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.

AB - 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.

KW - HUMDISEASE

KW - MICROBIO

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UR - http://www.scopus.com/inward/citedby.url?scp=38849134279&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2008.01.016

DO - 10.1016/j.cell.2008.01.016

M3 - Article

C2 - 18267072

AN - SCOPUS:38849134279

SN - 0092-8674

VL - 132

SP - 397

EP - 409

JO - Cell

JF - Cell

IS - 3

ER -

Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer

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