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

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

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
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
Publication status	Published - Feb 8 2008

Keywords

HUMDISEASE
MICROBIO

ASJC Scopus subject areas

Cell Biology
Molecular Biology

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10.1016/j.cell.2008.01.016

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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

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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.",

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AU - Waddington, Simon N.

AU - McVey, John H.

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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.

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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.

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Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer

Abstract

Keywords

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