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 journalArticle

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 languageEnglish
Pages (from-to)397-409
Number of pages13
JournalCell
Volume132
Issue number3
DOIs
Publication statusPublished - Feb 8 2008

Keywords

  • HUMDISEASE
  • MICROBIO

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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  • 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