Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo

O. Kalyuzhniy, N. C. Di Paolo, M. Silvestry, S. E. Hofherr, Michael A Barry, P. L. Stewart, D. M. Shayakhmetov

Research output: Contribution to journalArticle

245 Citations (Scopus)

Abstract

Human species C adenovirus serotype 5 (Ad5) is the most common viral vector used in clinical studies worldwide. Ad5 vectors infect liver cells in vivo with high efficiency via a poorly defined mechanism, which involves virus binding to vitamin K-dependent blood coagulation factors. Here, we report that the major Ad5 capsid protein, hexon, binds human coagulation factor X (FX) with an affinity of 229 pM. This affinity is 40-fold stronger than the reported affinity of Ad5 fiber for the cellular receptor coxsackievirus and adenovirus receptor, CAR. Cryoelectron microscopy and single-particle image reconstruction revealed that the FX attachment site is localized to the central depression at the top of the hexon trimer. Hexon-mutated virus bearing a large insertion in hexon showed markedly reduced FX binding in vitro and failed to deliver a transgene to hepatocytes in vivo. This study describes the mechanism of FX binding to Ad5 and demonstrates the critical role of hexon for virus infection of hepatocytes in vivo.

Original languageEnglish (US)
Pages (from-to)5483-5488
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number14
DOIs
StatePublished - Apr 8 2008

Fingerprint

Virus Diseases
Factor X
Adenoviridae
Hepatocytes
Cryoelectron Microscopy
Virus Attachment
Blood Coagulation Factors
Computer-Assisted Image Processing
Vitamin K
Enterovirus
Capsid Proteins
Transgenes
Serogroup
Viruses
Liver

Keywords

  • Gene transfer
  • Virus targeting

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo. / Kalyuzhniy, O.; Di Paolo, N. C.; Silvestry, M.; Hofherr, S. E.; Barry, Michael A; Stewart, P. L.; Shayakhmetov, D. M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 14, 08.04.2008, p. 5483-5488.

Research output: Contribution to journalArticle

Kalyuzhniy, O. ; Di Paolo, N. C. ; Silvestry, M. ; Hofherr, S. E. ; Barry, Michael A ; Stewart, P. L. ; Shayakhmetov, D. M. / Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 14. pp. 5483-5488.
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AU - Barry, Michael A

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