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Author Notes:

Address correspondence to Harvey R. Herschman, hherschman@mednet.ucla.edu.

We thank Jose S. Gil (UCLA) for help with the real-time PCR protocols for viral genome copies and Ding Xu (UCSD) for help with heparan sulfate analysis. We also thank Sotirios Tetradis (UCLA) for helpful comments on the manuscript and experimental design.

We declare no conflict of interest.

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Subjects:

Research Funding:

This work was supported by NIH grants P50 CA086306-08 (H.R.H.) and GM33063 and HL107150 (J.D.E.).

A.K.Z. is the recipient of an American Society of Hematology (ASH) Scholar Award.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Virology
  • GENE-TRANSFER
  • FACTOR-X
  • PROTEOGLYCAN BINDING
  • AMINO-ACIDS
  • RECEPTOR
  • IDENTIFICATION
  • HEXON
  • EXPRESSION
  • INFECTION
  • THERAPY

Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

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Journal Title:

Journal of Virology

Volume:

Volume 90, Number 1

Publisher:

, Pages 412-420

Type of Work:

Article | Final Publisher PDF

Abstract:

Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) are promising gene therapy vectors. Both display liver tropism and are currently thought to enter hepatocytes in vivo through cell surface heparan sulfate proteoglycans (HSPGs). To test directly this hypothesis, we created mice that lack Ext1, an enzyme required for heparan sulfate biosynthesis, in hepatocytes. Ext1HEP mutant mice exhibit an 8-fold reduction of heparan sulfate in primary hepatocytes and a 5-fold reduction of heparan sulfate in whole liver tissue. Conditional hepatocyte Ext1 gene deletion greatly reduced AAV2 liver transduction following intravenous injection. Ad5 transduction requires blood coagulation factor X (FX); FX binds to the Ad5 capsid hexon protein and bridges the virus to HSPGs on the cell surface. Ad5.FX transduction was abrogated in primary hepatocytes from Ext1HEP mice. However, in contrast to the case with AAV2, Ad5 transduction was not significantly reduced in the livers of Ext1HEP mice. FX remained essential for Ad5 transduction in vivo in Ext1HEP mice. We conclude that while AAV2 requires HSPGs for entry into mouse hepatocytes, HSPGs are dispensable for Ad5 hepatocyte transduction in vivo. This study reopens the question of how adenovirus enters cells in vivo.

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© 2015, American Society for Microbiology. All Rights Reserved.

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