Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors

Gene Therapy volume 8, pages 1347–1353 (2001)Cite this article

Abstract

Intravenous administration of adenoviral vectors results mostly in hepatocyte transduction and subsequent hepatotoxicity. Because hepatocytes express high levels of the primary adenovirus receptor CAR, untargeting hepatocytes requires CAR-binding ablation. The amino acid residues of the viral fiber responsible for CAR-binding are known. We have constructed a mutant adenoviral vector unable to bind CAR and studied vector biodistribution and hepatotoxicity after intravenous administration. In contrast to a vector with wild-type fiber, the infectivity of the CAR-ablated vector is greatly reduced and not susceptible to inhibition with wild-type knob. Biodistribution and hepatotoxicity are, however, not affected by CAR-binding ablation. A possible explanation could be related to an increased blood persistence detected for the CAR-ablated vectors combined with their residual infectivity through other receptors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Muruve DA, Barnes MJ, Stillman IE, Libermann TA . Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo Hum Gene Ther 1999 10: 965–976

    Article  CAS  PubMed  Google Scholar 

  2. Dmitriev I et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism J Virol 1998 72: 9706–9713

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Haisma HJ et al. Targeting of adenoviral vectors through a bispecific single-chain antibody Cancer Gene Ther 2000 7: 901–904

    Article  CAS  PubMed  Google Scholar 

  4. Wickham TJ . Targeting adenovirus Gene Therapy 2000 7: 110–114

    Article  CAS  PubMed  Google Scholar 

  5. Roelvink PW et al. Identification of a conserved receptor-binding site on the fiber proteins of CAR-recognizing adenoviridae Science 1999 286: 1568–1571

    Article  CAS  PubMed  Google Scholar 

  6. Fechner H et al. Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers Gene Therapy 1999 6: 1520–1535

    Article  CAS  PubMed  Google Scholar 

  7. Alemany R, Suzuki K, Curiel DT . Blood clearance rates of adenovirus type 5 in mice J Gen Virol 2000 81: 2605–2609

    Article  CAS  PubMed  Google Scholar 

  8. Douglas JT et al. A system for the propagation of adenoviral vectors with genetically modified receptor specificities Nat Biotechnol 1999 17: 470–475

    Article  CAS  PubMed  Google Scholar 

  9. Legrand V et al. Fiberless recombinant adenoviruses: virus maturation and infectivity in the absence of fiber J Virol 1999 73: 907–919

    CAS  PubMed  PubMed Central  Google Scholar 

  10. O'Carroll SJ et al. Quantifying adenoviral titers by spectrophotometry Biotechniques 2000 28: 408–410, 412

    Article  CAS  PubMed  Google Scholar 

  11. Mittereder N, March KL, Trapnell BC . Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy J Virol 1996 70: 7498–7509

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hong SS et al. Adenovirus type 5 fiber knob binds to MHC class I alpha2 domain at the surface of human epithelial and B lymphoblastoid cells EMBO J 1997 16: 2294–2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dechecchi MC, Tamanini A, Bonizzato A, Cabrini G . Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions Virology 2000 268: 382–390

    Article  CAS  PubMed  Google Scholar 

  14. Paielli DL et al. Evaluation of the biodistribution, persistence, toxicity, and potential of germ line transmission of a replication-competent human adenovirus following intraprostatic administration in the mouse Mol Ther 2000 1: 263–274

    Article  CAS  PubMed  Google Scholar 

  15. Christ M et al. Modulation of the inflammatory properties and hepatotoxicity of recombinant adenovirus vectors by the viral E4 gene products Hum Gene Ther 2000 11: 415–427

    Article  CAS  PubMed  Google Scholar 

  16. Worgall S, Wolff G, Falck-Pedersen E, Crystal RG . Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration Hum Gene Ther 1997 8: 37–44

    Article  CAS  PubMed  Google Scholar 

  17. Huard J et al. The route of administration is a major determinant of the transduction efficiency of rat tissues by adenoviral recombinants Gene Therapy 1995 2: 107–115

    CAS  PubMed  Google Scholar 

  18. Wood M et al. Biodistribution of an adenoviral vector carrying the luciferase reporter gene following intravesical or intravenous administration to a mouse Cancer Gene Ther 1999 6: 367–372

    Article  CAS  PubMed  Google Scholar 

  19. Walter I et al. Rapid and sensitive detection of enhanced green fluorescent protein expression in paraffin sections by confocal laser scanning microscopy Histochem J 2000 32: 99–103

    Article  CAS  PubMed  Google Scholar 

  20. Tao N et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver Mol Ther 2001 3: 28–35

    Article  CAS  PubMed  Google Scholar 

  21. Hegenbarth S et al. Liver sinusoidal endothelial cells are not permissive for adenovirus type 5 Hum Gene Ther 2000 11: 481–486

    Article  CAS  PubMed  Google Scholar 

  22. Lieber A et al. The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors J Virol 1997 71: 8798–8807

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zsengeller Z et al. Internalization of adenovirus by alveolar macrophages initiates early proinflammatory signaling during acute respiratory tract infection J Virol 2000 74: 9655–9667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dmitriev I et al. Ectodomain of coxsackievirus and adenovirus receptor genetically fused to epidermal growth factor mediates adenovirus targeting to epidermal growth factor receptor-positive cells J Virol 2000 74: 6875–6884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are indebted to Joanne Douglas, Toshiro Seki, Igor Dmitriev, and Victor Krasnykh for providing valuable material. We are grateful to Baogen Lu and Kaori Suzuki for technical assistance. We thank Cristina Balague for critical reading of the manuscript and Paul Reynolds for helpful discussions. This work was supported by grants R01 HL50255, R01 CA74242, R01 CA83821, R01 CA8688–01, N01 CO-97110, P50 CA83591, P50 CA89019, U19 DK57858, and the Juvenile Diabetes Foundation.

Author information

Authors and Affiliations

  1. Division of Human Gene Therapy, Department of Medicine, Pathology and Surgery, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA

    R Alemany & DT Curiel

Authors
  1. R Alemany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. DT Curiel
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alemany, R., Curiel, D. CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors. Gene Ther 8, 1347–1353 (2001). https://doi.org/10.1038/sj.gt.3301515

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301515

Keywords

This article is cited by

Search

Advanced search

Quick links