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.

  • Original Article
  • Published:

Herpes simplex virus 1 recombinant virions exhibiting the amino terminal fragment of urokinase-type plasminogen activator can enter cells via the cognate receptor

Gene Therapy volume 13, pages 621–629 (2006)Cite this article

Abstract

Earlier this laboratory constructed a herpes simplex virus 1 recombinant (R5111) that carries a IL13 ligand inserted into glycoprotein D and can enter cells via the IL13Rα2 receptor commonly expressed on the surface of malignant glioma cells. In this report, we describe the properties of two recombinant viruses carrying chiemric gD genes. In R5181 recombinant virus the chimeric gene consisted on the residues 20–155 of urokinase plaminogen activator (uPA) inserted between residues 24 and 25 of gD. In R5182 the insert consisted of a 23-residue sequence encoding the uPA binding domain for the urokinase plaminogen activator receptor (uPAR). These viruses were constructed for three reasons, to increase the number of viruses that specifically target receptors on the surface of malignant glioma cells, to determine whether viruses exhibiting novel ligands could enter cells via receptors anchored to the cell surface via glycosylphosphatidylinositol anchor as has been recently demonstrated for nectin1, and to determine whether receptors other than IL13Rα2 could be targeted by genetic engineering of the virus. We report that R5181 but not R5182 recombinant virus was able to enter cells expressing uPAR. The results indicate that HSV-1 recombinant viruses can be engineered to enter cells via a variety of unrelated nonviral receptors, including receptors that are anchored to the cells surface but without transmembrane domains.

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 2
Figure 3
Figure 1
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  1. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Therapy 2000; 10: 867–874.

    Article  Google Scholar 

  2. Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Therapy 2000; 7: 859–866.

    Article  CAS  PubMed  Google Scholar 

  3. Roizman B, Knipe DM . Herpes simplex viruses and their replication. In: Knipe DM, Howley P, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (eds). Fields Virology, 4th edn. Lippincott Williams & Wilkins: New York, 2001, pp 2399–2459.

    Google Scholar 

  4. Zhou G, Ye GJ, Debinski W, Roizman B . Engineered herpes simplex virus 1 is dependent on IL13Ralpha 2 receptor for cell entry and independent of glycoprotein D receptor interaction. Proc Natl Acad Sci USA 2002; 99: 15124–15129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Laquerre S, Argnani R, Anderson DB, Zucchini S, Manservigi R, Glorioso JC . Heparan sulfate proteoglycan binding by herpes simplex virus type 1 glycoproteins B and C, which differ in their contributions to virus attachment, penetration, and cell-to-cell spread. J Virol 1998; 72: 6119–6130.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhou G, Roizman B . Characterization of a recombinant herpes simplex virus 1 designed to enter cells via the IL13Ralpha2 receptor of malignant glioma cells. J Virol 2005; 79: 5272–5277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gianni T, Campadelli-Fiume G, Menotti L . Entry of herpes simplex virus mediated by chimeric forms of nectin1 retargeted to endosomes or to lipid rafts occurs through acidic endosomes. J Virol 2004; 78: 12268–12276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gladson CL, Pijuan-Thompson V, Olman MA, Gillespie GY, Yocoub IZ . Up-regulation of urokinase and urokinase receptor genes in malignant astrocytoma. Am J Pathol 1995; 146: 1150–1160.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Yamamoto M, Sawaya R, Mohanam S, Rao VH, Bruner JM, Nicholson GL et al. Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res 1994; 54: 5016–5020.

    CAS  PubMed  Google Scholar 

  10. Ploug M, Ronne E, Behrendt N, Jensen AL, Blasi F, Dano K . Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem 1991; 266: 1926–1933.

    CAS  PubMed  Google Scholar 

  11. Moller JV, le Maire M . Detergent binding as a measure of hydrophobic surface area of integral membrane proteins. Biol Chem 1993; 268: 18659–18672.

    CAS  Google Scholar 

  12. Cantero D, Friess H, Deflorin J, Zimmermann A, Brundler MA, Riesle E et al. Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer 1997; 75: 388–395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhou G, Roizman B . The domains of glycoprotein D required to block apoptosis depend on whether glycoprotein D is present in the virions carrying herpes simplex virus 1 genome lacking the gene encoding the glycoprotein. J Virol 2001; 75: 6166–6172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nelles L, Lijnen HR, Collen D, Holmes WEJ . Characterization of recombinant human single chain urokinase-type plasminogen activator mutants produced by site-specific mutagenesis of lysine 158. J Biol Chem 1987; 262: 5682–5689.

    CAS  PubMed  Google Scholar 

  15. Wei Y, Waltz DA, Rao N, Drummond RJ, Rosenberg S, Chapman HA . Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem 1994; 269: 32380–32388.

    CAS  PubMed  Google Scholar 

  16. Roller RJ, Roizman B . The herpes simplex virus 1 RNA binding protein US11 is a virion component and associates with ribosomal 60S subunits. J Virol 1992; 66: 3624–3632.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Reuning U, Magdolen V, Wilhelm O, Fischer K, Lutz V, Graeff H et al. Multifunctional potential of the plasminogen activation system in tumor invasion and metastasis (review). Int J Oncol 1998; 13: 893–906.

    CAS  PubMed  Google Scholar 

  18. Fowler B, Mackman N, Parmer RJ, Miles LA . Binding of human single chain urokinase to Chinese Hamster Ovary cells and cloning of hamster u-PAR. Thromb Haemost 1998; 80: 148–154.

    Article  CAS  PubMed  Google Scholar 

  19. Roldan AL, Cubellis MV, Masucci MT, Behrendt N, Lund LR, Dano K et al. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J 1990; 9: 467–474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Englund PT . The structure and biosynthesis of glycosyl phosphatidylinositol protein anchors. Annu Rev Biochem 1993; 62: 121–138.

    Article  CAS  PubMed  Google Scholar 

  21. Barnathan ES, Kuo A, Rosenfeld L, Kariko K, Leski M, Robbiati F et al. Interaction of single-chain urokinase-type plasminogen activator with human endothelial cells. J Biol Chem 1990; 265: 2865–2872.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr G Campadelli Frume for the J1.1, J-HveA and J-Nectin cell line, Dr DA Dichek for the pULscuPA plasmids and Dr HA Chapman for the plasmids containing a human uPAR cDNA, respectively. The studies conducted at the University of Chicago were aided by National Cancer Institute Grants CA CA87661, CA83939, CA71933, CA78766, and CA88860. HK was the recipient of a JHIF Scholarship Award.

Author information

Authors and Affiliations

  1. The Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, Chicago, IL, USA

    H Kamiyama, G Zhou & B Roizman

Authors
  1. H Kamiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Roizman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Roizman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kamiyama, H., Zhou, G. & Roizman, B. Herpes simplex virus 1 recombinant virions exhibiting the amino terminal fragment of urokinase-type plasminogen activator can enter cells via the cognate receptor. Gene Ther 13, 621–629 (2006). https://doi.org/10.1038/sj.gt.3302685

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302685

Keywords

This article is cited by

Search

Advanced search

Quick links