1887

Abstract

Liver tropism hampers systemic administration of adenovirus in gene therapy and virotherapy. In consequence, tumour targeting requires the combination of capsid modifications that abrogate liver transduction and redirect adenoviral vectors to tumour cells. Coxsackievirus and adenovirus receptor (CAR), integrins and heparan sulfate glycosaminoglycans (HSG) are receptors involved in adenovirus type 5 (Ad5) entry into cells. The and properties of Ad5 vectors unable to bind CAR, integrins and HSG with and without Arg–Gly–Asp (RGD) inserted at the HI loop of the fiber were studied. As was previously observed with CAR-ablated vectors, CAR and integrin double binding-ablated vectors transduced hepatocytes less efficiently but not . On the contrary, the role of HSG on Ad5 infectivity was evident only when CAR binding was abrogated, but the shaft mutation that ablated HSG binding on the background of a normal capsid was sufficient to abrogate liver transduction . The insertion of amino acids RGD at the HI loop in a shaft-mutated fiber only partially rescued integrin-mediated infectivity. These results indicate that the shaft mutation precluded HSG binding and affected the structure of the fiber. The insertion of ligands at the hexon or protein IX may be required to benefit from the fiber shaft mutation-detargeting properties.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.81889-0
2006-09-01
2019-11-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/87/9/2487.html?itemId=/content/journal/jgv/10.1099/vir.0.81889-0&mimeType=html&fmt=ahah

References

  1. Alemany, R. & Curiel, D. T. ( 2001; ). CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors. Gene Ther 8, 1347–1353.[CrossRef]
    [Google Scholar]
  2. Alemany, R., Balague, C. & Curiel, D. T. ( 2000a; ). Replicative adenoviruses for cancer therapy. Nat Biotechnol 18, 723–727.[CrossRef]
    [Google Scholar]
  3. Alemany, R., Suzuki, K. & Curiel, D. T. ( 2000b; ). Blood clearance rates of adenovirus type 5 in mice. J Gen Virol 81, 2605–2609.
    [Google Scholar]
  4. Bergelson, J. M., Cunningham, J. A., Droguett, G., Kurt-Jones, E. A., Krithivas, A., Hong, J. S., Horwitz, M. S., Crowell, R. L. & Finberg, R. W. ( 1997; ). Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323.[CrossRef]
    [Google Scholar]
  5. Dechecchi, M. C., Tamanini, A., Bonizzato, A. & Cabrini, G. ( 2000; ). Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions. Virology 268, 382–390.[CrossRef]
    [Google Scholar]
  6. Dechecchi, M. C., Melotti, P., Bonizzato, A., Santacatterina, M., Chilosi, M. & Cabrini, G. ( 2001; ). Heparan sulfate glycosaminoglycans are receptors sufficient to mediate the initial binding of adenovirus types 2 and 5. J Virol 75, 8772–8780.[CrossRef]
    [Google Scholar]
  7. Dmitriev, I., Krasnykh, V., Miller, C. R., Wang, M., Kashentseva, E., Mikheeva, G., Belousova, N. & Curiel, D. T. ( 1998; ). An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol 72, 9706–9713.
    [Google Scholar]
  8. Douglas, J. T., Miller, C. R., Kim, M., Dmitriev, I., Mikheeva, G., Krasnykh, V. & Curiel, D. T. ( 1999; ). A system for the propagation of adenoviral vectors with genetically modified receptor specificities. Nat Biotechnol 17, 470–475.[CrossRef]
    [Google Scholar]
  9. Einfeld, D. A., Schroeder, R., Roelvink, P. W., Lizonova, A., King, C. R., Kovesdi, I. & Wickham, T. J. ( 2001; ). Reducing the native tropism of adenovirus vectors requires removal of both CAR and integrin interactions. J Virol 75, 11284–11291.[CrossRef]
    [Google Scholar]
  10. Grompe, M., Jones, S. N., Loulseged, H. & Caskey, C. T. ( 1992; ). Retroviral-mediated gene transfer of human ornithine transcarbamylase into primary hepatocytes of spf and spf-ash mice. Hum Gene Ther 3, 35–44.[CrossRef]
    [Google Scholar]
  11. He, T. C., Zhou, S., da Costa, L. T., Yu, J., Kinzler, K. W. & Vogelstein, B. ( 1998; ). A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A 95, 2509–2514.[CrossRef]
    [Google Scholar]
  12. Krasnykh, V., Dmitriev, I., Mikheeva, G., Miller, C. R., Belousova, N. & Curiel, D. T. ( 1998; ). Characterization of an adenovirus vector containing a heterologous peptide epitope in the HI loop of the fiber knob. J Virol 72, 1844–1852.
    [Google Scholar]
  13. Leissner, P., Legrand, V., Schlesinger, Y., Hadji, D. A., van Raaij, M., Cusack, S., Pavirani, A. & Mehtali, M. ( 2001; ). Influence of adenoviral fiber mutations on viral encapsidation, infectivity and in vivo tropism. Gene Ther 8, 49–57.[CrossRef]
    [Google Scholar]
  14. Martin, K., Brie, A., Saulnier, P., Perricaudet, M., Yeh, P. & Vigne, E. ( 2003; ). Simultaneous CAR- and α V integrin-binding ablation fails to reduce Ad5 liver tropism. Mol Ther 8, 485–494.[CrossRef]
    [Google Scholar]
  15. Mizuguchi, H., Koizumi, N., Hosono, T., Ishii-Watabe, A., Uchida, E., Utoguchi, N., Watanabe, Y. & Hayakawa, T. ( 2002; ). CAR- or αv integrin-binding ablated adenovirus vectors, but not fiber-modified vectors containing RGD peptide, do not change the systemic gene transfer properties in mice. Gene Ther 9, 769–776.[CrossRef]
    [Google Scholar]
  16. Nemerow, G. R. & Stewart, P. L. ( 1999; ). Role of α V integrins in adenovirus cell entry and gene delivery. Microbiol Mol Biol Rev 63, 725–734.
    [Google Scholar]
  17. Nettelbeck, D. M., Rivera, A. A., Kupsch, J., Dieckmann, D., Douglas, J. T., Kontermann, R. E., Alemany, R. & Curiel, D. T. ( 2004; ). Retargeting of adenoviral infection to melanoma: combining genetic ablation of native tropism with a recombinant bispecific single-chain diabody (scDb) adapter that binds to fiber knob and HMWMAA. Int J Cancer 108, 136–145.[CrossRef]
    [Google Scholar]
  18. Nicol, C. G., Graham, D., Miller, W. H., White, S. J., Smith, T. A., Nicklin, S. A., Stevenson, S. C. & Baker, A. H. ( 2004; ). Effect of adenovirus serotype 5 fiber and penton modifications on in vivo tropism in rats. Mol Ther 10, 344–354.[CrossRef]
    [Google Scholar]
  19. Reynolds, P., Dmitriev, I. & Curiel, D. ( 1999; ). Insertion of an RGD motif into the HI loop of adenovirus fiber protein alters the distribution of transgene expression of the systemically administered vector. Gene Ther 6, 1336–1339.[CrossRef]
    [Google Scholar]
  20. Roelvink, P. W., Mi Lee, G., Einfeld, D. A., Kovesdi, I. & Wickham, T. J. (1999; ). Identification of a conserved receptor-binding site on the fiber proteins of CAR-recognizing Adenoviridae. Science 286, 1568–1571.[CrossRef]
    [Google Scholar]
  21. Rostand, K. S. & Esko, J. D. ( 1997; ). Microbial adherence to and invasion through proteoglycans. Infect Immun 65, 1–8.
    [Google Scholar]
  22. Shayakhmetov, D. M., Li, Z. Y., Ni, S. & Lieber, A. ( 2004; ). Analysis of adenovirus sequestration in the liver, transduction of hepatic cells, and innate toxicity after injection of fiber-modified vectors. J Virol 78, 5368–5381.[CrossRef]
    [Google Scholar]
  23. Smith, T., Idamakanti, N., Kylefjord, H., Rollence, M., King, L., Kaloss, M., Kaleko, M. & Stevenson, S. C. ( 2002; ). In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus–adenovirus receptor. Mol Ther 5, 770–779.[CrossRef]
    [Google Scholar]
  24. Smith, T. A., Idamakanti, N., Marshall-Neff, J. & 12 other authors ( 2003a; ). Receptor interactions involved in adenoviral-mediated gene delivery after systemic administration in non-human primates. Hum Gene Ther 14, 1595–1604.[CrossRef]
    [Google Scholar]
  25. Smith, T. A., Idamakanti, N., Rollence, M. L., Marshall-Neff, J., Kim, J., Mulgrew, K., Nemerow, G. R., Kaleko, M. & Stevenson, S. C. ( 2003b; ). Adenovirus serotype 5 fiber shaft influences in vivo gene transfer in mice. Hum Gene Ther 14, 777–787.[CrossRef]
    [Google Scholar]
  26. van Raaij, M. J., Mitraki, A., Lavigne, G. & Cusack, S. ( 1999; ). A triple β-spiral in the adenovirus fibre shaft reveals a new structural motif for a fibrous protein. Nature 401, 935–938.[CrossRef]
    [Google Scholar]
  27. Vellinga, J., Rabelink, M. J., Cramer, S. J., van den Wollenberg, D. J., Van der Meulen, H., Leppard, K. N., Fallaux, F. J. & Hoeben, R. C. ( 2004; ). Spacers increase the accessibility of peptide ligands linked to the carboxyl terminus of adenovirus minor capsid protein IX. J Virol 78, 3470–3479.[CrossRef]
    [Google Scholar]
  28. Vigne, E., Mahfouz, I., Dedieu, J. F., Brie, A., Perricaudet, M. & Yeh, P. ( 1999; ). RGD inclusion in the hexon monomer provides adenovirus type 5-based vectors with a fiber knob-independent pathway for infection. J Virol 73, 5156–5161.
    [Google Scholar]
  29. Villanueva, A., Garcia, C., Paules, A. B. & 8 other authors ( 1998; ). Disruption of the antiproliferative TGF-β signaling pathways in human pancreatic cancer cells. Oncogene 17, 1969–1978.[CrossRef]
    [Google Scholar]
  30. Von Seggern, D. J., Kehler, J., Endo, R. I. & Nemerow, G. R. ( 1998; ). Complementation of a fibre mutant adenovirus by packaging cell lines stably expressing the adenovirus type 5 fibre protein. J Gen Virol 79, 1461–1468.
    [Google Scholar]
  31. Wickham, T. J., Mathias, P., Cheresh, D. A. & Nemerow, G. R. ( 1993; ). Integrins α V β 3 and α V β 5 promote adenovirus internalization but not virus attachment. Cell 73, 309–319.[CrossRef]
    [Google Scholar]
  32. Wu, E., Pache, L., Von Seggern, D. J., Mullen, T. M., Mikyas, Y., Stewart, P. L. & Nemerow, G. R. ( 2003; ). Flexibility of the adenovirus fiber is required for efficient receptor interaction. J Virol 77, 7225–7235.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.81889-0
Loading
/content/journal/jgv/10.1099/vir.0.81889-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error