Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1

Abstract

The importance of herpes simplex viruses (HSV) as human pathogens and the emerging prospect of using mutant derivatives of HSV-1 as potential anti-cancer therapeutics have necessitated a thorough investigation into the molecular basis of host-cell permissiveness to HSV. Here we show that NIH-3T3 cells transformed with the oncogenes v-erbB, activated sos or activated ras become significantly more permissive to HSV-1. Inhibitors of the Ras signalling pathway, such as farnesyl transferase inhibitor 1 and PD98059, effectively suppressed HSV-1 infection of ras-transformed cells. Enhanced permissiveness of the transformed cells was linked to the inhibition of virus-induced activation (phosphorylation) of the double-stranded RNA-activated protein kinase (PKR), thereby allowing viral transcripts to be translated in these cells. An HSV-1-derived oncolytic mutant, R3616, was also found to infect preferentially both transformed cells and PKR/ (but not PKR+/+) mouse embryo fibroblasts. These observations suggest that HSV-1 specifically targets cells with an activated Ras signalling pathway, and have important ramifications in the use of engineered HSV in cancer therapy, the development of strategies against HSV infections, and the controversial role of HSV in human cancers.

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Figure 1: Effect of various oncogenes (v-erbB, activated sos, activated ras) on host-cell permissiveness to HSV-1 infection.
Figure 2: Effect of various Ras pathway inhibitors on HSV-1 infection in H-ras cells.
Figure 3: HSV-1-specific RT–PCR products in infected NIH-3T3 cells and H-ras cells.
Figure 4: Host-cell permissiveness to HSV-1 is linked to PKR phosphorylation status on infection.
Figure 5: Infection of transformed cell lines and PKR+/+ and PKR−/− mouse embryo fibroblasts by HSV-1 and R3616.
Figure 6: Involvement of Ras in the determination of host-cell permissiveness to viruses.

References

  1. 1

    Whitley, R. J., Kimberlin, D. W. & Roizman, B. Clin. Infect. Dis. 26, 541–555 (1998).

    CAS  Article  Google Scholar 

  2. 2

    Markert, J. M. et al. Rev. Med. Virol. 10, 17–30 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Andreansky, S. S. et al. Cancer Res. 57, 1502–1509 (1997).

    CAS  Google Scholar 

  4. 4

    Yazaki, T., Manz, H. J., Rabkin, S. D. & Martuza, R. L. Cancer Res. 55, 4752–4756 (1995).

    CAS  Google Scholar 

  5. 5

    Oyama, M. et al. Hum. Gene Ther. 10, 1683–1693 (2000).

    Article  Google Scholar 

  6. 6

    Coukos, G. et al. Cancer Gene Ther. 7, 275–283 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Sundaresan, P., Hunter, W. D., Martuza, R. L. & Rabkin, S. D. J. Virol. 74, 3832–3841 (2000).

    CAS  Article  Google Scholar 

  8. 8

    Markert, J. M. et al. Gene Ther. 7, 867–874 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Shields, J. M., Pruitt, K., McFall, A., Shaub, A. & Der C. J. Trends Cell Biol. 10, 147–154 (2000).

    CAS  Article  Google Scholar 

  10. 10

    Gibbs, J. B. et al. Curr. Opin. Chem. Biol. 1, 197–203 (1997).

    CAS  Article  Google Scholar 

  11. 11

    Garrington, T. P. & Johnson, G. L. Curr. Opin. Cell Biol. 11, 211–218 (1999).

    CAS  Article  Google Scholar 

  12. 12

    Roovers, K. & Assoian, R. K. BioEssays 22, 818–826 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J. & Saltiel, A. R. Proc. Natl Acad. Sci. USA 92, 7686–7689 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Cuenda, A. et al. FEBS Lett. 364, 229–233 (1995).

    CAS  Article  Google Scholar 

  15. 15

    Dong, Z., Huang, C. & Ma, W. Y. Anticancer Res. 19, 3743–3747 (1999).

    CAS  Google Scholar 

  16. 16

    Nakamura, I. et al. J. Cell Physiol. 172, 230–239 (1997).

    CAS  Article  Google Scholar 

  17. 17

    White, M. A. et al. Cell 24, 533–541 (1995).

    Article  Google Scholar 

  18. 18

    Khosravi-Far, R. et al. Mol. Cell Biol. 16, 3923–3933 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Webb, C. P., Van Aelst, L., Wigler, M. H. & Woude, G. F Proc. Natl Acad. Sci. USA 21, 8773–8778 (1998).

    Article  Google Scholar 

  20. 20

    Roizman, B. & Sears. A. E. in Fields Virology (eds Fields, B. N., Knipe, D. M. & Howley, P. M.) 2231–2295 (Lippincott-Raven, Philadelphia, 1996).

    Google Scholar 

  21. 21

    Williams, B. R. Oncogene 18, 6112–6120 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Clemens, M. J. & Elia, A. J. Interferon Cytokine Res. 17, 503–524 (1997).

    CAS  Article  Google Scholar 

  23. 23

    Andreansky, S. S. et al. Proc. Natl Acad. Sci. USA 93, 11313–11318 (1996).

    CAS  Article  Google Scholar 

  24. 24

    He, B., Gross, M. & Roizman, B. Proc. Natl Acad. Sci. USA 94, 843–848 (1997).

    CAS  Article  Google Scholar 

  25. 25

    Slamon, D. J. & Cline, M. J. Proc. Natl Acad. Sci. USA 81, 7141–7155 (1984).

    CAS  Article  Google Scholar 

  26. 26

    Strong, J. E., Coffey, M. C., Tang, D., Sabinin, P. & Lee, P. W. K. EMBO J. 17, 3351–3362 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Coffey, M. C., Strong, J. E., Forsyth, P. A. & Lee, P. W. K. Science 282, 1332–1334 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Jones, C. Clin. Microbiol. Rev. 8, 549–556 (1995).

    CAS  Article  Google Scholar 

  29. 29

    Helbing, C. C., Veillette, C., Riabowol, K., Johnston, R. N. & Garkavtsev, I. Cancer Res. 57, 1255–1258 (1997).

    CAS  Google Scholar 

  30. 30

    Chou, J., Kern, E. R., Whitley, R. J. & Roizman, B. Science 250, 1262–1266 (1990).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank B. Roizman for the HSV-1 (strain F) and mutant R3616; D. Faller for the NIH-3T3 and H-ras-transformed cells; M. Karin for sos-transformed cells (TNIH#5); H.-J. Kung for THC-11 cells; B. Williams for the PKR/ and PKR+/+ mouse embryo fibroblasts; R. N. Johnston for NIH3T3 c-myc cells; C. P. Webb for Ras effector domain mutant cell lines; P. Olivo for the anti-ICP8 antibody; K. M. Lee and K. Fonseca for assistance with immunofluorescence studies; and W. Yong, F. Yong, M. Schultz and D. Bazett-Jones for assistance with microscopy. This work was supported by the Canadian Institutes of Health Research (P.W.K.L.). F.F. is a recipient of a Studentship from the Canadian Institutes of Health Research.

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Correspondence to Patrick W. K. Lee.

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Farassati, F., Yang, AD. & Lee, P. Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1. Nat Cell Biol 3, 745–750 (2001). https://doi.org/10.1038/35087061

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