1887

Abstract

The cytopathogenicity of vesicular stomatitis virus (VSV) has been attributed mainly to the host shut-off activity of the viral matrix (M) protein, which inhibits both nuclear transcription and nucleocytoplasmic RNA transport, thereby effectively suppressing the synthesis of type I interferon (IFN). The M protein from persistently VSV-infected cells was shown to harbour characteristic amino acid substitutions (M51R, V221F and S226R) implicated in IFN induction. This study demonstrates that infection of human fibroblasts with recombinant VSV containing the M51R substitution resulted in IFN induction, whereas neither the V221F nor the S226R substitution effected an IFN-inducing phenotype. Only when V221F was combined with S226R were the host shut-off activity of the M protein abolished and IFN induced, independently of M51R. The M33A substitution, previously implicated in VSV cytotoxicity, did not affect host shut-off activity. M-mutant VSV containing all four amino acid substitutions retained cytotoxic properties in both Vero cells and IFN-competent primary fibroblasts. Infected-cell death was associated with the formation of giant polynucleated cells, suggesting that the fusion activity of the VSV G protein was involved. Accordingly, M-mutant VSV expressing a fusion-defective G protein or with a deletion of the G gene showed significantly reduced cytotoxic properties and caused long-lasting infections in Vero cells and mouse hippocampal slice cultures. In contrast, a G-deleted VSV expressing wild-type M protein remained cytotoxic. These findings indicate that the host shut-off activity of the M protein dominates VSV cytotoxicty, whilst the fusion-active G protein is mainly responsible for the cytotoxicity remaining with M-mutant VSV.

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2010-11-01
2019-11-15
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References

  1. Ahmed, M. & Lyles, D. S. ( 1997; ). Identification of a consensus mutation in M protein of vesicular stomatitis virus from persistently infected cells that affects inhibition of host-directed gene expression. Virology 237, 378–388.[CrossRef]
    [Google Scholar]
  2. Ahmed, M. & Lyles, D. S. ( 1998; ). Effect of vesicular stomatitis virus matrix protein on transcription directed by host RNA polymerases I, II, and III. J Virol 72, 8413–8419.
    [Google Scholar]
  3. Ahmed, M., McKenzie, M. O., Puckett, S., Hojnacki, M., Poliquin, L. & Lyles, D. S. ( 2003; ). Ability of the matrix protein of vesicular stomatitis virus to suppress beta interferon gene expression is genetically correlated with the inhibition of host RNA and protein synthesis. J Virol 77, 4646–4657.[CrossRef]
    [Google Scholar]
  4. Barber, G. N. ( 2004; ). Vesicular stomatitis virus as an oncolytic vector. Viral Immunol 17, 516–527.[CrossRef]
    [Google Scholar]
  5. Barber, G. N. ( 2005; ). VSV-tumor selective replication and protein translation. Oncogene 24, 7710–7719.[CrossRef]
    [Google Scholar]
  6. Black, B. L., Rhodes, R. B., McKenzie, M. & Lyles, D. S. ( 1993; ). The role of vesicular stomatitis virus matrix protein in inhibition of host-directed gene expression is genetically separable from its function in virus assembly. J Virol 67, 4814–4821.
    [Google Scholar]
  7. Chew, T., Noyce, R., Collins, S. E., Hancock, M. H. & Mossman, K. L. ( 2009; ). Characterization of the interferon regulatory factor 3-mediated antiviral response in a cell line deficient for IFN production. Mol Immunol 46, 393–399.[CrossRef]
    [Google Scholar]
  8. Cory, A. H., Owen, T. C., Barltrop, J. A. & Cory, J. G. ( 1991; ). Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun 3, 207–212.
    [Google Scholar]
  9. Dancho, B., McKenzie, M. O., Connor, J. H. & Lyles, D. S. ( 2009; ). Vesicular stomatitis virus matrix protein mutations that affect association with host membranes and viral nucleocapsids. J Biol Chem 284, 4500–4509.[CrossRef]
    [Google Scholar]
  10. De Palma, M., Mazzieri, R., Politi, L. S., Pucci, F., Zonari, E., Sitia, G., Mazzoleni, S., Moi, D., Venneri, M. A. & other authors ( 2008; ). Tumor-targeted interferon-α delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14, 299–311.[CrossRef]
    [Google Scholar]
  11. DePolo, N. J. & Holland, J. J. ( 1986; ). Very rapid generation/amplification of defective interfering particles by vesicular stomatitis virus variants isolated from persistent infection. J Gen Virol 67, 1195–1198.[CrossRef]
    [Google Scholar]
  12. Desforges, M., Charron, J., Berard, S., Beausoleil, S., Stojdl, D. F., Despars, G., Laverdiere, B., Bell, J. C., Talbot, P. J. & other authors ( 2001; ). Different host-cell shutoff strategies related to the matrix protein lead to persistence of vesicular stomatitis virus mutants on fibroblast cells. Virus Res 76, 87–102.[CrossRef]
    [Google Scholar]
  13. Desforges, M., Despars, G., Berard, S., Gosselin, M., McKenzie, M. O., Lyles, D. S., Talbot, P. J. & Poliquin, L. ( 2002; ). Matrix protein mutations contribute to inefficient induction of apoptosis leading to persistent infection of human neural cells by vesicular stomatitis virus. Virology 295, 63–73.[CrossRef]
    [Google Scholar]
  14. Eckardt-Michel, J., Lorek, M., Baxmann, D., Grunwald, T., Keil, G. M. & Zimmer, G. ( 2008; ). The fusion protein of respiratory syncytial virus triggers p53-dependent apoptosis. J Virol 82, 3236–3249.[CrossRef]
    [Google Scholar]
  15. Faria, P. A., Chakraborty, P., Levay, A., Barber, G. N., Ezelle, H. J., Enninga, J., Arana, C., van Deursen, J. & Fontoura, B. M. ( 2005; ). VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway. Mol Cell 17, 93–102.[CrossRef]
    [Google Scholar]
  16. Ferri, K. F., Jacotot, E., Geuskens, M. & Kroemer, G. ( 2000; ). Apoptosis and karyogamy in syncytia induced by the HIV-1-envelope glycoprotein complex. Cell Death Differ 7, 1137–1139.[CrossRef]
    [Google Scholar]
  17. Francoeur, A. M., Poliquin, L. & Stanners, C. P. ( 1987; ). The isolation of interferon-inducing mutants of vesicular stomatitis virus with altered viral P function for the inhibition of total protein synthesis. Virology 160, 236–245.[CrossRef]
    [Google Scholar]
  18. Fredericksen, B. L. & Whitt, M. A. ( 1995; ). Vesicular stomatitis virus glycoprotein mutations that affect membrane fusion activity and abolish virus infectivity. J Virol 69, 1435–1443.
    [Google Scholar]
  19. Fultz, P. N., Shadduck, J. A., Kang, C. Y. & Streilein, J. W. ( 1982; ). Vesicular stomatitis virus can establish persistent infections in Syrian hamsters. J Gen Virol 63, 493–497.[CrossRef]
    [Google Scholar]
  20. Gaddy, D. F. & Lyles, D. S. ( 2005; ). Vesicular stomatitis viruses expressing wild-type or mutant M proteins activate apoptosis through distinct pathways. J Virol 79, 4170–4179.[CrossRef]
    [Google Scholar]
  21. Gaddy, D. F. & Lyles, D. S. ( 2007; ). Oncolytic vesicular stomatitis virus induces apoptosis via signaling through PKR, Fas, and Daxx. J Virol 81, 2792–2804.[CrossRef]
    [Google Scholar]
  22. Gaudier, M., Gaudin, Y. & Knossow, M. ( 2002; ). Crystal structure of vesicular stomatitis virus matrix protein. EMBO J 21, 2886–2892.[CrossRef]
    [Google Scholar]
  23. Hanika, A., Larisch, B., Steinmann, E., Schwegmann-Wessels, C., Herrler, G. & Zimmer, G. ( 2005; ). Use of influenza C virus glycoprotein HEF for generation of vesicular stomatitis virus pseudotypes. J Gen Virol 86, 1455–1465.[CrossRef]
    [Google Scholar]
  24. Her, L. S., Lund, E. & Dahlberg, J. E. ( 1997; ). Inhibition of Ran guanosine triphosphatase-dependent nuclear transport by the matrix protein of vesicular stomatitis virus. Science 276, 1845–1848.[CrossRef]
    [Google Scholar]
  25. Higuchi, H., Bronk, S. F., Bateman, A., Harrington, K., Vile, R. G. & Gores, G. J. ( 2000; ). Viral fusogenic membrane glycoprotein expression causes syncytia formation with bioenergetic cell death: implications for gene therapy. Cancer Res 60, 6396–6402.
    [Google Scholar]
  26. Holland, J. J. & Villarreal, L. P. ( 1974; ). Persistent noncytocidal vesicular stomatitis virus infections mediated by defective T particles that suppress virion transcriptase. Proc Natl Acad Sci U S A 71, 2956–2960.[CrossRef]
    [Google Scholar]
  27. Holland, J. J., Villarreal, L. P., Welsh, R. M., Oldstone, M. B., Kohne, D., Lazzarini, R. & Scolnick, E. ( 1976; ). Long-term persistent vesicular stomatitis virus and rabies virus infection of cells in vitro. J Gen Virol 33, 193–211.[CrossRef]
    [Google Scholar]
  28. Jayakar, H. R. & Whitt, M. A. ( 2002; ). Identification of two additional translation products from the matrix (M) gene that contribute to vesicular stomatitis virus cytopathology. J Virol 76, 8011–8018.[CrossRef]
    [Google Scholar]
  29. Jayakar, H. R., Jeetendra, E. & Whitt, M. A. ( 2004; ). Rhabdovirus assembly and budding. Virus Res 106, 117–132.[CrossRef]
    [Google Scholar]
  30. Jeetendra, E., Ghosh, K., Odell, D., Li, J., Ghosh, H. P. & Whitt, M. A. ( 2003; ). The membrane-proximal region of vesicular stomatitis virus glycoprotein G ectodomain is critical for fusion and virus infectivity. J Virol 77, 12807–12818.[CrossRef]
    [Google Scholar]
  31. Kahn, J. S., Roberts, A., Weibel, C., Buonocore, L. & Rose, J. K. ( 2001; ). Replication-competent or attenuated, nonpropagating vesicular stomatitis viruses expressing respiratory syncytial virus (RSV) antigens protect mice against RSV challenge. J Virol 75, 11079–11087.[CrossRef]
    [Google Scholar]
  32. Kalhoro, N. H., Veits, J., Rautenschlein, S. & Zimmer, G. ( 2009; ). A recombinant vesicular stomatitis virus replicon vaccine protects chickens from highly pathogenic avian influenza virus (H7N1). Vaccine 27, 1174–1183.[CrossRef]
    [Google Scholar]
  33. Kapadia, S. U., Simon, I. D. & Rose, J. K. ( 2008; ). SARS vaccine based on a replication-defective recombinant vesicular stomatitis virus is more potent than one based on a replication-competent vector. Virology 376, 165–172.[CrossRef]
    [Google Scholar]
  34. Kopecky, S. A. & Lyles, D. S. ( 2003; ). The cell-rounding activity of the vesicular stomatitis virus matrix protein is due to the induction of cell death. J Virol 77, 5524–5528.[CrossRef]
    [Google Scholar]
  35. Kopecky, S. A., Willingham, M. C. & Lyles, D. S. ( 2001; ). Matrix protein and another viral component contribute to induction of apoptosis in cells infected with vesicular stomatitis virus. J Virol 75, 12169–12181.[CrossRef]
    [Google Scholar]
  36. Lichty, B. D., Power, A. T., Stojdl, D. F. & Bell, J. C. ( 2004; ). Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med 10, 210–216.[CrossRef]
    [Google Scholar]
  37. Lin, E. H., Salon, C., Brambilla, E., Lavillette, D., Szecsi, J., Cosset, F. L. & Coll, J. L. ( 2010; ). Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer. Cancer Gene Ther 17, 256–265.[CrossRef]
    [Google Scholar]
  38. Lyles, D. S. ( 2000; ). Cytopathogenesis and inhibition of host gene expression by RNA viruses. Microbiol Mol Biol Rev 64, 709–724.[CrossRef]
    [Google Scholar]
  39. Majid, A. M., Ezelle, H., Shah, S. & Barber, G. N. ( 2006; ). Evaluating replication-defective vesicular stomatitis virus as a vaccine vehicle. J Virol 80, 6993–7008.[CrossRef]
    [Google Scholar]
  40. Mayer, D., Fischer, H., Schneider, U., Heimrich, B. & Schwemmle, M. ( 2005; ). Borna disease virus replication in organotypic hippocampal slice cultures from rats results in selective damage of dentate granule cells. J Virol 79, 11716–11723.[CrossRef]
    [Google Scholar]
  41. Muller, U., Steinhoff, U., Reis, L. F., Hemmi, S., Pavlovic, J., Zinkernagel, R. M. & Aguet, M. ( 1994; ). Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921.[CrossRef]
    [Google Scholar]
  42. Nishiyama, Y., Ito, Y., Shimokata, K., Nagata, I., Kurachi, N. & Sugiura, Y. ( 1977; ). Comparative studies on cytopathic effects induced by vesicular stomatitis virus in two cell types. Microbiol Immunol 21, 693–702.[CrossRef]
    [Google Scholar]
  43. Nishiyama, Y., Ito, Y. & Shimokata, K. ( 1978; ). Properties of the viruses selected during persistent infection of L cells with VSV. J Gen Virol 40, 481–484.[CrossRef]
    [Google Scholar]
  44. Paternostre, M., Viard, M., Meyer, O., Ghanam, M., Ollivon, M. & Blumenthal, R. ( 1997; ). Solubilization and reconstitution of vesicular stomatitis virus envelope using octylglucoside. Biophys J 72, 1683–1694.[CrossRef]
    [Google Scholar]
  45. Petersen, J. M., Her, L. S., Varvel, V., Lund, E. & Dahlberg, J. E. ( 2000; ). The matrix protein of vesicular stomatitis virus inhibits nucleocytoplasmic transport when it is in the nucleus and associated with nuclear pore complexes. Mol Cell Biol 20, 8590–8601.[CrossRef]
    [Google Scholar]
  46. Platanias, L. C. ( 2005; ). Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5, 375–386.[CrossRef]
    [Google Scholar]
  47. Publicover, J., Ramsburg, E. & Rose, J. K. ( 2005; ). A single-cycle vaccine vector based on vesicular stomatitis virus can induce immune responses comparable to those generated by a replication-competent vector. J Virol 79, 13231–13238.[CrossRef]
    [Google Scholar]
  48. Ramseur, J. M. & Friedman, R. M. ( 1978; ). Prolonged infection of L cells with vesicular stomatitis virus. Defective interfering forms and temperature-sensitive mutants as factors in the infection. Virology 85, 253–261.[CrossRef]
    [Google Scholar]
  49. Ren, C., Kumar, S., Chanda, D., Kallman, L., Chen, J., Mountz, J. D. & Ponnazhagan, S. ( 2008; ). Cancer gene therapy using mesenchymal stem cells expressing interferon-beta in a mouse prostate cancer lung metastasis model. Gene Ther 15, 1446–1453.[CrossRef]
    [Google Scholar]
  50. Roberts, A., Buonocore, L., Price, R., Forman, J. & Rose, J. K. ( 1999a; ). Attenuated vesicular stomatitis viruses as vaccine vectors. J Virol 73, 3723–3732.
    [Google Scholar]
  51. Roberts, P. C., Kipperman, T. & Compans, R. W. ( 1999b; ). Vesicular stomatitis virus G protein acquires pH-independent fusion activity during transport in a polarized endometrial cell line. J Virol 73, 10447–10457.
    [Google Scholar]
  52. Roche, S., Bressanelli, S., Rey, F. A. & Gaudin, Y. ( 2006; ). Crystal structure of the low-pH form of the vesicular stomatitis virus glycoprotein G. Science 313, 187–191.[CrossRef]
    [Google Scholar]
  53. Roche, S., Rey, F. A., Gaudin, Y. & Bressanelli, S. ( 2007; ). Structure of the prefusion form of the vesicular stomatitis virus glycoprotein G. Science 315, 843–848.[CrossRef]
    [Google Scholar]
  54. Schwartz, J. A., Buonocore, L., Roberts, A., Suguitan, A., Jr, Kobasa, D., Kobinger, G., Feldmann, H., Subbarao, K. & Rose, J. K. ( 2007; ). Vesicular stomatitis virus vectors expressing avian influenza H5 HA induce cross-neutralizing antibodies and long-term protection. Virology 366, 166–173.[CrossRef]
    [Google Scholar]
  55. Sekellick, M. J. & Marcus, P. I. ( 1978; ). Persistent infection. I. Interferon-inducing defective-interfering particles as mediators of cell sparing: possible role in persistent infection by vesicular stomatitis virus. Virology 85, 175–186.[CrossRef]
    [Google Scholar]
  56. Sekellick, M. J. & Marcus, P. I. ( 1979; ). Persistent infection. II. Interferon-inducing temperature-sensitive mutants as mediators of cell sparing: possible role in persistent infection by vesicular stomatitis virus. Virology 95, 36–47.[CrossRef]
    [Google Scholar]
  57. Stojdl, D. F., Lichty, B., Knowles, S., Marius, R., Atkins, H., Sonenberg, N. & Bell, J. C. ( 2000; ). Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med 6, 821–825.[CrossRef]
    [Google Scholar]
  58. Sun, X., Belouzard, S. & Whittaker, G. R. ( 2008; ). Molecular architecture of the bipartite fusion loops of vesicular stomatitis virus glycoprotein G, a class III viral fusion protein. J Biol Chem 283, 6418–6427.[CrossRef]
    [Google Scholar]
  59. Tovey, M. G., Lallemand, C. & Thyphronitis, G. ( 2008; ). Adjuvant activity of type I interferons. Biol Chem 389, 541–545.
    [Google Scholar]
  60. van den Broek, M. F., Muller, U., Huang, S., Zinkernagel, R. M. & Aguet, M. ( 1995; ). Immune defence in mice lacking type I and/or type II interferon receptors. Immunol Rev 148, 5–18.[CrossRef]
    [Google Scholar]
  61. van den Pol, A. N., Dalton, K. P. & Rose, J. K. ( 2002; ). Relative neurotropism of a recombinant rhabdovirus expressing a green fluorescent envelope glycoprotein. J Virol 76, 1309–1327.[CrossRef]
    [Google Scholar]
  62. von Kobbe, C., van Deursen, J. M., Rodrigues, J. P., Sitterlin, D., Bachi, A., Wu, X., Wilm, M., Carmo-Fonseca, M. & Izaurralde, E. ( 2000; ). Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98. Mol Cell 6, 1243–1252.[CrossRef]
    [Google Scholar]
  63. Wollmann, G., Robek, M. D. & van den Pol, A. N. ( 2007; ). Variable deficiencies in the interferon response enhance susceptibility to vesicular stomatitis virus oncolytic actions in glioblastoma cells but not in normal human glial cells. J Virol 81, 1479–1491.[CrossRef]
    [Google Scholar]
  64. Youngner, J. S. & Quagliana, D. O. ( 1976; ). Temperature-sensitive mutants of vesicular stomatitis virus are conditionally defective particles that interfere with and are rescued by wild-type virus. J Virol 19, 102–107.
    [Google Scholar]
  65. Yuan, H., Yoza, B. K. & Lyles, D. S. ( 1998; ). Inhibition of host RNA polymerase II-dependent transcription by vesicular stomatitis virus results from inactivation of TFIID. Virology 251, 383–392.[CrossRef]
    [Google Scholar]
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