1887

Journal of General Virology

Volume 91, Issue 2

Viral host-range factor C7 or K1 is essential for modified vaccinia virus Ankara late gene expression in human and murine cells, irrespective of their capacity to inhibit protein kinase R-mediated phosphorylation of eukaryotic translation initiation factor 2 Free

Abstract

Vaccinia virus (VACV) infection induces phosphorylation of eukaryotic translation initiation factor 2 (eIF2), which inhibits cellular and viral protein synthesis. In turn, VACV has evolved the capacity to antagonize this antiviral response by expressing the viral host-range proteins K3 and E3. This study revealed that the host-range genes K1L and C7L also prevent eIF2 phosphorylation in modified VACV Ankara (MVA) infection of several human and murine cell lines. Moreover, C7L-deleted MVA (MVA-ΔC7L) lacked late gene expression, which could be rescued by the function of host-range factor K1 or C7. It was demonstrated that viral gene expression was blocked after viral DNA replication and that it was independent of apoptosis induction. Furthermore, it was found that eIF2 phosphorylation in MVA-ΔC7L-infected cells is mediated by protein kinase R (PKR) as shown in murine embryonic fibroblasts lacking PKR function, and it was shown that this was not due to reduced E3L gene expression. The block of eIF2 phosphorylation by C7 could be complemented by K1 in cells infected with MVA-ΔC7L encoding a reinserted K1L gene (MVA-ΔC7L-K1L). Importantly, these data illustrated that eIF2 phosphorylation by PKR is not responsible for the block of late viral gene expression. This suggests that other mechanisms targeted by C7 and K1 are essential for completing the MVA gene expression cycle and probably also for VACV replication in a diverse set of cell types.

  • Received:
  • Accepted:
  • Published Online:
© SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.015347-0
2010-02-01
2019-11-21
Loading full text...

Full text loading...

/deliver/fulltext/jgv/91/2/470.html?itemId=/content/journal/jgv/10.1099/vir.0.015347-0&mimeType=html&fmt=ahah

References

  1. Acres, B. & Bonnefoy, J. Y. ( 2008; ). Clinical development of MVA-based therapeutic cancer vaccines. Expert Rev Vaccines 7, 889–893.[CrossRef]
    [Google Scholar]
  2. Antoine, G., Scheiflinger, F., Dorner, F. & Falkner, F. G. ( 1998; ). The complete genomic sequence of the modified vaccinia Ankara strain: comparison with other orthopoxviruses. Virology 244, 365–396.[CrossRef]
    [Google Scholar]
  3. Assarsson, E., Greenbaum, J. A., Sundstrom, M., Schaffer, L., Hammond, J. A., Pasquetto, V., Oseroff, C., Hendrickson, R. C., Lefkowitz, E. J. & other authors ( 2008; ). Kinetic analysis of a complete poxvirus transcriptome reveals an immediate-early class of genes. Proc Natl Acad Sci U S A 105, 2140–2145.[CrossRef]
    [Google Scholar]
  4. Berlanga, J. J., Ventoso, I., Harding, H. P., Deng, J., Ron, D., Sonenberg, N., Carrasco, L. & de Haro, C. ( 2006; ). Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses. EMBO J 25, 1730–1740.[CrossRef]
    [Google Scholar]
  5. Budt, M., Niederstadt, L., Valchanova, R. S., Jonjic, S. & Brune, W. ( 2009; ). Specific inhibition of the PKR-mediated antiviral response by the murine cytomegalovirus proteins m142 and m143. J Virol 83, 1260–1270.[CrossRef]
    [Google Scholar]
  6. Carroll, M. W. & Moss, B. ( 1997; ). Host range and cytopathogenicity of the highly attenuated MVA strain of vaccinia virus: propagation and generation of recombinant viruses in a nonhuman mammalian cell line. Virology 238, 198–211.[CrossRef]
    [Google Scholar]
  7. Chakrabarti, S., Brechling, K. & Moss, B. ( 1985; ). Vaccinia virus expression vector: coexpression of β-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol 5, 3403–3409.
     [Google Scholar]
  8. Clemens, M. J. ( 2001; ). Initiation factor eIF2α phosphorylation in stress responses and apoptosis. Prog Mol Subcell Biol 27, 57–89.
     [Google Scholar]
  9. Davies, M. V., Chang, H. W., Jacobs, B. L. & Kaufman, R. J. ( 1993; ). The E3L and K3L vaccinia virus gene products stimulate translation through inhibition of the double-stranded RNA-dependent protein kinase by different mechanisms. J Virol 67, 1688–1692.
     [Google Scholar]
  10. Drexler, I., Staib, C. & Sutter, G. ( 2004; ). Modified vaccinia virus Ankara as antigen delivery system: how can we best use its potential? Curr Opin Biotechnol 15, 506–512.[CrossRef]
    [Google Scholar]
  11. Earl, P. L. & Moss, B. ( 1991; ). Expression of proteins in mammalian cells using vaccinia viral vectors. In Current Protocols in Molecular Biology, pp. 16.15.1–16.18.10. Edited by F. M. Ausubel, R. Brent, R. E. Kingston, D. D. Moore, J. G. Seidman, J. A. Smith & K. Struhl. New York, NY: John Wiley and Sons.
  12. Engelstad, M. & Smith, G. L. ( 1993; ). The vaccinia virus 42-kDa envelope protein is required for the envelopment and egress of extracellular virus and for virus virulence. Virology 194, 627–637.[CrossRef]
    [Google Scholar]
  13. Fischer, S. F., Ludwig, H., Holzapfel, J., Kvansakul, M., Chen, L., Huang, D. C., Sutter, G., Knese, M. & Hacker, G. ( 2006; ). Modified vaccinia virus Ankara protein F1L is a novel BH3-domain-binding protein and acts together with the early viral protein E3L to block virus-associated apoptosis. Cell Death Differ 13, 109–118.[CrossRef]
    [Google Scholar]
  14. García, M. A., Meurs, E. F. & Esteban, M. ( 2007; ). The dsRNA protein kinase PKR: virus and cell control. Biochimie 89, 799–811.[CrossRef]
    [Google Scholar]
  15. Gómez, C. E., Nájera, J. L., Krupa, M. & Esteban, M. ( 2008; ). The poxvirus vectors MVA and NYVAC as gene delivery systems for vaccination against infectious diseases and cancer. Curr Gene Ther 8, 97–120.[CrossRef]
    [Google Scholar]
  16. Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M. & Ron, D. ( 2000a; ). Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6, 1099–1108.[CrossRef]
    [Google Scholar]
  17. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H. & Ron, D. ( 2000b; ). PERK is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5, 897–904.[CrossRef]
    [Google Scholar]
  18. Hornemann, S., Harlin, O., Staib, C., Kisling, S., Erfle, V., Kaspers, B., Hacker, G. & Sutter, G. ( 2003; ). Replication of modified vaccinia virus Ankara in primary chicken embryo fibroblasts requires expression of the interferon resistance gene E3L. J Virol 77, 8394–8407.[CrossRef]
    [Google Scholar]
  19. Hsiao, J. C., Chung, C. S., Drillien, R. & Chang, W. ( 2004; ). The cowpox virus host range gene, CP77, affects phosphorylation of eIF2α and vaccinia viral translation in apoptotic HeLa cells. Virology 329, 199–212.[CrossRef]
    [Google Scholar]
  20. Jordan, R., Wang, L., Graczyk, T. M., Block, T. M. & Romano, P. R. ( 2002; ). Replication of a cytopathic strain of bovine viral diarrhea virus activates PERK and induces endoplasmic reticulum stress-mediated apoptosis of MDBK cells. J Virol 76, 9588–9599.[CrossRef]
    [Google Scholar]
  21. Keck, J. G., Baldick, C. J., Jr & Moss, B. ( 1990; ). Role of DNA replication in vaccinia virus gene expression: a naked template is required for transcription of three late trans-activator genes. Cell 61, 801–809.[CrossRef]
    [Google Scholar]
  22. Khabar, K. S., Dhalla, M., Siddiqui, Y., Zhou, A., Al Ahdal, M. N., Der, S. D., Silverman, R. H. & Williams, B. R. ( 2000; ). Effect of deficiency of the double-stranded RNA-dependent protein kinase, PKR, on antiviral resistance in the presence or absence of ribonuclease L: HSV-1 replication is particularly sensitive to deficiency of the major IFN-mediated enzymes. J Interferon Cytokine Res 20, 653–659.[CrossRef]
    [Google Scholar]
  23. Ludwig, H., Mages, J., Staib, C., Lehmann, M. H., Lang, R. & Sutter, G. ( 2005; ). Role of viral factor E3L in modified vaccinia virus Ankara infection of human HeLa cells: regulation of the virus life cycle and identification of differentially expressed host genes. J Virol 79, 2584–2596.[CrossRef]
    [Google Scholar]
  24. Ludwig, H., Suezer, Y., Waibler, Z., Kalinke, U., Schnierle, B. S. & Sutter, G. ( 2006; ). Double-stranded RNA-binding protein E3 controls translation of viral intermediate RNA, marking an essential step in the life cycle of modified vaccinia virus Ankara. J Gen Virol 87, 1145–1155.[CrossRef]
    [Google Scholar]
  25. Meng, X., Chao, J. & Xiang, Y. ( 2008; ). Identification from diverse mammalian poxviruses of host-range regulatory genes functioning equivalently to vaccinia virus C7L. Virology 372, 372–383.[CrossRef]
    [Google Scholar]
  26. Meng, X., Jiang, C., Arsenio, J., Dick, K., Cao, J. & Xiang, Y. ( 2009; ). Vaccinia virus K1L and C7L inhibit antiviral activities induced by type I interferons. J Virol 83, 10627–10636.[CrossRef]
    [Google Scholar]
  27. Meyer, H., Sutter, G. & Mayr, A. ( 1991; ). Mapping of deletions in the genome of the highly attenuated vaccinia virus MVA and their influence on virulence. J Gen Virol 72, 1031–1038.[CrossRef]
    [Google Scholar]
  28. Nájera, J. L., Gómez, C. E., Domingo-Gil, E., Gherardi, M. M. & Esteban, M. ( 2006; ). Cellular and biochemical differences between two attenuated poxvirus vaccine candidates (MVA and NYVAC) and role of the C7L gene. J Virol 80, 6033–6047.[CrossRef]
    [Google Scholar]
  29. Oguiura, N., Spehner, D. & Drillien, R. ( 1993; ). Detection of a protein encoded by the vaccinia virus C7L open reading frame and study of its effect on virus multiplication in different cell lines. J Gen Virol 74, 1409–1413.[CrossRef]
    [Google Scholar]
  30. Perkus, M. E., Goebel, S. J., Davis, S. W., Johnson, G. P., Limbach, K., Norton, E. K. & Paoletti, E. ( 1990; ). Vaccinia virus host range genes. Virology 179, 276–286.[CrossRef]
    [Google Scholar]
  31. Ramsey-Ewing, A. & Moss, B. ( 1995; ). Restriction of vaccinia virus replication in CHO cells occurs at the stage of viral intermediate protein synthesis. Virology 206, 984–993.[CrossRef]
    [Google Scholar]
  32. Sperling, K. M., Schwantes, A., Staib, C., Schnierle, B. S. & Sutter, G. ( 2009; ). The orthopoxvirus 68-kilodalton ankyrin-like protein is essential for DNA replication and complete gene expression of modified vaccinia virus Ankara in nonpermissive human and murine cells. J Virol 83, 6029–6038.[CrossRef]
    [Google Scholar]
  33. Staib, C. & Sutter, G. ( 2003; ). Live viral vectors: vaccinia virus. Methods Mol Med 87, 51–68.
     [Google Scholar]
  34. Staib, C., Drexler, I., Ohlmann, M., Wintersperger, S., Erfle, V. & Sutter, G. ( 2000; ). Transient host range selection for genetic engineering of modified vaccinia virus Ankara. Biotechniques 28, 1137–1142.
     [Google Scholar]
  35. Staib, C., Lowel, M., Erfle, V. & Sutter, G. ( 2003; ). Improved host range selection for recombinant modified vaccinia virus Ankara. Biotechniques 34, 694–696.
     [Google Scholar]
  36. Sutter, G. & Moss, B. ( 1992; ). Nonreplicating vaccinia vector efficiently expresses recombinant genes. Proc Natl Acad Sci U S A 89, 10847–10851.[CrossRef]
    [Google Scholar]
  37. Sutter, G. & Staib, C. ( 2003; ). Vaccinia vectors as candidate vaccines: the development of modified vaccinia virus Ankara for antigen delivery. Curr Drug Targets Infect Disord 3, 263–271.[CrossRef]
    [Google Scholar]
  38. Sutter, G., Ramsey-Ewing, A., Rosales, R. & Moss, B. ( 1994; ). Stable expression of the vaccinia virus K1L gene in rabbit cells complements the host range defect of a vaccinia virus mutant. J Virol 68, 4109–4116.
     [Google Scholar]
  39. Thornberry, N. A. ( 1998; ). Caspases: key mediators of apoptosis. Chem Biol 5, R97–R103.[CrossRef]
    [Google Scholar]
  40. Treiman, M., Caspersen, C. & Christensen, S. B. ( 1998; ). A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases. Trends Pharmacol Sci 19, 131–135.[CrossRef]
    [Google Scholar]
  41. Turner, P. C. & Moyer, R. W. ( 2002; ). Poxvirus immune modulators: functional insights from animal models. Virus Res 88, 35–53.[CrossRef]
    [Google Scholar]
  42. Vos, J. C. & Stunnenberg, H. G. ( 1988; ). Derepression of a novel class of vaccinia virus genes upon DNA replication. EMBO J 7, 3487–3492.
     [Google Scholar]
  43. Werden, S. J., Rahman, M. M. & McFadden, G. ( 2008; ). Poxvirus host range genes. Adv Virus Res 71, 135–171.
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.015347-0
Loading
Viral host-range factor C7 or K1 is essential for modified vaccinia virus Ankara late gene expression in human and murine cells, irrespective of their capacity to inhibit protein kinase R-mediated phosphorylation of eukaryotic translation initiation factor 2α
J. Gen. Virol. 91, 470 (2010); https://doi.org/10.1099/vir.0.015347-0
/content/journal/jgv/10.1099/vir.0.015347-0
/content/journal/jgv/10.1099/vir.0.015347-0
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