Interleukin-18 (IL-18) is a proinflammatory cytokine that plays a key role in the activation of natural killer and T helper 1 cell responses principally by inducing interferon-γ (IFN-γ). Human and mouse secreted IL-18-binding proteins (IL-18BPs) have recently been described which block IL-18 activity but have no sequence similarity to membrane IL-18 receptors. Several poxvirus genes encode proteins with sequence similarity to IL-18BPs. Here we show that vaccinia, ectromelia and cowpox viruses secrete from infected cells a soluble IL-18BP (vIL-18BP) that may modulate the host antiviral response. The ectromelia virus protein was found to block NF-κB activation and induction of IFN-γ in response to IL-18. The highly attenuated vaccinia virus modified virus Ankara encodes IL-18-binding activity, and thus deletion of the vIL-18BP may improve further the safety and immunogenicity of this promising human vaccine candidate. We confirm that molluscum contagiosum virus, a molluscipoxvirus that produces small skin tumours in immunocompetent individuals and opportunistic infections in immunodeficient AIDS patients, also encodes a related, larger vIL-18BP (gene MC54L). This protein may contribute to the lack of inflammatory response characteristic of molluscum contagiosum virus lesions. The expression of vIL-18BPs by distinct poxvirus genera that cause local or general viral dissemination, or persistent or acute infections in the host, emphasizes the importance of IL-18 in response to viral infections.


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  1. Aizawa, Y., Akita, K., Taniai, M., Torigoe, K., Mori, T., Nishida, Y., Ushio, S., Nukada, Y., Tanimoto, T., Ikegami, H., Ikeda, M. & Kurimoto, M. (1999). Cloning and expression of interleukin-18 binding protein.FEBS Letters 445, 338-342.[CrossRef] [Google Scholar]
  2. Alcamı́, A. & Smith, G. L. (1992). A soluble receptor for interleukin-1β encoded by vaccinia virus: a novel mechanism of virus modulation of the host response to infection.Cell 71, 153-167.[CrossRef] [Google Scholar]
  3. Alcamı́, A., Symons, J. A., Collins, P. D., Williams, T. J. & Smith, G. L. (1998a). Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus.Journal of Immunology 160, 624-633. [Google Scholar]
  4. Alcamı́, A., Symons, J. A., Khanna, A. & Smith, G. L. (1998b). Poxviruses: capturing cytokines and chemokines.Seminars in Virology 8, 419-427.[CrossRef] [Google Scholar]
  5. 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]
  6. Bachelerie, F., Alcamı́, J., Arenzana-Seisdedos, F. & Virelizier, J. L. (1991). HIV enhancer activity perpetuated by NF-kappa B induction on infection of monocytes.Nature 350, 709-712.[CrossRef] [Google Scholar]
  7. Blanchard, T. J., Alcamı́, A., Andrea, P. & Smith, G. L. (1998). Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins: implications for use as a human vaccine.Journal of General Virology 79, 1159-1167. [Google Scholar]
  8. Dairaghi, D. J., Greaves, D. R. & Schall, T. J. (1998). Abduction of chemokine elements by herpesviruses.Seminars in Virology 8, 377-385.[CrossRef] [Google Scholar]
  9. Damon, I., Murphy, P. M. & Moss, B. (1998). Broad spectrum chemokine antagonistic activity of a human poxvirus chemokine homolog.Proceedings of the National Academy of Sciences, USA 95, 6403-6407.[CrossRef] [Google Scholar]
  10. Dinarello, C. A. (1999). IL-18: a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family.Journal of Allergy and Clinical Immunology 103, 11-24.[CrossRef] [Google Scholar]
  11. Esposito, J. R., Condit, R. C. & Obijeski, J. (1981). The preparation of orthopoxvirus DNA.Journal of Virological Methods 2, 175-179.[CrossRef] [Google Scholar]
  12. Fenner, F., Wittek, R. & Dumbell, K. R. (1989).The Orthopoxviruses, London: Academic Press.
  13. Fujioka, N., Akazawa, R., Ohashi, K., Fujii, M., Ikeda, M. & Kurimoto, M. (1999). Interleukin-18 protects mice against acute herpes simplex virus type 1 infection.Journal of Virology 73, 2401-2409. [Google Scholar]
  14. Kojima, H., Aizawa, Y., Yanai, Y., Nagaoka, K., Takeuchi, M., Ohta, T., Ikegami, H., Ikeda, M. & Kurimoto, M. (1999). An essential role for NF-kappa B in IL-18-induced IFN-gamma expression in KG-1 cells.Journal of Immunology 162, 5063-5069. [Google Scholar]
  15. Krathwohl, M. D., Hromas, R., Brown, D. R., Broxmeyer, H. E. & Fife, K. H. (1997). Functional characterization of the CC chemokine-like molecules encoded by molluscum contagiosum virus types 1 and 2.Proceedings of the National Academy of Sciences, USA 94, 9875-9880.[CrossRef] [Google Scholar]
  16. Meyer, H., Ropp, S. L. & Esposito, J. J. (1997). Gene for A-type inclusion body protein is useful for a polymerase chain reaction assay to differentiate orthopoxviruses.Journal of Virological Methods 64, 217-221.[CrossRef] [Google Scholar]
  17. Moratilla, M., Agromayor, M., Nuñez, A., Funes, J. M., Varas, A. J., Lopez-Estebaranz, J. L., Esteban, M. & Martin-Gallardo, A. (1997). A random DNA sequencing, computer-based approach for the generation of a gene map of molluscum contagiosum virus.Virus Genes 14, 73-80.[CrossRef] [Google Scholar]
  18. Moss, B. (1996). Poxviridae: the viruses and their replication. In Fields Virology, pp. 2637-2671. Edited by B. N. Fields, D. M. Knipe & P. M. Howley. Philadelphia: Lippincott–Raven.
  19. Nash, P., Barrett, J., Cao, J. X., Hota-Mitchell, S., Lalani, A. S., Everett, H., Xu, X. M., Robichaud, J., Hnatiuk, S., Ainslie, C., Seet, B. T. & McFadden, G. (1999). Immunomodulation by viruses: the myxoma virus story.Immunological Reviews 168, 103-120.[CrossRef] [Google Scholar]
  20. Novick, D., Kim, S. H., Fantuzzi, G., Reznikov, L. L., Dinarello, C. A. & Rubinstein, M. (1999). Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response.Immunity 10, 127-136.[CrossRef] [Google Scholar]
  21. Nuñez, A., Funes, J. M., Agromayor, M., Moratilla, M., Varas, A. J., Lopez-Estebaranz, J. L., Esteban, M. & Martin-Gallardo, A. (1996). Detection and typing of molluscum contagiosum virus in skin lesions by using a simple lysis method and polymerase chain reaction.Journal of Medical Virology 50, 342-349.[CrossRef] [Google Scholar]
  22. Senkevich, T. G., Bugert, J. J., Sisler, J. R., Koonin, E. V., Darai, G. & Moss, B. (1996). Genome sequence of a human tumorigenic poxvirus: prediction of specific host response–evasion genes.Science 273, 813-816.[CrossRef] [Google Scholar]
  23. Smith, G. L., Symons, J. A., Khanna, A., Vanderplasschen, A. & Alcamı́, A. (1997). Vaccinia virus immune evasion.Immunological Reviews 159, 137-154.[CrossRef] [Google Scholar]
  24. Smith, G. L., Symons, J. A. & Alcamı́, A. (1998). Poxviruses: interfering with interferon.Seminars in Virology 8, 409-418.[CrossRef] [Google Scholar]
  25. Spriggs, M. K. (1996). One step ahead of the game: viral immunomodulatory molecules.Annual Review of Immunology 14, 101-130.[CrossRef] [Google Scholar]
  26. Spriggs, M., Hruby, D. E., Maliszewski, C. R., Pickup, D. J., Sims, J. E., Buller, R. M. L. & Vanslyke, J. (1992). Vaccinia and cowpox viruses encode a novel secreted interleukin-1 binding protein.Cell 71, 145-152.[CrossRef] [Google Scholar]
  27. Takeda, K., Tsutsui, H., Yoshimoto, T., Adachi, O., Yoshida, N., Kishimoto, T., Okamura, H., Nakanishi, K. & Akira, S. (1998). Defective NK cell activity and Th1 response in IL-18-deficient mice.Immunity 8, 383-390.[CrossRef] [Google Scholar]
  28. Tanaka-Kataoka, M., Kunikata, T., Takayama, S., Iwaki, K., Ohashi, K., Ikeda, M. & Kurimoto, M. (1999). In vivo antiviral effect of interleukin 18 in a mouse model of vaccinia virus infection.Cytokine 11, 593-599.[CrossRef] [Google Scholar]
  29. Xiang, Y. & Moss, B. (1999a). Identification of human and mouse homologs of the MC51L-53L-54L family of secreted glycoproteins encoded by the molluscum contagiosum poxvirus.Virology 257, 297-302.[CrossRef] [Google Scholar]
  30. Xiang, Y. & Moss, B. (1999b). IL-18 binding and inhibition of interferon gamma induction by human poxvirus-encoded proteins.Proceedings of the National Academy of Sciences, USA 96, 11537-11542.[CrossRef] [Google Scholar]

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