1887

Abstract

Human herpesvirus-8 (HHV-8) is aetiologically linked to Kaposi's sarcoma and primary effusion lymphoma. Although interferon- (IFN-) and interferon- (IFN-) are both antiviral cytokines, IFN- blocks entry of HHV-8 into the lytic phase, whereas IFN- induces an increase in the percentage of cells undergoing lytic replication. Multiple events in the lytic cascade must be completed to produce infectious virus. The ability of both types of IFN to affect the production of infectious virus was explored. Both IFN- and IFN- induced expression of the antiviral proteins double-stranded RNA-activated protein kinase (PKR) and 2′5′-oligoadenylate synthetase (2′5′-OAS) in HHV-8-infected BCBL-1 cells. Higher levels resulted from incubation with IFN- than with IFN-, whereas IFN- induced higher levels of IRF-1 than did IFN-. IFN- induced a minor increase in lytic viral gene expression, which was not accompanied by a detectible increase in infectious virus. When lytic replication of HHV-8 was induced using TPA, high levels of infectious virus appeared in the conditioned medium. When IFN- was present during TPA stimulation, the production of infectious virus was reduced by at least a 60 %, and IFN- fully blocked TPA-induced production of infectious virus. The greater reduction of viral production that occurred with IFN- is consistent with the higher levels of the antiviral proteins PKR and 2′5′-OAS induced by IFN- than by IFN-. These studies indicate that the augmentation of cellular antiviral defences by IFN- was sufficient to prevent production of infectious virus despite IFN--induced entry of some cells into the lytic phase of HHV-8 replication.

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2004-10-01
2024-03-28
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References

  1. Aboulafavia D., Miles S. A., Saks S. R., Mitsuyasu R. 1989; Intravenous recombinant tumor necrosis factor in the treatment of AIDS-related Kaposi's sarcoma. J Acquir Immune Defic Syndr 2:54–58
    [Google Scholar]
  2. Adams M. D., Dubnick M., Kerlavage A. R., Moreno R., Kelley J. M., Utterback T. R., Nagle J. W., Fields C., Venter J. C. 1992; Sequence identification of 2,375 human brain genes. Nature 355:632–634 [CrossRef]
    [Google Scholar]
  3. Balachandran S., Roberts P. C., Brown L. E., Truong H., Pattnaik A. K., Archer D. R., Barber G. N. 2000; Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13:129–141 [CrossRef]
    [Google Scholar]
  4. Barber G. N. 2001; Host defense, viruses and apoptosis. Cell Death Differ 8:113–126 [CrossRef]
    [Google Scholar]
  5. Benech P., Mory Y., Revel M., Chebath J. 1985; Structure of two forms of the interferon-induced (2′5′)-oligo A synthetase of human cells based on cDNAs and gene sequences. EMBO J 4:2249–2256
    [Google Scholar]
  6. Biron C. A. 1999; Initial and innate responses to viral infections - pattern setting in immunity or disease. Curr Opin Microbiol 2:374–381 [CrossRef]
    [Google Scholar]
  7. Biron C. A., Nguyen K. B., Pien G. C., Cousens L. P., Salazar-Mather T. P. 1999; Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220 [CrossRef]
    [Google Scholar]
  8. Blackbourn D. J., Fujimura S., Kutzkey T., Levy J. A. 2000; Induction of human herpesvirus-8 gene expression by recombinant interferon gamma. AIDS 14:98–99 [CrossRef]
    [Google Scholar]
  9. Castelli J. C., Hassel B. A., Maran A., Paranjape J., Hewitt J. A., Li X. L., Hsu Y. T., Silverman R. H., Youle R. J. 1998; The role of 2′-5′ oligoadenylate-activated ribonuclease L in apoptosis. Cell Death Differ 5:313–320 [CrossRef]
    [Google Scholar]
  10. Chang Y., Cesarman E., Pessin M. S., Lee F., Culpepper J., Knowles D. M., Moore P. S. 1994; Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865–1869 [CrossRef]
    [Google Scholar]
  11. Chang Y., Ziegler J., Wabinga H. 8 other authors 1996; Kaposi's sarcoma-associated herpesvirus and Kaposi's sarcoma in Africa. Uganda Kaposi's Sarcoma Study Group. Arch Intern Med 156:202–204 [CrossRef]
    [Google Scholar]
  12. Chang J., Renne R., Dittmer D., Ganem D. 2000; Inflammatory cytokines and the reactivation of Kaposi's sarcoma-associated herpesvirus lytic replication. Virology 266:17–25 [CrossRef]
    [Google Scholar]
  13. Clemens M. J., Elia A. 1997; The double-stranded RNA-dependent protein kinase PKR: structure and function. J Interferon Cytokine Res 17:503–524 [CrossRef]
    [Google Scholar]
  14. D'Agostino G., Arico E., Santodonato L. 9 other authors; 1999; Type I consensus IFN (IFN-con1) gene transfer into KSHV/HHV-8-infected BCBL-1 cells causes inhibition of viral lytic cycle activation via induction of apoptosis and abrogates tumorigenicity in SCID mice. J Interferon Cytokine Res 19:1305–1316 [CrossRef]
    [Google Scholar]
  15. Der S. D., Yang Y. L., Weissmann C., Williams B. R. 1997; A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci U S A 94:3279–3283 [CrossRef]
    [Google Scholar]
  16. Dictor M., Rambech E., Way D., Witte M., Bendsoe N. 1996; Human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) DNA in Kaposi's sarcoma lesions, AIDS Kaposi's sarcoma cell lines, endothelial Kaposi's sarcoma simulators, and the skin of immunosuppressed patients. Am J Pathol 148:2009–2016
    [Google Scholar]
  17. Doly J., Civas A., Navarro S., Uze G. 1998; Type I interferons: expression and signalization. Cell Mol Life Sci 54:1109–1121 [CrossRef]
    [Google Scholar]
  18. Fiorelli V., Gendelman R., Sirianni M. C. 8 other authors 1998; γ -Interferon produced by CD8+ T cells infiltrating Kaposi's sarcoma induces spindle cells with angiogenic phenotype and synergy with human immunodeficiency virus-1 Tat protein: an immune response to human herpesvirus-8 infection?. Blood 91:956–967
    [Google Scholar]
  19. Fischl M. A., Finkelstein D. M., He W., Powderly W. G., Triozzi P. L., Steigbigel R. T. 1996; A phase II study of recombinant human interferon-alpha 2a and zidovudine in patients with AIDS-related Kaposi's sarcoma. AIDS Clinical Trials Group. J Acquir Immune Defic Syndr Hum Retrovirol 11:379–384 [CrossRef]
    [Google Scholar]
  20. Ganser A., Brucher W., Brodt H. R., Busch W., Brandhorst I., Helm E. B., Hoelzer D. 1986; Treatment of AIDS-related Kaposi's sarcoma with recombinant gamma-interferon. Onkologie 9:163–166 [CrossRef]
    [Google Scholar]
  21. Gao S. J., Boshoff C., Jayachandra S., Weiss R. A., Chang Y., Moore P. S. 1997; KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15:1979–1985 [CrossRef]
    [Google Scholar]
  22. Grundhoff A., Ganem D. 2003; The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus permits replication of terminal repeat-containing plasmids. J Virol 77:2779–2783 [CrossRef]
    [Google Scholar]
  23. Hartmann R., Norby P. L., Martensen P. M., Jorgensen P., James M. C., Jacobsen C., Moestrup S. K., Clemens M. J., Justesen J. 1998; Activation of 2′-5′ oligoadenylate synthetase by single-stranded and double-stranded RNA aptamers. J Biol Chem 273:3236–3246 [CrossRef]
    [Google Scholar]
  24. Hu J., Garber A. C., Renne R. 2002; The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus supports latent DNA replication in dividing cells. J Virol 76:11677–11687 [CrossRef]
    [Google Scholar]
  25. Inoue N., Winter J., Lal R. B., Offermann M. K., Koyano S. 2003; Characterization of entry mechanisms of human herpesvirus 8 by using an Rta-dependent reporter cell line. J Virol 77:8147–8152 [CrossRef]
    [Google Scholar]
  26. Justesen J., Hartmann R., Kjeldgaard N. O. 2000; Gene structure and function of the 2′-5′-oligoadenylate synthetase family. Cell Mol Life Sci 57:1593–1612 [CrossRef]
    [Google Scholar]
  27. Kessler B. M., Glas R., Ploegh H. L. 2002; MHC class I antigen processing regulated by cytosolic proteolysis-short cuts that alter peptide generation. Mol Immunol 39:171–179 [CrossRef]
    [Google Scholar]
  28. Kimura T., Nakayama K., Penninger J. 8 other authors 1994; Involvement of the IRF-1 transcription factor in antiviral responses to interferons. Science 264:1921–1924 [CrossRef]
    [Google Scholar]
  29. Kirchhoff S., Koromilas A. E., Schaper F., Grashoff M., Sonenberg N., Hauser H. 1995; IRF-1 induced cell growth inhibition and interferon induction requires the activity of the protein kinase PKR. Oncogene 11:439–445
    [Google Scholar]
  30. Krigel R. L., Odajnyk C. M., Laubenstein L. J., Ostreicher R., Wernz J., Vilcek J., Rubinstein P., Friedman-Kien A. E. 1985; Therapeutic trial of interferon-gamma in patients with epidemic Kaposi's sarcoma. J Biol Response Mod 4:358–364
    [Google Scholar]
  31. Krown S. E. 1991; Interferon and other biologic agents for the treatment of Kaposi's sarcoma. Hematol Oncol Clin North Am 5:311–322
    [Google Scholar]
  32. Krown S. E., Paredes J., Bundow D., Polsky B., Gold J. W., Flomenberg N. 1992; Interferon-alpha, zidovudine, and granulocyte-macrophage colony-stimulating factor: a phase I AIDS Clinical Trials Group study in patients with Kaposi's sarcoma associated with AIDS. J Clin Oncol 10:1344–1351
    [Google Scholar]
  33. Krug L. T., Pozharskaya V. P., Yu Y., Inoue N., Offermann M. K. 2004; Inhibition of infection and replication of human herpesvirus 8 in microvascular endothelial cells by alpha interferon and phosphonoformic acid. J Virol 78:8359–8371 [CrossRef]
    [Google Scholar]
  34. Lohoff M., Ferrick D., Mittrucker H. W., Duncan G. S., Bischof S., Rollinghoff M., Mak T. W. 1997; Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. Immunity 6:681–689 [CrossRef]
    [Google Scholar]
  35. Lukac D. M., Renne R., Kirshner J. R., Ganem D. 1998; Reactivation of Kaposi's sarcoma-associated herpesvirus infection from latency by expression of the ORF 50 transactivator, a homolog of the EBV R protein. Virology 252:304–312 [CrossRef]
    [Google Scholar]
  36. Lukac D. M., Kirshner J. R., Ganem D. 1999; Transcriptional activation by the product of open reading frame 50 of Kaposi's sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells. J Virol 73:9348–9361
    [Google Scholar]
  37. Marie I., Rebouillat D., Hovanessian A. G. 1999; The expression of both domains of the 69/71 kDa 2′,5′ oligoadenylate synthetase generates a catalytically active enzyme and mediates an anti-viral response. Eur J Biochem 262:155–165 [CrossRef]
    [Google Scholar]
  38. Mercader M., Taddeo B., Panella J. R., Chandran B., Nickoloff B. J., Foreman K. E. 2000; Induction of HHV-8 lytic cycle replication by inflammatory cytokines produced by HIV-1-infected T cells. Am J Pathol 156:1961–1971 [CrossRef]
    [Google Scholar]
  39. Meurs E., Chong K., Galabru J., Thomas N. S., Kerr I. M., Williams B. R., Hovanessian A. G. 1990; Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62:379–390 [CrossRef]
    [Google Scholar]
  40. Milligan S., Robinson M., O'Donnell E., Blackbourn D. 2004; Inflammatory cytokines inhibit Kaposi's sarcoma-associated herpesvirus lytic gene transcription in in vitro-infected endothelial cells. J Virol 78:2591–2596 [CrossRef]
    [Google Scholar]
  41. Monini P., Carlini F., Sturzl M. 19 other authors 1999; Alpha interferon inhibits human herpesvirus 8 (HHV-8) reactivation in primary effusion lymphoma cells and reduces HHV-8 load in cultured peripheral blood mononuclear cells. J Virol 73:4029–4041
    [Google Scholar]
  42. Moore P. S., Chang Y. 2001; Kaposi's sarcoma-associated herpesvirus. In Fields Virology , 4th edn. pp  2803–2833 Edited by Fields B., Knipe D., Howley P. Philadelphia: Lippincott-Raven Publishers;
    [Google Scholar]
  43. Novelli F., D'Elios M. M., Bernabei P., Ozmen L., Rigamonti L., Almerigogna F., Forni G., Del Prete G. 1997; Expression and role in apoptosis of the alpha- and beta-chains of the IFN-gamma receptor on human Th1 and Th2 clones. J Immunol 159:206–213
    [Google Scholar]
  44. Pozharskaya V. P., Weakland L. L., Zimring J. C., Krug L. T., Unger E. R., Neisch A., Joshi H., Inoue N., Offermann M. K. 2004; Short duration of elevated vIRF-1 expression during lytic replication of human herpesvirus 8 limits its ability to block antiviral responses induced by alpha interferon in BCBL-1 cells. J Virol 78:6621–6635 [CrossRef]
    [Google Scholar]
  45. Rainbow L., Platt G. M., Simpson G. R., Sarid R., Gao S. J., Stoiber H., Herrington C. S., Moore P. S., Schulz T. F. 1997; The 222- to 234-kilodalton latent nuclear protein (LNA) of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) is encoded by orf73 and is a component of the latency-associated nuclear antigen. J Virol 71:5915–5921
    [Google Scholar]
  46. Roizman B., Philip P. E. 2001; The family herpesviridae : a brief introduction. In Fields Virology , 4th edn. pp  2381–2397 Edited by Fields B., Knipe D., Howley P. Philadelphia: Lippincott-Raven Publishers;
    [Google Scholar]
  47. Ronni T., Sareneva T., Pirhonen J., Julkunen I. 1995; Activation of IFN-alpha, IFN-gamma, MxA, and IFN regulatory factor 1 genes in influenza A virus-infected human peripheral blood mononuclear cells. J Immunol 154:2764–2774
    [Google Scholar]
  48. Samuel C. E. 2001; Antiviral actions of interferons. Clin Microbiol Rev 14:778–809 [CrossRef]
    [Google Scholar]
  49. Samuel C. E., Kuhen K. L., George C. X., Ortega L. G., Rende-Fournier R., Tanaka H. 1997; The PKR protein kinase - an interferon-inducible regulator of cell growth and differentiation. Int J Hematol 65:227–237 [CrossRef]
    [Google Scholar]
  50. Sarid R., Flore O., Bohenzky R., Chang Y., Moore P. S. 1998; Transcription mapping of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1). J Virol 72:1005–1012
    [Google Scholar]
  51. Sarkar S. N., Sen G. C. 1998; Production, purification, and characterization of recombinant 2′, 5′-oligoadenylate synthetases. Methods 15:233–242 [CrossRef]
    [Google Scholar]
  52. Sawyer L. A., Metcalf J. A., Zoon K. C., Boone E. J., Kovacs J. A., Lane H. C., Quinnan G. V. Jr 1990; Effects of interferon-alpha in patients with AIDS-associated Kaposi's sarcoma are related to blood interferon levels and dose. Cytokine 2:247–252 [CrossRef]
    [Google Scholar]
  53. Schindler C. 1999; Cytokines and JAK-STAT signaling. Exp Cell Res 253:7–14 [CrossRef]
    [Google Scholar]
  54. Schindler C. W. 2002; Series introduction. JAK-STAT signaling in human disease. J Clin Invest 109:1133–1137 [CrossRef]
    [Google Scholar]
  55. Schindler C., Brutsaert S. 1999; Interferons as a paradigm for cytokine signal transduction. Cell Mol Life Sci 55:1509–1522 [CrossRef]
    [Google Scholar]
  56. Seo T., Lee D., Shim Y. S., Angell J. E., Chidambaram N. V., Kalvakolanu D. V., Choe J. 2002; Viral interferon regulatory factor 1 of Kaposi's sarcoma-associated herpesvirus interacts with a cell death regulator, GRIM19, and inhibits interferon/retinoic acid-induced cell death. J Virol 76:8797–8807 [CrossRef]
    [Google Scholar]
  57. Sun R., Lin S. F., Gradoville L., Yuan Y., Zhu F., Miller G. 1998; A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 95:10866–10871 [CrossRef]
    [Google Scholar]
  58. Tan S. L., Katze M. G. 1999; The emerging role of the interferon-induced PKR protein kinase as an apoptotic effector: a new face of death?. J Interferon Cytokine Res 19:543–554 [CrossRef]
    [Google Scholar]
  59. Taniguchi T., Ogasawara K., Takaoka A., Tanaka N. 2001; IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19:623–655 [CrossRef]
    [Google Scholar]
  60. Wang S. E., Wu F. Y., Fujimuro M., Zong J., Hayward S. D., Hayward G. S. 2003; Role of CCAAT/enhancer-binding protein alpha (C/EBP α ) in activation of the Kaposi's sarcoma-associated herpesvirus (KSHV) lytic-cycle replication-associated protein (RAP) promoter in cooperation with the KSHV replication and transcription activator (RTA) and RAP. J Virol 77:600–623 [CrossRef]
    [Google Scholar]
  61. Whiteside S. T., King P., Goodbourn S. 1994; A truncated form of the IRF-2 transcription factor has the properties of a postinduction repressor of interferon-beta gene expression. J Biol Chem 269:27059–27065
    [Google Scholar]
  62. Williams B. R. 1999; PKR; a sentinel kinase for cellular stress. Oncogene 18:6112–6120 [CrossRef]
    [Google Scholar]
  63. Wu F. Y., Tang Q. Q., Chen H., ApRhys C., Farrell C., Chen J., Fujimuro M., Lane M. D., Hayward G. S. 2002; Lytic replication-associated protein (RAP) encoded by Kaposi sarcoma-associated herpesvirus causes p21CIP-1-mediated G1 cell cycle arrest through CCAAT/enhancer-binding protein- α . Proc Natl Acad Sci U S A 99:10683–10688 [CrossRef]
    [Google Scholar]
  64. Yaffe A., Schwarz Y., Hacohen D., Kinar Y., Nir U., Salzberg S. 1996; Inhibition of 2-5A synthetase expression by antisense RNA interferes with interferon-mediated antiviral and antiproliferative effects and induces anchorage-independent cell growth. Cell Growth Differ 7:969–978
    [Google Scholar]
  65. Yu Y., Black J. B., Goldsmith C. S., Browning P. J., Bhalla K., Offermann M. K. 1999; Induction of human herpesvirus-8 DNA replication and transcription by butyrate and TPA in BCBL-1 cells. J Gen Virol 80:83–90
    [Google Scholar]
  66. Zimring J. C., Goodbourn S., Offermann M. K. 1998; Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homologue that represses IRF-1 mediated transcription. J Virol 72:701–707
    [Google Scholar]
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