Skip to main content
NCBI home page
Molecular Medicine logoLink to Molecular Medicine
. 1998 Jun;4(6):402–412.

Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor confers resistance to the antiproliferative effect of interferon-alpha.

C C Flowers 1, S P Flowers 1, G J Nabel 1
PMCID: PMC2230276  PMID: 10780883

Abstract

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a 442 amino acid polypeptide-designated viral interferon regulatory factor (vIRF) that displays homology to members of the interferon regulatory factor (IRF) family that bind to consensus interferon sequences and transactivate cellular genes that can modulate growth inhibition. Studies were conducted to determine whether vIRF affects the growth suppression mediated by interferon-alpha (IFN-alpha) in a human B lymphocyte cell line. MATERIALS AND METHODS: The human B lymphocyte cell line Daudi, which is sensitive to the antiproliferative effects of IFN-alpha, was stably transfected to express vIRF, and the proliferative response of vIRF expressing cells to IFN-alpha was compared with controls. The effect of vIRF on IRF- 1 transactivation was analyzed by co-transfection of an IFN-alpha-responsive chloramphenicol acetyltransferase reporter and expression plasmids encoding IRF-1 and vIRF. Electrophoretic mobility shift assays were conducted to determine whether vIRF interferes with the DNA binding activity of IRF-1. RESULTS: Daudi human B lymphocyte cells expressing vIRF were resistant to the antiproliferative effects of IFN-alpha, whereas wild-type Daudi or Daudi cells transformed with vector DNA were growth inhibited by IFN-alpha. The activation of an interferon-responsive reporter by IFN-alpha or IRF-1 was repressed by expression of vIRF. IRF-1 DNA binding activity was unaffected by vIRF, and vIRF alone did not bind to the interferon consensus sequence. CONCLUSIONS: These studies revealed that vIRF functions to inhibit interferon-mediated growth control of a human B lymphocyte cell line by targeting IRF-1 transactivation of interferon-inducible genes. Since KSHV is a B lymphotropic herpesvirus associated with two forms of B lymphocyte neoplasms, these effects of vIRF likely contribute to B cell oncogenesis associated with KSHV infection.

Full text

PDF
402

Images in this article

405Fig. 1
on p.405
408Fig. 4
on p.408

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aman P., von Gabain A. An Epstein-Barr virus immortalization associated gene segment interferes specifically with the IFN-induced anti-proliferative response in human B-lymphoid cell lines. EMBO J. 1990 Jan;9(1):147–152. doi: 10.1002/j.1460-2075.1990.tb08090.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ambroziak J. A., Blackbourn D. J., Herndier B. G., Glogau R. G., Gullett J. H., McDonald A. R., Lennette E. T., Levy J. A. Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma patients. Science. 1995 Apr 28;268(5210):582–583. doi: 10.1126/science.7725108. [DOI] [PubMed] [Google Scholar]
  3. Arvanitakis L., Mesri E. A., Nador R. G., Said J. W., Asch A. S., Knowles D. M., Cesarman E. Establishment and characterization of a primary effusion (body cavity-based) lymphoma cell line (BC-3) harboring kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus. Blood. 1996 Oct 1;88(7):2648–2654. [PubMed] [Google Scholar]
  4. Bertin J., Armstrong R. C., Ottilie S., Martin D. A., Wang Y., Banks S., Wang G. H., Senkevich T. G., Alnemri E. S., Moss B. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1172–1176. doi: 10.1073/pnas.94.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boshoff C., Schulz T. F., Kennedy M. M., Graham A. K., Fisher C., Thomas A., McGee J. O., Weiss R. A., O'Leary J. J. Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med. 1995 Dec;1(12):1274–1278. doi: 10.1038/nm1295-1274. [DOI] [PubMed] [Google Scholar]
  6. Bovolenta C., Driggers P. H., Marks M. S., Medin J. A., Politis A. D., Vogel S. N., Levy D. E., Sakaguchi K., Appella E., Coligan J. E. Molecular interactions between interferon consensus sequence binding protein and members of the interferon regulatory factor family. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5046–5050. doi: 10.1073/pnas.91.11.5046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cesarman E., Chang Y., Moore P. S., Said J. W., Knowles D. M. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995 May 4;332(18):1186–1191. doi: 10.1056/NEJM199505043321802. [DOI] [PubMed] [Google Scholar]
  8. Chang Y., Cesarman E., Pessin M. S., Lee F., Culpepper J., Knowles D. M., Moore P. S. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865–1869. doi: 10.1126/science.7997879. [DOI] [PubMed] [Google Scholar]
  9. Decker L. L., Shankar P., Khan G., Freeman R. B., Dezube B. J., Lieberman J., Thorley-Lawson D. A. The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients. J Exp Med. 1996 Jul 1;184(1):283–288. doi: 10.1084/jem.184.1.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dupin N., Grandadam M., Calvez V., Gorin I., Aubin J. T., Havard S., Lamy F., Leibowitch M., Huraux J. M., Escande J. P. Herpesvirus-like DNA sequences in patients with Mediterranean Kaposi's sarcoma. Lancet. 1995 Mar 25;345(8952):761–762. doi: 10.1016/s0140-6736(95)90642-8. [DOI] [PubMed] [Google Scholar]
  11. Foreman K. E., Friborg J., Jr, Kong W. P., Woffendin C., Polverini P. J., Nickoloff B. J., Nabel G. J. Propagation of a human herpesvirus from AIDS-associated Kaposi's sarcoma. N Engl J Med. 1997 Jan 16;336(3):163–171. doi: 10.1056/NEJM199701163360302. [DOI] [PubMed] [Google Scholar]
  12. Fujita T., Sakakibara J., Sudo Y., Miyamoto M., Kimura Y., Taniguchi T. Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements. EMBO J. 1988 Nov;7(11):3397–3405. doi: 10.1002/j.1460-2075.1988.tb03213.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gao S. J., Boshoff C., Jayachandra S., Weiss R. A., Chang Y., Moore P. S. KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene. 1997 Oct 16;15(16):1979–1985. doi: 10.1038/sj.onc.1201571. [DOI] [PubMed] [Google Scholar]
  14. Gao S. J., Kingsley L., Hoover D. R., Spira T. J., Rinaldo C. R., Saah A., Phair J., Detels R., Parry P., Chang Y. Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med. 1996 Jul 25;335(4):233–241. doi: 10.1056/NEJM199607253350403. [DOI] [PubMed] [Google Scholar]
  15. Godden-Kent D., Talbot S. J., Boshoff C., Chang Y., Moore P., Weiss R. A., Mittnacht S. The cyclin encoded by Kaposi's sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1. J Virol. 1997 Jun;71(6):4193–4198. doi: 10.1128/jvi.71.6.4193-4198.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Harada H., Fujita T., Miyamoto M., Kimura Y., Maruyama M., Furia A., Miyata T., Taniguchi T. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell. 1989 Aug 25;58(4):729–739. doi: 10.1016/0092-8674(89)90107-4. [DOI] [PubMed] [Google Scholar]
  17. Harada H., Takahashi E., Itoh S., Harada K., Hori T. A., Taniguchi T. Structure and regulation of the human interferon regulatory factor 1 (IRF-1) and IRF-2 genes: implications for a gene network in the interferon system. Mol Cell Biol. 1994 Feb;14(2):1500–1509. doi: 10.1128/mcb.14.2.1500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harada H., Willison K., Sakakibara J., Miyamoto M., Fujita T., Taniguchi T. Absence of the type I IFN system in EC cells: transcriptional activator (IRF-1) and repressor (IRF-2) genes are developmentally regulated. Cell. 1990 Oct 19;63(2):303–312. doi: 10.1016/0092-8674(90)90163-9. [DOI] [PubMed] [Google Scholar]
  19. Jung J. U., Desrosiers R. C. Association of the viral oncoprotein STP-C488 with cellular ras. Mol Cell Biol. 1995 Dec;15(12):6506–6512. doi: 10.1128/mcb.15.12.6506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kanda K., Decker T., Aman P., Wahlström M., von Gabain A., Kallin B. The EBNA2-related resistance towards alpha interferon (IFN-alpha) in Burkitt's lymphoma cells effects induction of IFN-induced genes but not the activation of transcription factor ISGF-3. Mol Cell Biol. 1992 Nov;12(11):4930–4936. doi: 10.1128/mcb.12.11.4930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kedes D. H., Operskalski E., Busch M., Kohn R., Flood J., Ganem D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nat Med. 1996 Aug;2(8):918–924. doi: 10.1038/nm0896-918. [DOI] [PubMed] [Google Scholar]
  22. Kimura T., Nakayama K., Penninger J., Kitagawa M., Harada H., Matsuyama T., Tanaka N., Kamijo R., Vilcek J., Mak T. W. Involvement of the IRF-1 transcription factor in antiviral responses to interferons. Science. 1994 Jun 24;264(5167):1921–1924. doi: 10.1126/science.8009222. [DOI] [PubMed] [Google Scholar]
  23. Kirchhoff S., Schaper F., Hauser H. Interferon regulatory factor 1 (IRF-1) mediates cell growth inhibition by transactivation of downstream target genes. Nucleic Acids Res. 1993 Jun 25;21(12):2881–2889. doi: 10.1093/nar/21.12.2881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kozak M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell. 1986 Jan 31;44(2):283–292. doi: 10.1016/0092-8674(86)90762-2. [DOI] [PubMed] [Google Scholar]
  25. Lennette E. T., Blackbourn D. J., Levy J. A. Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients. Lancet. 1996 Sep 28;348(9031):858–861. doi: 10.1016/S0140-6736(96)03240-0. [DOI] [PubMed] [Google Scholar]
  26. Li M., Lee H., Yoon D. W., Albrecht J. C., Fleckenstein B., Neipel F., Jung J. U. Kaposi's sarcoma-associated herpesvirus encodes a functional cyclin. J Virol. 1997 Mar;71(3):1984–1991. doi: 10.1128/jvi.71.3.1984-1991.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lin R., Mustafa A., Nguyen H., Gewert D., Hiscott J. Mutational analysis of interferon (IFN) regulatory factors 1 and 2. Effects on the induction of IFN-beta gene expression. J Biol Chem. 1994 Jul 1;269(26):17542–17549. [PubMed] [Google Scholar]
  28. Maniatis T., Jeffrey A., van deSande H. Chain length determination of small double- and single-stranded DNA molecules by polyacrylamide gel electrophoresis. Biochemistry. 1975 Aug 26;14(17):3787–3794. doi: 10.1021/bi00688a010. [DOI] [PubMed] [Google Scholar]
  29. Meinl E., Hohlfeld R., Wekerle H., Fleckenstein B. Immortalization of human T cells by Herpesvirus saimiri. Immunol Today. 1995 Feb;16(2):55–58. doi: 10.1016/0167-5699(95)80087-5. [DOI] [PubMed] [Google Scholar]
  30. Moore P. S., Boshoff C., Weiss R. A., Chang Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science. 1996 Dec 6;274(5293):1739–1744. doi: 10.1126/science.274.5293.1739. [DOI] [PubMed] [Google Scholar]
  31. Moore P. S., Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995 May 4;332(18):1181–1185. doi: 10.1056/NEJM199505043321801. [DOI] [PubMed] [Google Scholar]
  32. Moore P. S., Gao S. J., Dominguez G., Cesarman E., Lungu O., Knowles D. M., Garber R., Pellett P. E., McGeoch D. J., Chang Y. Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae. J Virol. 1996 Jan;70(1):549–558. doi: 10.1128/jvi.70.1.549-558.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Moore P. S., Kingsley L. A., Holmberg S. D., Spira T., Gupta P., Hoover D. R., Parry J. P., Conley L. J., Jaffe H. W., Chang Y. Kaposi's sarcoma-associated herpesvirus infection prior to onset of Kaposi's sarcoma. AIDS. 1996 Feb;10(2):175–180. doi: 10.1097/00002030-199602000-00007. [DOI] [PubMed] [Google Scholar]
  34. Nelson N., Marks M. S., Driggers P. H., Ozato K. Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription. Mol Cell Biol. 1993 Jan;13(1):588–599. doi: 10.1128/mcb.13.1.588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Orenstein J. M., Alkan S., Blauvelt A., Jeang K. T., Weinstein M. D., Ganem D., Herndier B. Visualization of human herpesvirus type 8 in Kaposi's sarcoma by light and transmission electron microscopy. AIDS. 1997 Apr;11(5):F35–F45. doi: 10.1097/00002030-199705000-00001. [DOI] [PubMed] [Google Scholar]
  36. Renne R., Zhong W., Herndier B., McGrath M., Abbey N., Kedes D., Ganem D. Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med. 1996 Mar;2(3):342–346. doi: 10.1038/nm0396-342. [DOI] [PubMed] [Google Scholar]
  37. Rettig M. B., Ma H. J., Vescio R. A., Põld M., Schiller G., Belson D., Savage A., Nishikubo C., Wu C., Fraser J. Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. Science. 1997 Jun 20;276(5320):1851–1854. doi: 10.1126/science.276.5320.1851. [DOI] [PubMed] [Google Scholar]
  38. Russo J. J., Bohenzky R. A., Chien M. C., Chen J., Yan M., Maddalena D., Parry J. P., Peruzzi D., Edelman I. S., Chang Y. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14862–14867. doi: 10.1073/pnas.93.25.14862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sarid R., Sato T., Bohenzky R. A., Russo J. J., Chang Y. Kaposi's sarcoma-associated herpesvirus encodes a functional bcl-2 homologue. Nat Med. 1997 Mar;3(3):293–298. doi: 10.1038/nm0397-293. [DOI] [PubMed] [Google Scholar]
  40. Schalling M., Ekman M., Kaaya E. E., Linde A., Biberfeld P. A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nat Med. 1995 Jul;1(7):707–708. doi: 10.1038/nm0795-707. [DOI] [PubMed] [Google Scholar]
  41. Sharf R., Azriel A., Lejbkowicz F., Winograd S. S., Ehrlich R., Levi B. Z. Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. J Biol Chem. 1995 Jun 2;270(22):13063–13069. doi: 10.1074/jbc.270.22.13063. [DOI] [PubMed] [Google Scholar]
  42. Simpson G. R., Schulz T. F., Whitby D., Cook P. M., Boshoff C., Rainbow L., Howard M. R., Gao S. J., Bohenzky R. A., Simmonds P. Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet. 1996 Oct 26;348(9035):1133–1138. doi: 10.1016/S0140-6736(96)07560-5. [DOI] [PubMed] [Google Scholar]
  43. Soulier J., Grollet L., Oksenhendler E., Cacoub P., Cazals-Hatem D., Babinet P., d'Agay M. F., Clauvel J. P., Raphael M., Degos L. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995 Aug 15;86(4):1276–1280. [PubMed] [Google Scholar]
  44. Tamura T., Ishihara M., Lamphier M. S., Tanaka N., Oishi I., Aizawa S., Matsuyama T., Mak T. W., Taki S., Taniguchi T. An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes. Nature. 1995 Aug 17;376(6541):596–599. doi: 10.1038/376596a0. [DOI] [PubMed] [Google Scholar]
  45. Tanaka N., Ishihara M., Kitagawa M., Harada H., Kimura T., Matsuyama T., Lamphier M. S., Aizawa S., Mak T. W., Taniguchi T. Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1. Cell. 1994 Jun 17;77(6):829–839. doi: 10.1016/0092-8674(94)90132-5. [DOI] [PubMed] [Google Scholar]
  46. Tanaka N., Taniguchi T. Cytokine gene regulation: regulatory cis-elements and DNA binding factors involved in the interferon system. Adv Immunol. 1992;52:263–281. doi: 10.1016/s0065-2776(08)60877-9. [DOI] [PubMed] [Google Scholar]
  47. Taniguchi T., Harada H., Lamphier M. Regulation of the interferon system and cell growth by the IRF transcription factors. J Cancer Res Clin Oncol. 1995;121(9-10):516–520. doi: 10.1007/BF01197763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Thanos D., Maniatis T. Identification of the rel family members required for virus induction of the human beta interferon gene. Mol Cell Biol. 1995 Jan;15(1):152–164. doi: 10.1128/mcb.15.1.152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Thome M., Schneider P., Hofmann K., Fickenscher H., Meinl E., Neipel F., Mattmann C., Burns K., Bodmer J. L., Schröter M. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature. 1997 Apr 3;386(6624):517–521. doi: 10.1038/386517a0. [DOI] [PubMed] [Google Scholar]
  50. Whitby D., Howard M. R., Tenant-Flowers M., Brink N. S., Copas A., Boshoff C., Hatzioannou T., Suggett F. E., Aldam D. M., Denton A. S. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet. 1995 Sep 23;346(8978):799–802. doi: 10.1016/s0140-6736(95)91619-9. [DOI] [PubMed] [Google Scholar]
  51. Willman C. L., Sever C. E., Pallavicini M. G., Harada H., Tanaka N., Slovak M. L., Yamamoto H., Harada K., Meeker T. C., List A. F. Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia. Science. 1993 Feb 12;259(5097):968–971. doi: 10.1126/science.8438156. [DOI] [PubMed] [Google Scholar]
  52. Yamagata T., Nishida J., Tanaka S., Sakai R., Mitani K., Yoshida M., Taniguchi T., Yazaki Y., Hirai H. A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes. Mol Cell Biol. 1996 Apr;16(4):1283–1294. doi: 10.1128/MCB.16.4.1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Yamamoto H., Lamphier M. S., Fujita T., Taniguchi T., Harada H. The oncogenic transcription factor IRF-2 possesses a transcriptional repression and a latent activation domain. Oncogene. 1994 May;9(5):1423–1428. [PubMed] [Google Scholar]
  54. Zhong W., Wang H., Herndier B., Ganem D. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6641–6646. doi: 10.1073/pnas.93.13.6641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Zimring J. C., Goodbourn S., Offermann M. K. Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1-mediated transcription. J Virol. 1998 Jan;72(1):701–707. doi: 10.1128/jvi.72.1.701-707.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ

RESOURCES