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. 1992 Oct;66(10):5890–5897. doi: 10.1128/jvi.66.10.5890-5897.1992

A novel Ets-related transcription factor, Elf-1, binds to human immunodeficiency virus type 2 regulatory elements that are required for inducible trans activation in T cells.

J M Leiden 1, C Y Wang 1, B Petryniak 1, D M Markovitz 1, G J Nabel 1, C B Thompson 1
PMCID: PMC241465  PMID: 1527846

Abstract

Human immunodeficiency virus type 1 (HIV-1) and HIV-2 are structurally related retroviruses which both cause AIDS in humans. Although both viruses establish latency in quiescent human-peripheral-blood T cells, the asymptomatic phase of HIV-2 infection may be more prolonged than that of HIV-1. The latent phases of both HIV-1 and HIV-2 infection have been shown to be disrupted by T-cell activation, a process that requires host cell transcription factors. In the case of HIV-1, the transcription factor NF-kappa B is sufficient for inducible transcriptional activation. In contrast, factors in addition to NF-kappa B are required to activate HIV-2 transcription in infected T cells. In this report, we demonstrate that a novel Ets-related transcription factor, Elf-1, binds specifically to two purine-rich motifs in the HIV-2 enhancer. Mutagenesis experiments demonstrated that these Elf-1 binding sites are required for induction of HIV-2 transcription following T-cell-receptor-mediated T-cell activation. Moreover, Elf-1 is the only factor present in activated T-cell nuclear extracts that binds to these sites in electrophoretic mobility shift assays. Thus, Elf-1 is a novel transcription factor that appears to be required for the T-cell-receptor-mediated trans activation of HIV-2 gene expression. These results may explain differences in the clinical spectra of diseases caused by HIV-1 and HIV-2 and may also have implications for the design of therapeutic approaches to HIV-2 infection.

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Selected References

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

  1. Arya S. K., Gallo R. C. Human immunodeficiency virus type 2 long terminal repeat: analysis of regulatory elements. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9753–9757. doi: 10.1073/pnas.85.24.9753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arya S. K. Human and simian immunodeficiency retroviruses: activation and differential transactivation of gene expression. AIDS Res Hum Retroviruses. 1988 Jun;4(3):175–186. doi: 10.1089/aid.1988.4.175. [DOI] [PubMed] [Google Scholar]
  3. Arya S. K. Human immunodeficiency virus type-2 gene expression: two enhancers and their activation by T-cell activators. New Biol. 1990 Jan;2(1):57–65. [PubMed] [Google Scholar]
  4. Barabe P., Digoutte J. P., Tristan J. F., Peghini M., Griffet P., Jean P., Seignot P., Sarthou J. L., Leguenno B., Berlioz C. Infections par les virus de l'immunodéficience humaine (VIH1 et VIH2) à Dakar. Aspects épidémiologiques et cliniques. Med Trop (Mars) 1988 Oct-Dec;48(4):337–344. [PubMed] [Google Scholar]
  5. Bhat N. K., Komschlies K. L., Fujiwara S., Fisher R. J., Mathieson B. J., Gregorio T. A., Young H. A., Kasik J. W., Ozato K., Papas T. S. Expression of ets genes in mouse thymocyte subsets and T cells. J Immunol. 1989 Jan 15;142(2):672–678. [PubMed] [Google Scholar]
  6. Bosselut R., Duvall J. F., Gégonne A., Bailly M., Hémar A., Brady J., Ghysdael J. The product of the c-ets-1 proto-oncogene and the related Ets2 protein act as transcriptional activators of the long terminal repeat of human T cell leukemia virus HTLV-1. EMBO J. 1990 Oct;9(10):3137–3144. doi: 10.1002/j.1460-2075.1990.tb07511.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burtis K. C., Thummel C. S., Jones C. W., Karim F. D., Hogness D. S. The Drosophila 74EF early puff contains E74, a complex ecdysone-inducible gene that encodes two ets-related proteins. Cell. 1990 Apr 6;61(1):85–99. doi: 10.1016/0092-8674(90)90217-3. [DOI] [PubMed] [Google Scholar]
  8. Clavel F., Guyader M., Guétard D., Sallé M., Montagnier L., Alizon M. Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature. 1986 Dec 18;324(6098):691–695. doi: 10.1038/324691a0. [DOI] [PubMed] [Google Scholar]
  9. Clavel F., Guétard D., Brun-Vézinet F., Chamaret S., Rey M. A., Santos-Ferreira M. O., Laurent A. G., Dauguet C., Katlama C., Rouzioux C. Isolation of a new human retrovirus from West African patients with AIDS. Science. 1986 Jul 18;233(4761):343–346. doi: 10.1126/science.2425430. [DOI] [PubMed] [Google Scholar]
  10. Clavel F., Mansinho K., Chamaret S., Guetard D., Favier V., Nina J., Santos-Ferreira M. O., Champalimaud J. L., Montagnier L. Human immunodeficiency virus type 2 infection associated with AIDS in West Africa. N Engl J Med. 1987 May 7;316(19):1180–1185. doi: 10.1056/NEJM198705073161903. [DOI] [PubMed] [Google Scholar]
  11. Cortes E., Detels R., Aboulafia D., Li X. L., Moudgil T., Alam M., Bonecker C., Gonzaga A., Oyafuso L., Tondo M. HIV-1, HIV-2, and HTLV-I infection in high-risk groups in Brazil. N Engl J Med. 1989 Apr 13;320(15):953–958. doi: 10.1056/NEJM198904133201501. [DOI] [PubMed] [Google Scholar]
  12. Durand D. B., Shaw J. P., Bush M. R., Replogle R. E., Belagaje R., Crabtree G. R. Characterization of antigen receptor response elements within the interleukin-2 enhancer. Mol Cell Biol. 1988 Apr;8(4):1715–1724. doi: 10.1128/mcb.8.4.1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Emerman M., Guyader M., Montagnier L., Baltimore D., Muesing M. A. The specificity of the human immunodeficiency virus type 2 transactivator is different from that of human immunodeficiency virus type 1. EMBO J. 1987 Dec 1;6(12):3755–3760. doi: 10.1002/j.1460-2075.1987.tb02710.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fujiwara S., Fisher R. J., Bhat N. K., Diaz de la Espina S. M., Papas T. S. A short-lived nuclear phosphoprotein encoded by the human ets-2 proto-oncogene is stabilized by activation of protein kinase C. Mol Cell Biol. 1988 Nov;8(11):4700–4706. doi: 10.1128/mcb.8.11.4700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fujiwara S., Koizumi S., Fisher R. J., Bhat N. K., Papas T. S. Phosphorylation of the ETS-2 protein: regulation by the T-cell antigen receptor-CD3 complex. Mol Cell Biol. 1990 Mar;10(3):1249–1253. doi: 10.1128/mcb.10.3.1249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gottschalk L. R., Leiden J. M. Identification and functional characterization of the human T-cell receptor beta gene transcriptional enhancer: common nuclear proteins interact with the transcriptional regulatory elements of the T-cell receptor alpha and beta genes. Mol Cell Biol. 1990 Oct;10(10):5486–5495. doi: 10.1128/mcb.10.10.5486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Greene W. C. The molecular biology of human immunodeficiency virus type 1 infection. N Engl J Med. 1991 Jan 31;324(5):308–317. doi: 10.1056/NEJM199101313240506. [DOI] [PubMed] [Google Scholar]
  18. Gunther C. V., Nye J. A., Bryner R. S., Graves B. J. Sequence-specific DNA binding of the proto-oncoprotein ets-1 defines a transcriptional activator sequence within the long terminal repeat of the Moloney murine sarcoma virus. Genes Dev. 1990 Apr;4(4):667–679. doi: 10.1101/gad.4.4.667. [DOI] [PubMed] [Google Scholar]
  19. Guyader M., Emerman M., Sonigo P., Clavel F., Montagnier L., Alizon M. Genome organization and transactivation of the human immunodeficiency virus type 2. Nature. 1987 Apr 16;326(6114):662–669. doi: 10.1038/326662a0. [DOI] [PubMed] [Google Scholar]
  20. Ho I. C., Bhat N. K., Gottschalk L. R., Lindsten T., Thompson C. B., Papas T. S., Leiden J. M. Sequence-specific binding of human Ets-1 to the T cell receptor alpha gene enhancer. Science. 1990 Nov 9;250(4982):814–818. doi: 10.1126/science.2237431. [DOI] [PubMed] [Google Scholar]
  21. Ho I. C., Leiden J. M. Regulation of the human T-cell receptor alpha gene enhancer: multiple ubiquitous and T-cell-specific nuclear proteins interact with four hypomethylated enhancer elements. Mol Cell Biol. 1990 Sep;10(9):4720–4727. doi: 10.1128/mcb.10.9.4720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ho I. C., Yang L. H., Morle G., Leiden J. M. A T-cell-specific transcriptional enhancer element 3' of C alpha in the human T-cell receptor alpha locus. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6714–6718. doi: 10.1073/pnas.86.17.6714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jones K. A. HIV trans-activation and transcription control mechanisms. New Biol. 1989 Nov;1(2):127–135. [PubMed] [Google Scholar]
  24. June C. H., Ledbetter J. A., Gillespie M. M., Lindsten T., Thompson C. B. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol. 1987 Dec;7(12):4472–4481. doi: 10.1128/mcb.7.12.4472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kanki P. J. Clinical significance of HIV-2 infection in West Africa. AIDS Clin Rev. 1989:95–108. [PubMed] [Google Scholar]
  26. Karim F. D., Urness L. D., Thummel C. S., Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A., Gunther C. V., Nye J. A. The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence. Genes Dev. 1990 Sep;4(9):1451–1453. doi: 10.1101/gad.4.9.1451. [DOI] [PubMed] [Google Scholar]
  27. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  28. Koizumi S., Fisher R. J., Fujiwara S., Jorcyk C., Bhat N. K., Seth A., Papas T. S. Isoforms of the human ets-1 protein: generation by alternative splicing and differential phosphorylation. Oncogene. 1990 May;5(5):675–681. [PubMed] [Google Scholar]
  29. Maekawa T., Sakura H., Kanei-Ishii C., Sudo T., Yoshimura T., Fujisawa J., Yoshida M., Ishii S. Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. EMBO J. 1989 Jul;8(7):2023–2028. doi: 10.1002/j.1460-2075.1989.tb03610.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Markovitz D. M., Hannibal M., Perez V. L., Gauntt C., Folks T. M., Nabel G. J. Differential regulation of human immunodeficiency viruses (HIVs): a specific regulatory element in HIV-2 responds to stimulation of the T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9098–9102. doi: 10.1073/pnas.87.23.9098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. McCune J. M. HIV-1: the infective process in vivo. Cell. 1991 Jan 25;64(2):351–363. doi: 10.1016/0092-8674(91)90644-e. [DOI] [PubMed] [Google Scholar]
  32. McKnight S., Tjian R. Transcriptional selectivity of viral genes in mammalian cells. Cell. 1986 Sep 12;46(6):795–805. doi: 10.1016/0092-8674(86)90061-9. [DOI] [PubMed] [Google Scholar]
  33. Mitchell P. J., Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989 Jul 28;245(4916):371–378. doi: 10.1126/science.2667136. [DOI] [PubMed] [Google Scholar]
  34. Miyatake S., Otsuka T., Yokota T., Lee F., Arai K. Structure of the chromosomal gene for granulocyte-macrophage colony stimulating factor: comparison of the mouse and human genes. EMBO J. 1985 Oct;4(10):2561–2568. doi: 10.1002/j.1460-2075.1985.tb03971.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Miyatake S., Yokota T., Lee F., Arai K. Structure of the chromosomal gene for murine interleukin 3. Proc Natl Acad Sci U S A. 1985 Jan;82(2):316–320. doi: 10.1073/pnas.82.2.316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  37. Pognonec P., Boulukos K. E., Gesquière J. C., Stéhelin D., Ghysdael J. Mitogenic stimulation of thymocytes results in the calcium-dependent phosphorylation of c-ets-1 proteins. EMBO J. 1988 Apr;7(4):977–983. doi: 10.1002/j.1460-2075.1988.tb02904.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Studier F. W., Rosenberg A. H., Dunn J. J., Dubendorff J. W. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol. 1990;185:60–89. doi: 10.1016/0076-6879(90)85008-c. [DOI] [PubMed] [Google Scholar]
  39. Tan T. H., Horikoshi M., Roeder R. G. Purification and characterization of multiple nuclear factors that bind to the TAX-inducible enhancer within the human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1989 Apr;9(4):1733–1745. doi: 10.1128/mcb.9.4.1733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Thompson C. B., Wang C. Y., Ho I. C., Bohjanen P. R., Petryniak B., June C. H., Miesfeldt S., Zhang L., Nabel G. J., Karpinski B. cis-acting sequences required for inducible interleukin-2 enhancer function bind a novel Ets-related protein, Elf-1. Mol Cell Biol. 1992 Mar;12(3):1043–1053. doi: 10.1128/mcb.12.3.1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Thompson C. C., Brown T. A., McKnight S. L. Convergence of Ets- and notch-related structural motifs in a heteromeric DNA binding complex. Science. 1991 Aug 16;253(5021):762–768. doi: 10.1126/science.1876833. [DOI] [PubMed] [Google Scholar]
  42. Tong-Starkesen S. E., Luciw P. A., Peterlin B. M. Signaling through T lymphocyte surface proteins, TCR/CD3 and CD28, activates the HIV-1 long terminal repeat. J Immunol. 1989 Jan 15;142(2):702–707. [PubMed] [Google Scholar]
  43. Turka L. A., Schatz D. G., Oettinger M. A., Chun J. J., Gorka C., Lee K., McCormack W. T., Thompson C. B. Thymocyte expression of RAG-1 and RAG-2: termination by T cell receptor cross-linking. Science. 1991 Aug 16;253(5021):778–781. doi: 10.1126/science.1831564. [DOI] [PubMed] [Google Scholar]
  44. Urness L. D., Thummel C. S. Molecular interactions within the ecdysone regulatory hierarchy: DNA binding properties of the Drosophila ecdysone-inducible E74A protein. Cell. 1990 Oct 5;63(1):47–61. doi: 10.1016/0092-8674(90)90287-o. [DOI] [PubMed] [Google Scholar]
  45. Wang C. Y., Petryniak B., Ho I. C., Thompson C. B., Leiden J. M. Evolutionarily conserved Ets family members display distinct DNA binding specificities. J Exp Med. 1992 May 1;175(5):1391–1399. doi: 10.1084/jem.175.5.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wasylyk B., Wasylyk C., Flores P., Begue A., Leprince D., Stehelin D. The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation. Nature. 1990 Jul 12;346(6280):191–193. doi: 10.1038/346191a0. [DOI] [PubMed] [Google Scholar]

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