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. 1990 Dec;87(23):9098–9102. doi: 10.1073/pnas.87.23.9098

Differential regulation of human immunodeficiency viruses (HIVs): a specific regulatory element in HIV-2 responds to stimulation of the T-cell antigen receptor.

D M Markovitz 1, M Hannibal 1, V L Perez 1, C Gauntt 1, T M Folks 1, G J Nabel 1
PMCID: PMC55111  PMID: 2147512

Abstract

The human immunodeficiency viruses (HIVs) types 1 and 2 have similar genetic organization but differ significantly in nucleic acid sequence. Although infection by either agent leads to symptoms of immunodeficiency, recent studies suggest potential differences in the time course and severity of these diseases. In this report, the transcriptional regulation and induction of these retroviruses were analyzed. We report that the regulation of HIV-2 differs from that of HIV-1: a distinct T-cell activation pathway, triggering of the CD3 component of the T-cell receptor complex, stimulates HIV-2 but not HIV-1 gene expression. The response to T-cell receptor stimulation in HIV-2 is mediated partly by an upstream regulatory element, termed CD3R, which is recognized by a sequence-specific DNA binding protein, NF-CD3R. Jurkat T leukemia cell lines containing HIV-2 provirus also showed increased viral replication after stimulation of the T-cell receptor complex, in contrast to HIV-1. These findings suggest that transcriptional regulation and induction of HIV-2 differ from HIV-1 and raise the possibility that different cofactors contribute to the activation of HIV-1- and HIV-2-associated AIDS.

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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. Baldwin A. S., Jr, Sharp P. A. Two transcription factors, NF-kappa B and H2TF1, interact with a single regulatory sequence in the class I major histocompatibility complex promoter. Proc Natl Acad Sci U S A. 1988 Feb;85(3):723–727. doi: 10.1073/pnas.85.3.723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Bielinska A., Krasnow S., Nabel G. J. NF-kappa B-mediated activation of the human immunodeficiency virus enhancer: site of transcriptional initiation is independent of the TATA box. J Virol. 1989 Sep;63(9):4097–4100. doi: 10.1128/jvi.63.9.4097-4100.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Böhnlein E., Lowenthal J. W., Siekevitz M., Ballard D. W., Franza B. R., Greene W. C. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell. 1988 Jun 3;53(5):827–836. doi: 10.1016/0092-8674(88)90099-2. [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. Couroucé A. M. A prospective study of HIV-2 prevalence in France. AIDS. 1988 Aug;2(4):261–265. [PubMed] [Google Scholar]
  13. Crabtree G. R. Contingent genetic regulatory events in T lymphocyte activation. Science. 1989 Jan 20;243(4889):355–361. doi: 10.1126/science.2783497. [DOI] [PubMed] [Google Scholar]
  14. Cross S. L., Halden N. F., Lenardo M. J., Leonard W. J. Functionally distinct NF-kappa B binding sites in the immunoglobulin kappa and IL-2 receptor alpha chain genes. Science. 1989 Apr 28;244(4903):466–469. doi: 10.1126/science.2497520. [DOI] [PubMed] [Google Scholar]
  15. Davis M. G., Kenney S. C., Kamine J., Pagano J. S., Huang E. S. Immediate-early gene region of human cytomegalovirus trans-activates the promoter of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8642–8646. doi: 10.1073/pnas.84.23.8642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Duh E. J., Maury W. J., Folks T. M., Fauci A. S., Rabson A. B. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974–5978. doi: 10.1073/pnas.86.15.5974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Dynan W. S., Tjian R. The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell. 1983 Nov;35(1):79–87. doi: 10.1016/0092-8674(83)90210-6. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Folks T. M., Clouse K. A., Justement J., Rabson A., Duh E., Kehrl J. H., Fauci A. S. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2365–2368. doi: 10.1073/pnas.86.7.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Galas D. J., Schmitz A. DNAse footprinting: a simple method for the detection of protein-DNA binding specificity. Nucleic Acids Res. 1978 Sep;5(9):3157–3170. doi: 10.1093/nar/5.9.3157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gardner P. Calcium and T lymphocyte activation. Cell. 1989 Oct 6;59(1):15–20. doi: 10.1016/0092-8674(89)90865-9. [DOI] [PubMed] [Google Scholar]
  24. Gilman M. Z., Wilson R. N., Weinberg R. A. Multiple protein-binding sites in the 5'-flanking region regulate c-fos expression. Mol Cell Biol. 1986 Dec;6(12):4305–4316. doi: 10.1128/mcb.6.12.4305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Greenberg M. E., Siegfried Z., Ziff E. B. Mutation of the c-fos gene dyad symmetry element inhibits serum inducibility of transcription in vivo and the nuclear regulatory factor binding in vitro. Mol Cell Biol. 1987 Mar;7(3):1217–1225. doi: 10.1128/mcb.7.3.1217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Griffin G. E., Leung K., Folks T. M., Kunkel S., Nabel G. J. Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature. 1989 May 4;339(6219):70–73. doi: 10.1038/339070a0. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Hirsch V. M., Olmsted R. A., Murphey-Corb M., Purcell R. H., Johnson P. R. An African primate lentivirus (SIVsm) closely related to HIV-2. Nature. 1989 Jun 1;339(6223):389–392. doi: 10.1038/339389a0. [DOI] [PubMed] [Google Scholar]
  30. Ho D. D., Moudgil T., Alam M. Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med. 1989 Dec 14;321(24):1621–1625. doi: 10.1056/NEJM198912143212401. [DOI] [PubMed] [Google Scholar]
  31. Israël A., Kimura A., Kieran M., Yano O., Kanellopoulos J., Le Bail O., Kourilsky P. A common positive trans-acting factor binds to enhancer sequences in the promoters of mouse H-2 and beta 2-microglobulin genes. Proc Natl Acad Sci U S A. 1987 May;84(9):2653–2657. doi: 10.1073/pnas.84.9.2653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kanki P. J. Clinical significance of HIV-2 infection in West Africa. AIDS Clin Rev. 1989:95–108. [PubMed] [Google Scholar]
  33. Leung K., Nabel G. J. HTLV-1 transactivator induces interleukin-2 receptor expression through an NF-kappa B-like factor. Nature. 1988 Jun 23;333(6175):776–778. doi: 10.1038/333776a0. [DOI] [PubMed] [Google Scholar]
  34. Loveday C., Pomeroy L., Weller I. V., Quirk J., Hawkins A., Williams H., Smith A., Williams P., Tedder R. S., Adler M. W. Human immunodeficiency viruses in patients attending a sexually transmitted disease clinic in London, 1982-7. BMJ. 1989 Feb 18;298(6671):419–422. doi: 10.1136/bmj.298.6671.419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Manger B., Weiss A., Imboden J., Laing T., Stobo J. D. The role of protein kinase C in transmembrane signaling by the T cell antigen receptor complex. Effects of stimulation with soluble or immobilized CD3 antibodies. J Immunol. 1987 Oct 15;139(8):2755–2760. [PubMed] [Google Scholar]
  36. Maniatis T., Goodbourn S., Fischer J. A. Regulation of inducible and tissue-specific gene expression. Science. 1987 Jun 5;236(4806):1237–1245. doi: 10.1126/science.3296191. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Neumann P. W., O'Shaughnessy M. V., Lepine D., D'Souza I., Major C., McLaughlin B. Laboratory diagnosis of the first cases of HIV-2 infection in Canada. CMAJ. 1989 Jan 15;140(2):125–128. [PMC free article] [PubMed] [Google Scholar]
  39. Osborn L., Kunkel S., Nabel G. J. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. doi: 10.1073/pnas.86.7.2336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pokrovskii V. V., Suvorova Z. K., Mangushev T. N. Infektsiia, vyzvannaia virusom immunodefitsita cheloveka tipa 2, v SSSR. Zh Mikrobiol Epidemiol Immunobiol. 1988 Oct;(10):18–20. [PubMed] [Google Scholar]
  41. Poulsen A. G., Kvinesdal B., Aaby P., Mølbak K., Frederiksen K., Dias F., Lauritzen E. Prevalence of and mortality from human immunodeficiency virus type 2 in Bissau, West Africa. Lancet. 1989 Apr 15;1(8642):827–831. doi: 10.1016/s0140-6736(89)92281-2. [DOI] [PubMed] [Google Scholar]
  42. Queen C., Baltimore D. Immunoglobulin gene transcription is activated by downstream sequence elements. Cell. 1983 Jul;33(3):741–748. doi: 10.1016/0092-8674(83)90016-8. [DOI] [PubMed] [Google Scholar]
  43. Rosen C. A., Sodroski J. G., Haseltine W. A. The location of cis-acting regulatory sequences in the human T cell lymphotropic virus type III (HTLV-III/LAV) long terminal repeat. Cell. 1985 Jul;41(3):813–823. doi: 10.1016/s0092-8674(85)80062-3. [DOI] [PubMed] [Google Scholar]
  44. Ruben S., Poteat H., Tan T. H., Kawakami K., Roeder R., Haseltine W., Rosen C. A. Cellular transcription factors and regulation of IL-2 receptor gene expression by HTLV-I tax gene product. Science. 1988 Jul 1;241(4861):89–92. doi: 10.1126/science.2838905. [DOI] [PubMed] [Google Scholar]
  45. Ruef C., Dickey P., Schable C. A., Griffith B., Williams A. E., D'Aquila R. T. A second case of the acquired immunodeficiency syndrome due to human immunodeficiency virus type 2 in the United States: the clinical implications. Am J Med. 1989 Jun;86(6 Pt 1):709–712. doi: 10.1016/0002-9343(89)90451-8. [DOI] [PubMed] [Google Scholar]
  46. Schwab R., Crow M. K., Russo C., Weksler M. E. Requirements for T cell activation by OKT3 monoclonal antibody: role of modulation of T3 molecules and interleukin 1. J Immunol. 1985 Sep;135(3):1714–1718. [PubMed] [Google Scholar]
  47. Shaw J. P., Utz P. J., Durand D. B., Toole J. J., Emmel E. A., Crabtree G. R. Identification of a putative regulator of early T cell activation genes. Science. 1988 Jul 8;241(4862):202–205. doi: 10.1126/science.3260404. [DOI] [PubMed] [Google Scholar]
  48. Singh H., Sen R., Baltimore D., Sharp P. A. A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes. Nature. 1986 Jan 9;319(6049):154–158. doi: 10.1038/319154a0. [DOI] [PubMed] [Google Scholar]
  49. SivaRaman L., Subramanian S., Thimmappaya B. Identification of a factor in HeLa cells specific for an upstream transcriptional control sequence of an EIA-inducible adenovirus promoter and its relative abundance in infected and uninfected cells. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5914–5918. doi: 10.1073/pnas.83.16.5914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. 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]
  51. Tong-Starksen S. E., Luciw P. A., Peterlin B. M. Human immunodeficiency virus long terminal repeat responds to T-cell activation signals. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6845–6849. doi: 10.1073/pnas.84.19.6845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Treisman R. Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors. Cell. 1986 Aug 15;46(4):567–574. doi: 10.1016/0092-8674(86)90882-2. [DOI] [PubMed] [Google Scholar]
  53. Weiss A., Imboden J. B. Cell surface molecules and early events involved in human T lymphocyte activation. Adv Immunol. 1987;41:1–38. doi: 10.1016/s0065-2776(08)60029-2. [DOI] [PubMed] [Google Scholar]

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