Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1991 Dec;65(12):6645–6653. doi: 10.1128/jvi.65.12.6645-6653.1991

Human T-cell leukemia virus type II Rex binding and activity require an intact splice donor site and a specific RNA secondary structure.

A C Black 1, C T Ruland 1, M T Yip 1, J Luo 1, B Tran 1, A Kalsi 1, E Quan 1, M Aboud 1, I S Chen 1, J D Rosenblatt 1
PMCID: PMC250733  PMID: 1942248

Abstract

The human T-cell leukemia virus type II (HTLV-II) regulatory protein Rex augments cytoplasmic levels of unspliced gag-pol mRNA by acting through a Rex-responsive element (RxRE) in the long terminal repeat. Purified Rex protein binds to long terminal repeat mRNA. Here, using an immunobinding assay to measure the binding of Rex protein to mutated RxRE RNAs, we show that efficient Rex binding requires a stem-bulge-loop RNA secondary structure (nucleotides [nt] 465 to 500) and specific sequences both within the stem-bulge (nt 470 to 476) and within a conserved upstream splice donor site (nt 449 to 455). Rex function in a transient transfection expression system correlates with Rex protein-RxRE RNA binding. The ability of HTLV-II Rex to interact directly with the HTLV-II splice donor site suggests that HTLV-II Rex may increase expression of unspliced gag-pol mRNA, in part, by inhibiting splicing.

Full text

PDF
6645

Selected References

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

  1. Ahmed Y. F., Hanly S. M., Malim M. H., Cullen B. R., Greene W. C. Structure-function analyses of the HTLV-I Rex and HIV-1 Rev RNA response elements: insights into the mechanism of Rex and Rev action. Genes Dev. 1990 Jun;4(6):1014–1022. doi: 10.1101/gad.4.6.1014. [DOI] [PubMed] [Google Scholar]
  2. Ballaun C., Farrington G. K., Dobrovnik M., Rusche J., Hauber J., Böhnlein E. Functional analysis of human T-cell leukemia virus type I rex-response element: direct RNA binding of Rex protein correlates with in vivo activity. J Virol. 1991 Aug;65(8):4408–4413. doi: 10.1128/jvi.65.8.4408-4413.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bhagavati S., Ehrlich G., Kula R. W., Kwok S., Sninsky J., Udani V., Poiesz B. J. Detection of human T-cell lymphoma/leukemia virus type I DNA and antigen in spinal fluid and blood of patients with chronic progressive myelopathy. N Engl J Med. 1988 May 5;318(18):1141–1147. doi: 10.1056/NEJM198805053181801. [DOI] [PubMed] [Google Scholar]
  4. Black A. C., Chen I. S., Arrigo S., Ruland C. T., Allogiamento T., Chin E., Rosenblatt J. D. Regulation of HTLV-II gene expression by Rex involves positive and negative cis-acting elements in the 5'long terminal repeat. Virology. 1991 Apr;181(2):433–444. doi: 10.1016/0042-6822(91)90875-c. [DOI] [PubMed] [Google Scholar]
  5. Bogerd H. P., Huckaby G. L., Ahmed Y. F., Hanly S. M., Greene W. C. The type I human T-cell leukemia virus (HTLV-I) Rex trans-activator binds directly to the HTLV-I Rex and the type 1 human immunodeficiency virus Rev RNA response elements. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5704–5708. doi: 10.1073/pnas.88.13.5704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cann A. J., Rosenblatt J. D., Wachsman W., Shah N. P., Chen I. S. Identification of the gene responsible for human T-cell leukaemia virus transcriptional regulation. Nature. 1985 Dec 12;318(6046):571–574. doi: 10.1038/318571a0. [DOI] [PubMed] [Google Scholar]
  7. Chen I. S., McLaughlin J., Golde D. W. Long terminal repeats of human T-cell leukaemia virus II genome determine target cell specificity. Nature. 1984 May 17;309(5965):276–279. doi: 10.1038/309276a0. [DOI] [PubMed] [Google Scholar]
  8. Chen I. S., Slamon D. J., Rosenblatt J. D., Shah N. P., Quan S. G., Wachsman W. The x gene is essential for HTLV replication. Science. 1985 Jul 5;229(4708):54–58. doi: 10.1126/science.2990037. [DOI] [PubMed] [Google Scholar]
  9. Felber B. K., Paskalis H., Kleinman-Ewing C., Wong-Staal F., Pavlakis G. N. The pX protein of HTLV-I is a transcriptional activator of its long terminal repeats. Science. 1985 Aug 16;229(4714):675–679. doi: 10.1126/science.2992082. [DOI] [PubMed] [Google Scholar]
  10. Fujisawa J., Seiki M., Kiyokawa T., Yoshida M. Functional activation of the long terminal repeat of human T-cell leukemia virus type I by a trans-acting factor. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2277–2281. doi: 10.1073/pnas.82.8.2277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  12. Grassmann R., Berchtold S., Aepinus C., Ballaun C., Boehnlein E., Fleckenstein B. In vitro binding of human T-cell leukemia virus rex proteins to the rex-response element of viral transcripts. J Virol. 1991 Jul;65(7):3721–3727. doi: 10.1128/jvi.65.7.3721-3727.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hanly S. M., Rimsky L. T., Malim M. H., Kim J. H., Hauber J., Duc Dodon M., Le S. Y., Maizel J. V., Cullen B. R., Greene W. C. Comparative analysis of the HTLV-I Rex and HIV-1 Rev trans-regulatory proteins and their RNA response elements. Genes Dev. 1989 Oct;3(10):1534–1544. doi: 10.1101/gad.3.10.1534. [DOI] [PubMed] [Google Scholar]
  14. Haseltine W. A., Sodroski J., Patarca R., Briggs D., Perkins D., Wong-Staal F. Structure of 3' terminal region of type II human T lymphotropic virus: evidence for new coding region. Science. 1984 Jul 27;225(4660):419–421. doi: 10.1126/science.6330894. [DOI] [PubMed] [Google Scholar]
  15. Hidaka M., Inoue J., Yoshida M., Seiki M. Post-transcriptional regulator (rex) of HTLV-1 initiates expression of viral structural proteins but suppresses expression of regulatory proteins. EMBO J. 1988 Feb;7(2):519–523. doi: 10.1002/j.1460-2075.1988.tb02840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hinuma Y., Nagata K., Hanaoka M., Nakai M., Matsumoto T., Kinoshita K. I., Shirakawa S., Miyoshi I. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6476–6480. doi: 10.1073/pnas.78.10.6476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Inoue J., Yoshida M., Seiki M. Transcriptional (p40x) and post-transcriptional (p27x-III) regulators are required for the expression and replication of human T-cell leukemia virus type I genes. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3653–3657. doi: 10.1073/pnas.84.11.3653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kalyanaraman V. S., Sarngadharan M. G., Robert-Guroff M., Miyoshi I., Golde D., Gallo R. C. A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science. 1982 Nov 5;218(4572):571–573. doi: 10.1126/science.6981847. [DOI] [PubMed] [Google Scholar]
  19. Kim J. H., Kaufman P. A., Hanly S. M., Rimsky L. T., Greene W. C. Rex transregulation of human T-cell leukemia virus type II gene expression. J Virol. 1991 Jan;65(1):405–414. doi: 10.1128/jvi.65.1.405-414.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lee H., Swanson P., Shorty V. S., Zack J. A., Rosenblatt J. D., Chen I. S. High rate of HTLV-II infection in seropositive i.v. drug abusers in New Orleans. Science. 1989 Apr 28;244(4903):471–475. doi: 10.1126/science.2655084. [DOI] [PubMed] [Google Scholar]
  21. Mount S. M. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. doi: 10.1093/nar/10.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nakamaye K. L., Eckstein F. Inhibition of restriction endonuclease Nci I cleavage by phosphorothioate groups and its application to oligonucleotide-directed mutagenesis. Nucleic Acids Res. 1986 Dec 22;14(24):9679–9698. doi: 10.1093/nar/14.24.9679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ohta M., Nyunoya H., Tanaka H., Okamoto T., Akagi T., Shimotohno K. Identification of a cis-regulatory element involved in accumulation of human T-cell leukemia virus type II genomic mRNA. J Virol. 1988 Dec;62(12):4445–4451. doi: 10.1128/jvi.62.12.4445-4451.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ohtani K., Nakamura M., Saito S., Noda T., Ito Y., Sugamura K., Hinuma Y. Identification of two distinct elements in the long terminal repeat of HTLV-I responsible for maximum gene expression. EMBO J. 1987 Feb;6(2):389–395. doi: 10.1002/j.1460-2075.1987.tb04767.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415–7419. doi: 10.1073/pnas.77.12.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Robert-Guroff M., Weiss S. H., Giron J. A., Jennings A. M., Ginzburg H. M., Margolis I. B., Blattner W. A., Gallo R. C. Prevalence of antibodies to HTLV-I, -II, and -III in intravenous drug abusers from an AIDS endemic region. JAMA. 1986 Jun 13;255(22):3133–3137. [PubMed] [Google Scholar]
  27. Rosenblatt J. D., Cann A. J., Slamon D. J., Smalberg I. S., Shah N. P., Fujii J., Wachsman W., Chen I. S. HTLV-II transactivation is regulated by the overlapping tax/rex nonstructural genes. Science. 1988 May 13;240(4854):916–919. doi: 10.1126/science.2834826. [DOI] [PubMed] [Google Scholar]
  28. Rosenblatt J. D., Golde D. W., Wachsman W., Giorgi J. V., Jacobs A., Schmidt G. M., Quan S., Gasson J. C., Chen I. S. A second isolate of HTLV-II associated with atypical hairy-cell leukemia. N Engl J Med. 1986 Aug 7;315(6):372–377. doi: 10.1056/NEJM198608073150606. [DOI] [PubMed] [Google Scholar]
  29. Sodroski J. G., Rosen C. A., Haseltine W. A. Trans-acting transcriptional activation of the long terminal repeat of human T lymphotropic viruses in infected cells. Science. 1984 Jul 27;225(4660):381–385. doi: 10.1126/science.6330891. [DOI] [PubMed] [Google Scholar]
  30. Sodroski J., Trus M., Perkins D., Patarca R., Wong-Staal F., Gelmann E., Gallo R., Haseltine W. A. Repetitive structure in the long-terminal-repeat element of a type II human T-cell leukemia virus. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4617–4621. doi: 10.1073/pnas.81.15.4617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tedder R. S., Shanson D. C., Jeffries D. J., Cheingsong-Popov R., Clapham P., Dalgleish A., Nagy K., Weiss R. A. Low prevalence in the UK of HTLV-I and HTLV-II infection in subjects with AIDS, with extended lymphadenopathy, and at risk of AIDS. Lancet. 1984 Jul 21;2(8395):125–128. doi: 10.1016/s0140-6736(84)91046-8. [DOI] [PubMed] [Google Scholar]
  32. Toyoshima H., Itoh M., Inoue J., Seiki M., Takaku F., Yoshida M. Secondary structure of the human T-cell leukemia virus type 1 rex-responsive element is essential for rex regulation of RNA processing and transport of unspliced RNAs. J Virol. 1990 Jun;64(6):2825–2832. doi: 10.1128/jvi.64.6.2825-2832.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wachsman W., Shimotohno K., Clark S. C., Golde D. W., Chen I. S. Expression of the 3' terminal region of human T-cell leukemia viruses. Science. 1984 Oct 12;226(4671):177–179. doi: 10.1126/science.6091270. [DOI] [PubMed] [Google Scholar]
  34. Wong-Staal F., Hahn B., Manzari V., Colombini S., Franchini G., Gelmann E. P., Gallo R. C. A survey of human leukaemias for sequences of a human retrovirus. Nature. 1983 Apr 14;302(5909):626–628. doi: 10.1038/302626a0. [DOI] [PubMed] [Google Scholar]
  35. Yip M. T., Dynan W. S., Green P. L., Black A. C., Arrigo S. J., Torbati A., Heaphy S., Ruland C., Rosenblatt J. D., Chen I. S. Human T-cell leukemia virus (HTLV) type II Rex protein binds specifically to RNA sequences of the HTLV long terminal repeat but poorly to the human immunodeficiency virus type 1 Rev-responsive element. J Virol. 1991 May;65(5):2261–2272. doi: 10.1128/jvi.65.5.2261-2272.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yoshida M., Miyoshi I., Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci U S A. 1982 Mar;79(6):2031–2035. doi: 10.1073/pnas.79.6.2031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yoshida M., Seiki M., Yamaguchi K., Takatsuki K. Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2534–2537. doi: 10.1073/pnas.81.8.2534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zuker M., Stiegler P. Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information. Nucleic Acids Res. 1981 Jan 10;9(1):133–148. doi: 10.1093/nar/9.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES