Abstract
Although human T-cell lymphotropic virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL), the role of viral gene expression in the progression to and maintenance of the leukemic state in vivo is unclear because of the inability of most previous studies to readily detect HTLV-I RNA in infected individuals. By using the reverse transcriptase-polymerase chain reaction, we detected spliced messages for the HTLV-I pX regulatory genes in primary uncultured cells from ATL patients and healthy asymptomatic carriers. In addition to the expected doubly spliced pX message, three alternatively spliced mRNAs were demonstrated (pX delta 17, pX-p21rex, and pX-orfII mRNAs, where orf = open reading frame). The same splice sites were shown in the messages from uncultured ATL cells and from the HTLV-I-producing C10/MJ cell line. Alternatively spliced pX mRNAs have the potential to code for known and putative pX gene products. Among the transcripts is a monocistronic mRNA likely to code for p21rex (pX-p21rex mRNA). Since alternative splicing of HTLV-I pX mRNA can be found in primary uncultured cells, it is likely to have a functional significance in vivo. This suggests possible roles for HTLV-I gene expression in the progression to and maintenance of ATL, as well as in the phase preceding it.
Full text
PDF




Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aldovini A., De Rossi A., Feinberg M. B., Wong-Staal F., Franchini G. Molecular analysis of a deletion mutant provirus of type I human T-cell lymphotropic virus: evidence for a doubly spliced x-lor mRNA. Proc Natl Acad Sci U S A. 1986 Jan;83(1):38–42. doi: 10.1073/pnas.83.1.38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arya S. K., Guo C., Josephs S. F., Wong-Staal F. Trans-activator gene of human T-lymphotropic virus type III (HTLV-III). Science. 1985 Jul 5;229(4708):69–73. doi: 10.1126/science.2990040. [DOI] [PubMed] [Google Scholar]
- Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Clarke M. F., Gelmann E. P., Reitz M. S., Jr Homology of human T-cell leukaemia virus envelope gene with class I HLA gene. Nature. 1983 Sep 1;305(5929):60–62. doi: 10.1038/305060a0. [DOI] [PubMed] [Google Scholar]
- Clarke M. F., Trainor C. D., Mann D. L., Gallo R. C., Reitz M. S. Methylation of human T-cell leukemia virus proviral DNA and viral RNA expression in short- and long-term cultures of infected cells. Virology. 1984 May;135(1):97–104. doi: 10.1016/0042-6822(84)90120-x. [DOI] [PubMed] [Google Scholar]
- Ensoli B., Barillari G., Salahuddin S. Z., Gallo R. C., Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature. 1990 May 3;345(6270):84–86. doi: 10.1038/345084a0. [DOI] [PubMed] [Google Scholar]
- Franchini G., Wong-Staal F., Gallo R. C. Human T-cell leukemia virus (HTLV-I) transcripts in fresh and cultured cells of patients with adult T-cell leukemia. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6207–6211. doi: 10.1073/pnas.81.19.6207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gazdar A. F., Carney D. N., Bunn P. A., Russell E. K., Jaffe E. S., Schechter G. P., Guccion J. G. Mitogen requirements for the in vitro propagation of cutaneous T-cell lymphomas. Blood. 1980 Mar;55(3):409–417. [PubMed] [Google Scholar]
- Grassmann R., Dengler C., Müller-Fleckenstein I., Fleckenstein B., McGuire K., Dokhelar M. C., Sodroski J. G., Haseltine W. A. Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector. Proc Natl Acad Sci U S A. 1989 May;86(9):3351–3355. doi: 10.1073/pnas.86.9.3351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoshino H., Esumi H., Miwa M., Shimoyama M., Minato K., Tobinai K., Hirose M., Watanabe S., Inada N., Kinoshita K. Establishment and characterization of 10 cell lines derived from patients with adult T-cell leukemia. Proc Natl Acad Sci U S A. 1983 Oct;80(19):6061–6065. doi: 10.1073/pnas.80.19.6061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Katz R. A., Skalka A. M. Control of retroviral RNA splicing through maintenance of suboptimal processing signals. Mol Cell Biol. 1990 Feb;10(2):696–704. doi: 10.1128/mcb.10.2.696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kinoshita T., Shimoyama M., Tobinai K., Ito M., Ito S., Ikeda S., Tajima K., Shimotohno K., Sugimura T. Detection of mRNA for the tax1/rex1 gene of human T-cell leukemia virus type I in fresh peripheral blood mononuclear cells of adult T-cell leukemia patients and viral carriers by using the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5620–5624. doi: 10.1073/pnas.86.14.5620. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kitamura T., Takano M., Hoshino H., Shimotohno K., Shimoyama M., Miwa M., Takaku F., Sugimura T. Methylation pattern of human T-cell leukemia virus in vivo and in vitro: pX and LTR regions are hypomethylated in vivo. Int J Cancer. 1985 May 15;35(5):629–635. doi: 10.1002/ijc.2910350510. [DOI] [PubMed] [Google Scholar]
- Klotman M. E., Kim S., Buchbinder A., DeRossi A., Baltimore D., Wong-Staal F. Kinetics of expression of multiply spliced RNA in early human immunodeficiency virus type 1 infection of lymphocytes and monocytes. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):5011–5015. doi: 10.1073/pnas.88.11.5011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kodaka T., Uchiyama T., Umadome H., Uchino H. Expression of cytokine mRNA in leukemic cells from adult T cell leukemia patients. Jpn J Cancer Res. 1989 Jun;80(6):531–536. doi: 10.1111/j.1349-7006.1989.tb01672.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mann D. L., O'Brien S. J., Gilbert D. A., Reid Y., Popovic M., Read-Connole E., Gallo R. C., Gazdar A. F. Origin of the HIV-susceptible human CD4+ cell line H9. AIDS Res Hum Retroviruses. 1989 Jun;5(3):253–255. doi: 10.1089/aid.1989.5.253. [DOI] [PubMed] [Google Scholar]
- Markham P. D., Salahuddin S. Z., Kalyanaraman V. S., Popovic M., Sarin P., Gallo R. C. Infection and transformation of fresh human umbilical cord blood cells by multiple sources of human T-cell leukemia-lymphoma virus (HTLV). Int J Cancer. 1983 Apr 15;31(4):413–420. doi: 10.1002/ijc.2910310404. [DOI] [PubMed] [Google Scholar]
- Marriott S. J., Lindholm P. F., Reid R. L., Brady J. N. Soluble HTLV-I Tax1 protein stimulates proliferation of human peripheral blood lymphocytes. New Biol. 1991 Jul;3(7):678–686. [PubMed] [Google Scholar]
- Miyoshi I., Kubonishi I., Yoshimoto S., Akagi T., Ohtsuki Y., Shiraishi Y., Nagata K., Hinuma Y. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature. 1981 Dec 24;294(5843):770–771. doi: 10.1038/294770a0. [DOI] [PubMed] [Google Scholar]
- Muesing M. A., Smith D. H., Cabradilla C. D., Benton C. V., Lasky L. A., Capon D. J. Nucleic acid structure and expression of the human AIDS/lymphadenopathy retrovirus. Nature. 1985 Feb 7;313(6002):450–458. doi: 10.1038/313450a0. [DOI] [PubMed] [Google Scholar]
- Nagashima K., Yoshida M., Seiki M. A single species of pX mRNA of human T-cell leukemia virus type I encodes trans-activator p40x and two other phosphoproteins. J Virol. 1986 Nov;60(2):394–399. doi: 10.1128/jvi.60.2.394-399.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Okayama A., Chen Y. M., Tachibana N., Shioiri S., Lee T. H., Tsuda K., Essex M. High incidence of antibodies to HTLV-I tax in blood relatives of adult T cell leukemia patients. J Infect Dis. 1991 Jan;163(1):47–52. doi: 10.1093/infdis/163.1.47. [DOI] [PubMed] [Google Scholar]
- Popovic M., Sarin P. S., Robert-Gurroff M., Kalyanaraman V. S., Mann D., Minowada J., Gallo R. C. Isolation and transmission of human retrovirus (human t-cell leukemia virus). Science. 1983 Feb 18;219(4586):856–859. doi: 10.1126/science.6600519. [DOI] [PubMed] [Google Scholar]
- Robert-Guroff M., Popovic M., Gartner S., Markham P., Gallo R. C., Reitz M. S. Structure and expression of tat-, rev-, and nef-specific transcripts of human immunodeficiency virus type 1 in infected lymphocytes and macrophages. J Virol. 1990 Jul;64(7):3391–3398. doi: 10.1128/jvi.64.7.3391-3398.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sadaie M. R., Rappaport J., Benter T., Josephs S. F., Willis R., Wong-Staal F. Missense mutations in an infectious human immunodeficiency viral genome: functional mapping of tat and identification of the rev splice acceptor. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9224–9228. doi: 10.1073/pnas.85.23.9224. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwartz S., Felber B. K., Benko D. M., Fenyö E. M., Pavlakis G. N. Cloning and functional analysis of multiply spliced mRNA species of human immunodeficiency virus type 1. J Virol. 1990 Jun;64(6):2519–2529. doi: 10.1128/jvi.64.6.2519-2529.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seiki M., Hattori S., Hirayama Y., Yoshida M. Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3618–3622. doi: 10.1073/pnas.80.12.3618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seiki M., Hikikoshi A., Taniguchi T., Yoshida M. Expression of the pX gene of HTLV-I: general splicing mechanism in the HTLV family. Science. 1985 Jun 28;228(4707):1532–1534. doi: 10.1126/science.2990031. [DOI] [PubMed] [Google Scholar]
- Smith C. W., Patton J. G., Nadal-Ginard B. Alternative splicing in the control of gene expression. Annu Rev Genet. 1989;23:527–577. doi: 10.1146/annurev.ge.23.120189.002523. [DOI] [PubMed] [Google Scholar]
- Sugamura K., Fujii M., Kannagi M., Sakitani M., Takeuchi M., Hinuma Y. Cell surface phenotypes and expression of viral antigens of various human cell lines carrying human T-cell leukemia virus. Int J Cancer. 1984 Aug 15;34(2):221–228. doi: 10.1002/ijc.2910340213. [DOI] [PubMed] [Google Scholar]
- Tanaka A., Takahashi C., Yamaoka S., Nosaka T., Maki M., Hatanaka M. Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1071–1075. doi: 10.1073/pnas.87.3.1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tendler C. L., Greenberg S. J., Blattner W. A., Manns A., Murphy E., Fleisher T., Hanchard B., Morgan O., Burton J. D., Nelson D. L. Transactivation of interleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type I-associated myelopathy: pathogenic implications and a rationale for immunotherapy. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5218–5222. doi: 10.1073/pnas.87.13.5218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wachsman W., Golde D. W., Temple P. A., Orr E. C., Clark S. C., Chen I. S. HTLV x-gene product: requirement for the env methionine initiation codon. Science. 1985 Jun 28;228(4707):1534–1537. doi: 10.1126/science.2990032. [DOI] [PubMed] [Google Scholar]
- Yoshida M., Seiki M. Recent advances in the molecular biology of HTLV-1: trans-activation of viral and cellular genes. Annu Rev Immunol. 1987;5:541–559. doi: 10.1146/annurev.iy.05.040187.002545. [DOI] [PubMed] [Google Scholar]