1887

Abstract

During productive infection of human T lymphocytes in cell culture, the expression of human immunodeficiency virus type 1 is temporally regulated by virus-encoded regulatory proteins. Among these Nef, whose function has not been clearly elucidated, is thought to alter CD4 T cells. We examined the possibility that the gene interferes with the translation process in a cell-free system. The results demonstrate that the gene product mediates an inhibitory effect on protein synthesis. Conversely, the use of antisense mRNA did not affect translation. Further observations suggest that this inhibitory effect is an inherent property of the gene product itself and not of its mRNA. The data show that the translational repression directed by Nef is a general phenomenon, acting on its own and on other messengers used as reporter mRNAs. We propose that, as a consequence, Nef can play an important role in the pathogenesis of AIDS.

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1994-11-01
2024-03-28
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References

  1. Cheng-Mayer C., Iannello P., Shaw K., Luciw P. A., Levy J. A. 1989; Differential effects of nef on HIV replication: implications for viral pathogenesis in the host. Science 246:1629–1632
    [Google Scholar]
  2. Ernst V., Levin D. H., London I. M. 1979; In situ phosphorylation of the α subunit of eukaryotic initiation factor 2 in reticulocyte lysates inhibited by heme deficiency, double-stranded RNA, oxidized glutathione, or the heme-regulated protein kinase. Proceedings of the National Academy of Sciences U.S.A: 762118–2122
    [Google Scholar]
  3. Galabru J., Hovanessian A. 1987; Autophosphorylation of the protein kinase dependent on double-stranded RNA. Journal of Biological Chemistry 262:15538–15544
    [Google Scholar]
  4. Garcia J. V., Miller A. D. 1991; Serine phosphorylation- independent downregulation of cell-surface CD4 by nef. Nature; London: 350508–511
    [Google Scholar]
  5. Garcia J. V., Alfano J., Miller A. D. 1993; The negative effect of human immunodeficiency virus type 1 nef on cell surface CD4 expression is not species specific and requires the cytoplasmic domain of CD4. Journal of Virology 67:1511–1516
    [Google Scholar]
  6. Greenway A. L., Mcphee D. A., Grgacic E., Hewish D., Lucantoni A., Macreadie I., Azad A. 1994; Nef 27, but not the Nef 25 isoform of human immunodeficiency virus-type 1 pNL4.3 down-regulates surface CD4 and IL-2R expression in peripheral blood mononuclear cells and transformed T cells. Virology 198:245–256
    [Google Scholar]
  7. Guy B., Kieny M. P., Riviere Y., Lepeuch C., Dott K., Girard M., Montagnier L. 1987; HIV F/3′ orf encodes a phosphoryl- ated GTP-binding protein resembling an oncogene product. Nature; London: 330266–269
    [Google Scholar]
  8. Hershey J. W. B. 1991; Translational control in mammalian cells. Annual Review of Biochemistry 60:717–755
    [Google Scholar]
  9. Hovanessian A. 1991; Interferon-induced and double-stranded RNA-activated enzymes: a specific protein kinase and 2′,5′- oligoadenylate synthetases. Journal of Interferon Research 11:199–205
    [Google Scholar]
  10. Jagus R., Anderson W. F., Safer B. 1981; The regulation of initiation of mammalian protein synthesis. Progress in Nucleic Acid Research and Molecular Biology 25:127–185
    [Google Scholar]
  11. Kaminchik J., Bashan N., Itach A., Sarver N., Gorecki M., Panet A. 1991; Genetic characterization of human immunodeficiency virus type 1 nef gene product translated in vitro and expressed in mammalian cells. Journal of Virology 65:583–588
    [Google Scholar]
  12. Koromilas A. E., Roy S., Barber G. N., Katze M. G., Sonenberg N. 1992; Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase. Science 257:1685–1689
    [Google Scholar]
  13. Kunkel T. A. 1985; Rapid and efficient site-specific mutagenesis without phenotypic selection. Proceedings of the National Academy of Sciences U.S.A: 82488–492
    [Google Scholar]
  14. Luciw P. A., Cheng-Mayer C., Levy J. A. 1987; Mutational analysis of the human immunodeficiency virus: the orf-B region down-regulates virus replication. Proceedings of the National Academy of Sciences U.S.A: 841434–1438
    [Google Scholar]
  15. Luria S., Chambers I., Berg P. 1991; Expression of the type 1 human immunodeficiency virus nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA. Proceedings of the National Academy of Sciences U.S.A: 885326–5330
    [Google Scholar]
  16. Poulin L., Levy J. A. 1992; The HIV-1 nef gene product is associated with phosphorylation of a 46 kD cellular protein. AIDS 6:787–791
    [Google Scholar]
  17. Sawai E. T., Baur A., Struble H., Peterlin B. M., Levy J. A., Cheng-Mayer C. 1994; Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes. Proceedings of the National Academy of Sciences U.S.A: 911539–1543
    [Google Scholar]
  18. Schwartz O., Riviere Y., Heard J. -M., Danos O. 1993; Reduced cell surface expression of processed human immunodeficiency virus type 1 envelope glycoprotein in the presence of nef. Journal of Virology 67:3274–3280
    [Google Scholar]
  19. Sen G. C., Lengyel P. 1992; The interferon system. Journal of Biological Chemistry 267:5017–5020
    [Google Scholar]
  20. Skowronski J., Parks D., Mariani R. 1993; Altered T cell activation and development in transgenic mice expressing the HIV- 1 nef gene. EMBO Journal 12:703–713
    [Google Scholar]
  21. Terwilliger E., Sodroski J. G., Rosen C. A., Haseltine W. A. 1986; Effects of mutations within the 3′ orf open reading frame region of human T-cell lymphotropic virus type III (HTLV-III/LAV) on replication and cytopathogenicity. Journal of Virology 60:754–760
    [Google Scholar]
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