1887

Abstract

Since modulation of the glutathione (GSH) level has been implicated in the regulation of human immuno-deficiency virus (HIV) transcription and expression, we have undertaken an analysis of the effect of sodium valproate (VPA) on HIV-1 replication. VPA, which is an anti-epileptic drug in widespread use in clinical medicine, has been shown to depress the activity of GSH reductase, an enzyme required for maintaining high cellular levels of reduced GSH. The effect of this drug on HIV-1 replication has been studied in primary infected cells, i.e. peripheral blood mononuclear cells (PBMC) and monocyte/macrophages, in the CEM-SS cell line, and in chronically infected stimulated and non-stimulated U1 cells. We have shown that VPA markedly enhanced viral replication in all infected cells tested. Virus production was induced in U1 cells by VPA treatment and the stimulatory effects of tumour necrosis factor-α, interleukin-6 and granulocyte/macrophage colony-stimulating factor were augmented. The LTR-driven gene expression in Jurkat T cells was increased. However, the elevated viral production did not correlate with the effect of VPA on the intracellular GSH level. Thus, VPA stimulated HIV-1 replication in acutely and chronically infected cells and enhanced LTR-driven gene expression. These effects were observed for concentrations that are reached in the plasma of VPA-treated patients. Therefore, although the clinical significance of these data remains to be demonstrated, these results should be considered in the choice of an anticonvulsant drug in HIV-infected individuals.

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1996-09-01
2024-03-28
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References

  1. Ash R. J. 1986; Butyrate-induced reversal of herpes simplex virus restriction in neuroblastoma cells. Virology 155:584–592
    [Google Scholar]
  2. Attaguile G., Caruso A., Cutuli V. M. C., Di Giacomo C., Russo A., De Bernardis E., Amico-Roxas M. 1992; Influence of sodium valproate and carbamazepine on GSH levels in rat cerebral cortex. Drugs under Experimental and Clinical Research 18:465–467
    [Google Scholar]
  3. Boffa L. C., Vidaii G., Mann R. S., Ailfrey V. G. 1978; Suppression of histone deacetylation in vivo and in vitro by sodium butyrate. Journal of Biological Chemistry 253:3364–3366
    [Google Scholar]
  4. Bohan C. A., Robinson R. A., Luciw P. A., Srinivasan A. 1989; Mutational analysis of sodium butyrate inducible elements in the human immunodeficiency virus type I long terminal repeat. Virology 172:573–583
    [Google Scholar]
  5. Bradford M. 1976; A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72:248–254
    [Google Scholar]
  6. Buhl R., Holroyd K. J., Mastrangeli A., Cantin A. M., Jaffe H. A., Wells F. B., Saltini C., Crystal R. G. 1989; Systemic glutathione deficiency in symptom-free HIV seropositive individuals. Lancet ii:1294–1297
    [Google Scholar]
  7. Capek R., Esplin B. 1990; Mechanisms of anticonvulsant action of valproate: an overview and perspective. In Generalized Epilepsy pp 436–459 Edited by Avoli M., Gloor P., Kostopoulos G., Naquet R. Boston: Birkhäuser Boston;
    [Google Scholar]
  8. Chapman A., Keane P. E., Meldrum B. S., Simiand J., Vernieres J. C. 1982; Mechanism of anticonvulsant action of valproate. Progress in Neurobiology 19:315–359
    [Google Scholar]
  9. Cotariu D., Evans S., Zaidman J. L., Marcus O. 1990; Early changes in hepatic redox homeostasis following treatment with a single dose of valproic acid. Biochemical Pharmacology 40:589–593
    [Google Scholar]
  10. Cotariu D., Evans S., Lahat E., Theitler J., Bistritzer T., Zaidman J. L. 1992; Inhibition of human red blood cell glutathione reductase by valproic acid. Biochemical Pharmacology 43:425–429
    [Google Scholar]
  11. Dreifuss F. E., Santilli N., Langer D. H., Sweeney K. P., Moline K. A., Menander K. B. 1987; Valproic acid hepatic fatalities: a retrospective review. Neurology 37:379–385
    [Google Scholar]
  12. Eck H. P., Gmünder H., Hartman M., Petzoldt D., Daniel V., Drӧge W. 1989; Low concentrations of acid soluble thiols (cysteine) in the blood of HIV-l-infected patients. Biological Chemistry Hoppe Seyler 370:101–108
    [Google Scholar]
  13. Folks T. M., Justement J., Kinter A., Schnittman S., Orenstein J., Poli G., Fauci A. S. 1988; Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol 12-myristate acetate. Journal of Immunology 140:1117–1122
    [Google Scholar]
  14. Gartner S., Markovits P., Markovits D. M., Kaplan M. H., Gallo R. C., Popovic M. 1986; The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233:215–219
    [Google Scholar]
  15. Gautier C., Methali M., Lathe R. 1989; An ubiquitous mammalian expression vector. Nucleic Acids Research 17:83–89
    [Google Scholar]
  16. Ho W.-Z., Douglas S. 1992; Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte/macrophages in vitro . AIDS Research and Human Retroviruses 8:1249–1253
    [Google Scholar]
  17. Kalebic T., Kinter A., Poli G., Anderson M. E., Meister A., Fauci A. S. 1991; Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proceedings of the National Academy of Sciences, USA 88:986–990
    [Google Scholar]
  18. Kruh J. 1982; Effects of sodium butyrate, a new pharmacological agent, on cells in culture. Molecular and Cellular Biochemistry 42:65–82
    [Google Scholar]
  19. Kuntz-Simon G., Obert G. 1995; Sodium valproate, an anticonvulsant drug, stimulates human cytomegalovirus replication. Journal of General Virology 76:1409–1415
    [Google Scholar]
  20. Laughlin M. A., Zeichner S., Kolson D., Aiwine J. C., Seshamma T., Pomerantz R. J., Gonzales-Scarano F. 1993; Sodium butyrate treatment of cells latently infected with HIV-1 results in the expression of unspliced viral RNA. Virology 196:496–505
    [Google Scholar]
  21. Laughlin M. A., Chang G. Y., Oakes J. W., Gonzalez-Scarano F., Pomerantz R. J. 1995; Sodium butyrate stimulation of HIV-1 gene expression: a novel mechanism of induction independent of nf-κb. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 9:332–339
    [Google Scholar]
  22. Legrand-Poels S., Vaira D., Pincemail J., Van De Virst A., Piette J. 1990; Activation of human immunodeficiency virus type I by oxidative stress. AIDS Research and Human Retroviruses 6:1389–1396
    [Google Scholar]
  23. Levy R. H., Shen D. D. 1989; Valproate. Adsorbtion, distribution, and excretion. In Antiepileptic Drugs 3rd edn pp 583–599 Edited by Levy R., Mattson R., Meldrum B., Penry J. K., Dreifuss F. E. New York: Raven Press;
    [Google Scholar]
  24. Meister A. 1989; Metabolism and function of glutathione. In Glutathione:Chemical, Biochemical and Medical Aspects pp 376–474 Edited by Dolphin D., Poulson R., Avramovic O. New York: John Wiley;
    [Google Scholar]
  25. Meister A. 1991; Glutathione deficiency produced by inhibition of its synthesis and its reversal: applications in research and therapy. Pharmacology and Therapeutics 51:155–194
    [Google Scholar]
  26. Mihm S., Ennen J., Pessara U., Kurth R., Drӧge W. 1991; Inhibition of HIV-1 replication and nf-κb activity by cysteine and cysteine derivatives. AIDS 5:497–503
    [Google Scholar]
  27. Mihm S., Gaiter D., Drӧge W. 1995; Modulation of transcription factor NF-κB activity by intracellular glutathione levels and by variations of the extracellular cysteine supply. FASEB Journal 9:246–252
    [Google Scholar]
  28. Molina J. M., Scadden D. T., Byrn R., Dinarello C. A., Groopman J. E. 1989; Production of tumor necrosis factor and interleukin 1 by monocytic cells infected with human immunodeficiency virus. Journal of Clinical Investigation 84:733–737
    [Google Scholar]
  29. Moog C., Wick A., Le Ber P., Kirn A., Aubertin A. M. 1994; Bicyclic imidazo derivatives, a new class of highly selective inhibitors for the human immunodeficiency virus type I. Antiviral Research 24:275–288
    [Google Scholar]
  30. Mossman T. 1983; Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods 65:55–63
    [Google Scholar]
  31. Nordhoff A., Schirmer R. H., Mayatepek E., Becker K. 1994; No evidence for inhibition of human glutathione reductase by valproic acid. Biochemical Pharmacology 46:199–204
    [Google Scholar]
  32. Pace G. W., Leaf C. 1995; The role of oxidative stress in HIV disease. Free Radical Biology and Medicine 19:523–528
    [Google Scholar]
  33. Poli G., Bressler P., Kinter A., Duh E., Timmer W. C., Rabson A., Justement J. S., Stanley S., Fauci A. S. 1990a; Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor-α by transcriptional and post-transcriptional mechanisms. Journal of Experimental Medicine 172:151–158
    [Google Scholar]
  34. Poli G., Kinter A., Justement J. S., Kehrl J. H., Bressler P., Stanley S., Fauci A. S. 1990b; Tumor necrosis factor-α functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proceedings of the National Academy of Sciences, USA 87:782–785
    [Google Scholar]
  35. Ponchaut S., Veitch K. 1993; Valproate and mitochondria. Biochemical Pharmacology 46:199–204
    [Google Scholar]
  36. Prasad K. N., Sinha P. K. 1976; Effects of sodium butyrate on mammalian cells in culture. A review. In Vitro 12:125–132
    [Google Scholar]
  37. Roederer M., Staal F. J. T., Raju P. A., Ela S. W., Herzenberg L. A., Herzenberg L. A. 1990; Cytokine-stimulated human immunodeficiency virus replication is inhibited by N- acetyl-L-cysteine. Proceedings of the National Academy of Sciences, USA 87:4884–4888
    [Google Scholar]
  38. Roederer M., Raju P. A., Staal F. J. T., Herzenberg L. A., Herzenberg L. A. 1991; N-acetylcysteine inhibits latent HIV expression in chronically infected cells. AIDS Research and Human Retroviruses 7:563–567
    [Google Scholar]
  39. Saemundsen A. K., Kallin B., Klein G. 1980; Effect of n-butyrate on cellular and viral DNA synthesis in cells latently infected with Epstein–Barr virus. Virology 107:557–561
    [Google Scholar]
  40. Sambrook J., Fritsch E. F., Maniatis T. 1989 Molecular Cloning: A Laboratory Manual 2nd edn New York: Cold Spring Harbor Laboratory Press;
    [Google Scholar]
  41. Sambucetti L. C., Cherrington J. M., Wilkinson G. W. G., Mocarski E. S. 1989; nf-κb activation of the cytomegalovirus enhancer is mediated by a viral transactivator and by T-cell stimulation. EMBO Journal 8:4251–4258
    [Google Scholar]
  42. Sassone-Corsi P., Dougherty J. P., Wasylyk B., Chambon P. 1984; Stimulation of in vitro transcription from heterologous promoters by the SV40 enhancer. Proceedings of the National Academy of Sciences, USA 81:308–312
    [Google Scholar]
  43. Schreck R., Rieber P., Baeuerie P. A. 1990; Reactive oxygen intermediates as apparently widely used messengers in the activation of the nf- κ b transcription factor and HIV-1. EMBO Journal 10:2247–2258
    [Google Scholar]
  44. Simon G., Moog C., Obert G. 1994; Valproic acid reduces the intracellular level of glutathione and stimulates human immunodeficiency virus. Chemico-Biological Interactions 91:111–121
    [Google Scholar]
  45. Staal F. J. T., Roederer M., Herzenberg L. A., Herzenberg L. A. 1990; Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proceedings of the National Academy of Sciences, USA 87:9943–9947
    [Google Scholar]
  46. Staal F. J. T., Roederer M., Israelski D. M., Bubp J., Mole L. A., McShane D., Deresinski S. C., Ross W., Sussman H., Raju P. A., Anderson M. T., Moore W., Eta S. W., Herzenberg L. A., Herzenberg L. A. 1992; Intracellular glutathione levels in T cell subsets decrease in HIV-infected individuals. AIDS Research and Human Retroviruses 8:305–311
    [Google Scholar]
  47. Tanaka J., Sadanari H., Sato H., Fukuda S. 1991; Sodium butyrate-inducible replication of human cytomegalovirus in a human epithelial cell line. Virology 185:271–280
    [Google Scholar]
  48. Vamecq J., Vallée L., Fontaine M., Nuyts J. P., Lambert D., Poupaert J. 1993; Preliminary studies about novel strategies to reverse chemoresistance to adriamycin regarding glutathione metabolism, peroxisomal and extraperoxisomal hydroperoxide and valproic acid metabolic pathways. Biology of the Cell 77:17–26
    [Google Scholar]
  49. Van den Branden C., Roels F. 1985; Peroxisomal β-oxidation and sodium valproate. Biochemical Pharmacology 34:2147–2149
    [Google Scholar]
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