Medical Microbiology and Immunology

, Volume 194, Issue 1–2, pp 55–59 | Cite as

Effects of S-acetylglutathione in cell and animal model of herpes simplex virus type 1 infection

  • Jens-Uwe Vogel
  • Jaroslav Cinatl
  • Nurlan Dauletbaev
  • Sigune Buxbaum
  • Gernot Treusch
  • Jindrich CinatlJr
  • Valentin Gerein
  • Hans Wilhelm Doerr
Original Investigation


Intracellular glutathione (GSH) plays an important regulatory role in the host response to viral infections. Replenishment of intracellular GSH is a desirable yet challenging goal, since systemic GSH supplementation is rather inefficient due to a short half-life of GSH in blood plasma. Further, GSH is not taken up by cells directly, but needs to be broken down into amino acids and resynthesized to GSH intracellularly, this process often being impaired during viral infections. These obstacles may be overcome by a novel glutathione derivative S-acetylglutathione (S-GSH), which is more stable in plasma and taken up directly by cells with subsequent conversion to GSH. In the present study, in vitro effects of supplementation with S-GSH or GSH on intracellular GSH levels, cell survival and replication of human herpes simplex virus type 1 (HSV-1) were studied in human foreskin fibroblasts. In addition, in vivo effects of supplementation with S-GSH or GSH on HSV-1-induced mortality were studied in hr/hr mice. In cell culture, viral infection resulted in a significant decrease of intracellular GSH levels. S-GSH efficiently and dose-dependently (5 and 10 mM tested) restored intracellular GSH, and this replenishment was more efficient than with GSH supplementation. In mice, S-GSH, but not GSH, significantly decreased HSV-1-induced mortality (P<0.05). The data suggest that S-GSH is a suitable antiviral agent against HSV-1 both in vitro and in vivo, indicating that this drug may be of benefit in the adjunctive therapy of HSV-1 infections.


Intracellular glutathione S-acetylglutathione Herpes simplex virus type 1 infection Antiviral drugs 



This research was supported in part by “Hilfe für krebskranke Kinder Frankfurt e.V.” and by the foundation “Frankfurter Stiftung für krebskranke Kinder”.


  1. 1.
    Akerlund B, Jarstrand C, Lindeke B, Sonnerborg A, Akerblad AC, Rasool O (1996) Effect of N-acetylcysteine (NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. Eur J Clin Pharmacol 50:457–461PubMedGoogle Scholar
  2. 2.
    Anderson ME (1998) Glutathione: an overview of biosynthesis and modulation. Chem Biol Interact 111–112:1–14Google Scholar
  3. 3.
    Anderson ME, Meister A (1980) Dynamic state of glutathione in blood plasma. J Biol Chem 255:9530–9533PubMedGoogle Scholar
  4. 4.
    Anderson ME, Levey EJ, Meister A (1994) Preparation and use of glutathione monoesters. Methods Enzymol 234:492–499PubMedGoogle Scholar
  5. 5.
    Banki K, Hutter E, Gonchoroff NJ, Perl A (1998) Molecular ordering in HIV-induced apoptosis oxidative stress activation of caspases and cell survival are regulated by transaldolase. J Biol Chem 273:11944–11953CrossRefPubMedGoogle Scholar
  6. 6.
    Barbaro G, Di Lorenzo G, Soldini M, Parrotto S, Bellomo G, Belloni G, Grisorio B, Barbarini G (1996) Hepatic glutathione deficiency in chronic hepatitis C: quantitative evaluation in patients who are HIV positive and HIV negative and correlations with plasmatic and lymphocytic concentrations and with the activity of the liver disease. Am J Gastroenterol 91:2569–2573PubMedGoogle Scholar
  7. 7.
    Boya P, Pena A de la, Beloqui O, Larrea E, Conchillo M, Castelruiz Y, Civeira MP, Prieto J (1999) Antioxidant status and glutathione metabolism in peripheral blood mononuclear cells from patients with chronic hepatitis C. J Hepatol 31:808–814CrossRefPubMedGoogle Scholar
  8. 8.
    Buhl R, Jaffe HA, Holroyd KJ, Wells FB, Mastrangeli A, Saltini C, Cantin AM, Crystal RG (1989) Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet II:1294–1298CrossRefGoogle Scholar
  9. 9.
    Cinatl J Jr, Cinatl J, Rabenau H, Kornhuber B, Doerr HW (1992) HeLa cells grown continuously in protein-free medium: a novel model for the study of virus replication. Intervirology 33:41–48PubMedGoogle Scholar
  10. 10.
    Cinatl J Jr, Cinatl J, Weber B, Rabenau H, Gümbel HO, Chenot JF, Scholz M, Encke A, Doerr HW (1995) In vitro inhibition of human cytomegalovirus replication in human foreskin fibroblasts and endothelial cells by ascorbic acid 2-phosphate. Antiviral Res 27:405–418Google Scholar
  11. 11.
    Cinatl J Jr, Vogel J-U, Cinatl J, Kabickova H, Kornhuber B, Doerr HW (1997) Antiviral effects of 6-diazo-5-oxo-l-norleuzin on replication of herpes simplex virus type 1. Antiviral Res 33:165–175CrossRefPubMedGoogle Scholar
  12. 12.
    Cooper AJL (1997) Glutathione in the brain: disorders of glutathione metabolism. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, Kunk LM (eds) The molecular and genetic basis of neurological disease. Butterworth-Heinemann, Boston, pp 1195–1230Google Scholar
  13. 13.
    Dauletbaev N, Rickmann J, Viel K, Buhl R, Wagner TO, Bargon J (2001) Glutathione in induced sputum of healthy individuals and patients with asthma. Thorax 56:13–18CrossRefPubMedGoogle Scholar
  14. 14.
    De Rosa SC, Zaretsky MD, Dubs JG, Roederer M, Anderson M, Green A, Mitra D, Watanabe N, Nakamura H, Tjioe I, Deresinski SC, Moore WA, Ela SW, Parks D, Herzenberg LA, Herzenberg LA (2000) N-Acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 30:915–929CrossRefPubMedGoogle Scholar
  15. 15.
    Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671Google Scholar
  16. 16.
    Dröge W, Eck HP, Mihm S (1992) HIV-induced cysteine deficiency and T-cell dysfunction—a rationale for treatment with N-acetylcysteine. Immunol Today 13:211–214PubMedGoogle Scholar
  17. 17.
    Dröge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S, Gmünder H (1994) Functions of glutathione and glutathione disulfide in immunology and immunopathology. FASEB J 8:1131–1138PubMedGoogle Scholar
  18. 18.
    Eylar E, Rivera-Quinones C, Molina C, Baez I, Molina F, Mercado CM (1993) N-Acetylcysteine enhances T cell functions and T cell growth in culture. Int Immunol 5:97–101PubMedGoogle Scholar
  19. 19.
    Galzigna L, Rizzoli V, Schiapelli P, Moretto C, Bernareggi A (1995) S-Acetyl and S-phenylacetyl-glutathione as glutathione precursors in rat plasma and tissue preparations. Enzyme Protein 48:98–104Google Scholar
  20. 20.
    Garaci E, Palamara AT, Di Francesco P, Favalli C, Ciriolo MR, Rotilio G (1992) Glutathione inhibits replication and expression of viral proteins in cultured cells infected with Sendai virus. Biochem Biophys Res Commun 188:1090–1096PubMedGoogle Scholar
  21. 21.
    Garaci E, Palamara AT, Ciriolo MR, D’Agostini C, del-Latif MS, Aquaro S, Lafavia E, Rotilio G (1997) Intracellular GSH content and HIV replication in human macrophages. J Leukoc Biol 62:54–59PubMedGoogle Scholar
  22. 22.
    Helbling B, Von Overbeck J, Lauterburg BH (1994) Decreased synthesis of glutathione in patients with AIDS. Eur J Clin Invest 24:A38Google Scholar
  23. 23.
    Herzenberg LA, DeRosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, Deresinski SC, Herzenberg LA (1997) Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci USA 94:1967–1972PubMedGoogle Scholar
  24. 24.
    Kalebic T, Kinter A, Poli G, Anderson ME, Meister A, Fauci AS (1991) Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc Natl Acad Sci USA 88:986–990PubMedGoogle Scholar
  25. 25.
    Levy EJ, Anderson ME, Meister A (1994) Preparation and properties of glutathione ester and related derivatives. Methods Enzymol 234:499–505PubMedGoogle Scholar
  26. 26.
    Lu SC (1999) Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J 13:1169–1183PubMedGoogle Scholar
  27. 27.
    Meister A (1991) Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther 51:155–194PubMedGoogle Scholar
  28. 28.
    Nucci C, Palamara AT, Ciriolo MR, Nencioni L, Savini P, D’Agostini C, Rotilio G, Cerulli L, Garaci E (2000) Imbalance in corneal redox state during herpes simplex virus 1-induced keratitis in rabbits. Effectiveness of exogenous glutathione supply. Exp Eye Res 70:215–220CrossRefPubMedGoogle Scholar
  29. 29.
    Palamara AT, Perno CF, Ciriolo MR, Dini L, Balestra E, D’Agostini C, Di Francesco P, Favalli C, Rotilio G, Garaci E (1995) Evidence for antiviral activity of glutathione: in vitro inhibition of herpes simplex virus type 1 replication. Antiviral Res 27:237–253CrossRefPubMedGoogle Scholar
  30. 30.
    Palamara AT, Di Francesco P, Ciriolo MR, Bue C, Lafavia E, Rotilio G, Garaci E (1996) Cocaine increases Sendai virus replication in cultured epithelial cells: critical role of the intracellular redox status. Biochem Biophys Res Commun 228:579–585CrossRefPubMedGoogle Scholar
  31. 31.
    Peterson JD, Herzenberg LA, Vasquez K, Waltenbaugh C (1998) Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci USA 95:3071–3076CrossRefPubMedGoogle Scholar
  32. 32.
    Reed LI, Muench H (1938) A simple method of estimating fifty per cent endpoints. Am J Hyg 27:493–497Google Scholar
  33. 33.
    Shan X, Aw TY, Jones DP (1990) Glutathione-dependent protection against oxidative injury. Pharmacol Ther 47:61–71PubMedGoogle Scholar
  34. 34.
    Staal FJT, Roederer M, Herzenberg LA, Herzenberg LA (1990) Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proc Natl Acad Sci USA 87:9943–9947PubMedGoogle Scholar
  35. 35.
    Staal FJR, Roederer M, Raju PA, Anderson MT, Ela SW, Herzenberg LA, Herzenberg LA (1993) Antioxidants inhibit stimulation of HIV transcription. AIDS Res Hum Retroviruses 9:299–306PubMedGoogle Scholar
  36. 36.
    Wendel A, Cikryt P (1980) The level and half-life of glutathione in human plasma. FEBS Lett 120:209–211CrossRefPubMedGoogle Scholar
  37. 37.
    Witschi A, Junker E, Schranz C, Speck RF, Lauterburg BH (1995) Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS. AIDS Res Hum Retroviruses 11:141–143PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Jens-Uwe Vogel
    • 1
  • Jaroslav Cinatl
    • 1
  • Nurlan Dauletbaev
    • 2
  • Sigune Buxbaum
    • 1
  • Gernot Treusch
    • 3
  • Jindrich CinatlJr
    • 1
  • Valentin Gerein
    • 1
  • Hans Wilhelm Doerr
    • 1
  1. 1.Institute for Medical VirologyJohann Wolfgang Goethe University HospitalFrankfurt am MainGermany
  2. 2.Pulmonary Medicine, Second Department of Internal MedicineJohann Wolfgang Goethe University HospitalFrankfurt am MainGermany
  3. 3.Clear Vision S.á.r.l.HerisauSwitzerland

Personalised recommendations