Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Jun;87(12):4884–4888. doi: 10.1073/pnas.87.12.4884

Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine.

M Roederer 1, F J Staal 1, P A Raju 1, S W Ela 1, L A Herzenberg 1, L A Herzenberg 1
PMCID: PMC54223  PMID: 2112750

Abstract

We show that the stimulation of human immunodeficiency virus (HIV) brought about by tumor necrosis factor alpha and phorbol 12-myristate 13-acetate can be inhibited by adding N-acetyl-L-cysteine (NAC). NAC, which replenishes intracellular glutathione, effectively inhibits the tumor necrosis factor alpha- or phorbol ester-stimulated replication of HIV in acutely infected cell cultures. NAC also inhibits the cytokine-enhanced HIV long terminal repeat-directed expression of beta-galactosidase in in vitro HIV model systems. These results show that intracellular thiol levels influence HIV production. Furthermore, because NAC reverses tumor necrosis factor alpha toxicity both in cells and in animals and is a well-known drug that can be administered orally without known toxicity in humans, these results suggest that NAC is a possible therapeutic agent in AIDS.

Full text

PDF
4884

Images in this article

Selected References

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

  1. Aruoma O. I., Halliwell B., Hoey B. M., Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593–597. doi: 10.1016/0891-5849(89)90066-x. [DOI] [PubMed] [Google Scholar]
  2. Berkhout B., Silverman R. H., Jeang K. T. Tat trans-activates the human immunodeficiency virus through a nascent RNA target. Cell. 1989 Oct 20;59(2):273–282. doi: 10.1016/0092-8674(89)90289-4. [DOI] [PubMed] [Google Scholar]
  3. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  4. Buhl R., Jaffe H. A., Holroyd K. J., Wells F. B., Mastrangeli A., Saltini C., Cantin A. M., Crystal R. G. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet. 1989 Dec 2;2(8675):1294–1298. doi: 10.1016/s0140-6736(89)91909-0. [DOI] [PubMed] [Google Scholar]
  5. Burgunder J. M., Varriale A., Lauterburg B. H. Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol. 1989;36(2):127–131. doi: 10.1007/BF00609183. [DOI] [PubMed] [Google Scholar]
  6. Cantin A. M., North S. L., Hubbard R. C., Crystal R. G. Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol (1985) 1987 Jul;63(1):152–157. doi: 10.1152/jappl.1987.63.1.152. [DOI] [PubMed] [Google Scholar]
  7. Chandra A., Demirhan I., Arya S. K., Chandra P. D-penicillamine inhibits transactivation of human immunodeficiency virus type-1 (HIV-1) LTR by transactivator protein. FEBS Lett. 1988 Aug 29;236(2):282–286. doi: 10.1016/0014-5793(88)80038-3. [DOI] [PubMed] [Google Scholar]
  8. Chayt K. J., Harper M. E., Marselle L. M., Lewin E. B., Rose R. M., Oleske J. M., Epstein L. G., Wong-Staal F., Gallo R. C. Detection of HTLV-III RNA in lungs of patients with AIDS and pulmonary involvement. JAMA. 1986 Nov 7;256(17):2356–2359. [PubMed] [Google Scholar]
  9. Chlebowski R. T. Significance of altered nutritional status in acquired immune deficiency syndrome (AIDS). Nutr Cancer. 1985;7(1-2):85–91. doi: 10.1080/01635588509513843. [DOI] [PubMed] [Google Scholar]
  10. DeChatelet L. R., Shirley P. S., Johnston R. B., Jr Effect of phorbol myristate acetate on the oxidative metabolism of human polymorphonuclear leukocytes. Blood. 1976 Apr;47(4):545–554. [PubMed] [Google Scholar]
  11. Duh E. J., Maury W. J., Folks T. M., Fauci A. S., Rabson A. B. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974–5978. doi: 10.1073/pnas.86.15.5974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Eck H. P., Gmünder H., Hartmann M., Petzoldt D., Daniel V., Dröge W. Low concentrations of acid-soluble thiol (cysteine) in the blood plasma of HIV-1-infected patients. Biol Chem Hoppe Seyler. 1989 Feb;370(2):101–108. doi: 10.1515/bchm3.1989.370.1.101. [DOI] [PubMed] [Google Scholar]
  13. Folks T. M., Clouse K. A., Justement J., Rabson A., Duh E., Kehrl J. H., Fauci A. S. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2365–2368. doi: 10.1073/pnas.86.7.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Guillon J. M., Autran B., Denis M., Fouret P., Plata F., Mayaud C. M., Akoun G. M. Human immunodeficiency virus-related lymphocytic alveolitis. Chest. 1988 Dec;94(6):1264–1270. doi: 10.1378/chest.94.6.1264. [DOI] [PubMed] [Google Scholar]
  15. Kao S. Y., Calman A. F., Luciw P. A., Peterlin B. M. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature. 1987 Dec 3;330(6147):489–493. doi: 10.1038/330489a0. [DOI] [PubMed] [Google Scholar]
  16. Klebanoff S. J., Vadas M. A., Harlan J. M., Sparks L. H., Gamble J. R., Agosti J. M., Waltersdorph A. M. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986 Jun 1;136(11):4220–4225. [PubMed] [Google Scholar]
  17. Lähdevirta J., Maury C. P., Teppo A. M., Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med. 1988 Sep;85(3):289–291. doi: 10.1016/0002-9343(88)90576-1. [DOI] [PubMed] [Google Scholar]
  18. Meister A., Anderson M. E., Hwang O. Intracellular cysteine and glutathione delivery systems. J Am Coll Nutr. 1986;5(2):137–151. doi: 10.1080/07315724.1986.10720121. [DOI] [PubMed] [Google Scholar]
  19. Mintz M., Rapaport R., Oleske J. M., Connor E. M., Koenigsberger M. R., Denny T., Epstein L. G. Elevated serum levels of tumor necrosis factor are associated with progressive encephalopathy in children with acquired immunodeficiency syndrome. Am J Dis Child. 1989 Jul;143(7):771–774. doi: 10.1001/archpedi.1989.02150190021012. [DOI] [PubMed] [Google Scholar]
  20. Moldéus P., Berggren M., Grafström R. N-acetylcysteine protection against the toxicity of cigarette smoke and cigarette smoke condensates in various tissues and cells in vitro. Eur J Respir Dis Suppl. 1985;139:123–129. [PubMed] [Google Scholar]
  21. Moldéus P., Cotgreave I. A., Berggren M. Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration. 1986;50 (Suppl 1):31–42. doi: 10.1159/000195086. [DOI] [PubMed] [Google Scholar]
  22. Molina J. M., Scadden D. T., Byrn R., Dinarello C. A., Groopman J. E. Production of tumor necrosis factor alpha and interleukin 1 beta by monocytic cells infected with human immunodeficiency virus. J Clin Invest. 1989 Sep;84(3):733–737. doi: 10.1172/JCI114230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nolan G. P., Fiering S., Nicolas J. F., Herzenberg L. A. Fluorescence-activated cell analysis and sorting of viable mammalian cells based on beta-D-galactosidase activity after transduction of Escherichia coli lacZ. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2603–2607. doi: 10.1073/pnas.85.8.2603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Oliff A., Defeo-Jones D., Boyer M., Martinez D., Kiefer D., Vuocolo G., Wolfe A., Socher S. H. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. doi: 10.1016/0092-8674(87)90028-6. [DOI] [PubMed] [Google Scholar]
  25. Olsson B., Johansson M., Gabrielsson J., Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharmacol. 1988;34(1):77–82. doi: 10.1007/BF01061422. [DOI] [PubMed] [Google Scholar]
  26. Osborn L., Kunkel S., Nabel G. J. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. doi: 10.1073/pnas.86.7.2336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Scheib R. G., Parenti D. M., Simon G. L., Courtless J. W., Schulof R. S., Sarin P. S., Chandra P. Prolonged antiviral activity of D-penicillamine in human immunodeficiency virus-infected homosexual men. Am J Med. 1987 Sep;83(3):608–608. doi: 10.1016/0002-9343(87)90794-7. [DOI] [PubMed] [Google Scholar]
  28. Schulof R. S., Scheib R. G., Parenti D. M., Simon G. L., DiGioia R. A., Paxton H. M., Sztein M. B., Chandra P., Courtless J. W., Taguchi Y. T. Treatment of HTLV-III/LAV-infected patients with D-penicillamine. Arzneimittelforschung. 1986 Oct;36(10):1531–1534. [PubMed] [Google Scholar]
  29. Simon L. M., Suttorp N. Lung cell oxidant injury: decrease in oxidant mediated cytotoxicity by N-acetylcysteine. Eur J Respir Dis Suppl. 1985;139:132–135. [PubMed] [Google Scholar]
  30. Smilkstein M. J., Knapp G. L., Kulig K. W., Rumack B. H. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) N Engl J Med. 1988 Dec 15;319(24):1557–1562. doi: 10.1056/NEJM198812153192401. [DOI] [PubMed] [Google Scholar]
  31. Suffredini A. F., Ognibene F. P., Lack E. E., Simmons J. T., Brenner M., Gill V. J., Lane H. C., Fauci A. S., Parrillo J. E., Masur H. Nonspecific interstitial pneumonitis: a common cause of pulmonary disease in the acquired immunodeficiency syndrome. Ann Intern Med. 1987 Jul;107(1):7–13. doi: 10.7326/0003-4819-107-1-7. [DOI] [PubMed] [Google Scholar]
  32. Tong-Starkesen S. E., Luciw P. A., Peterlin B. M. Signaling through T lymphocyte surface proteins, TCR/CD3 and CD28, activates the HIV-1 long terminal repeat. J Immunol. 1989 Jan 15;142(2):702–707. [PubMed] [Google Scholar]
  33. Yoshie O., Majima T., Saito H. Membrane oxidative metabolism of human eosinophilic cell line EoL-1 in response to phorbol diester and formyl peptide: synergistic augmentation by interferon-gamma and tumor necrosis factor. J Leukoc Biol. 1989 Jan;45(1):10–20. doi: 10.1002/jlb.45.1.10. [DOI] [PubMed] [Google Scholar]
  34. Zimmerman R. J., Marafino B. J., Jr, Chan A., Landre P., Winkelhake J. L. The role of oxidant injury in tumor cell sensitivity to recombinant human tumor necrosis factor in vivo. Implications for mechanisms of action. J Immunol. 1989 Feb 15;142(4):1405–1409. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES