Skip to main content
PMC home page
Clinical and Diagnostic Laboratory Immunology logoLink to Clinical and Diagnostic Laboratory Immunology
. 1997 May;4(3):352–357. doi: 10.1128/cdli.4.3.352-357.1997

L-2-oxothiazolidine-4-carboxylic acid inhibits human immunodeficiency virus type 1 replication in mononuclear phagocytes and lymphocytes.

W Z Ho 1, S E Starr 1, A Sison 1, S D Douglas 1
PMCID: PMC170531  PMID: 9144376

Abstract

We investigated the effects of L-2-oxothiazolidine-4-carboxylic acid (OTC; Procysteine), a cysteine prodrug, on human immunodeficiency virus type 1 (HIV-1) expression in both adult peripheral and cord blood mononuclear phagocytes and lymphocytes. OTC suppressed HIV-1 expression in monocyte-derived macrophages (MDM) and lymphocytes in a dose-dependent fashion as determined by HIV-1 reverse transcriptase (RT) activity. This inhibitory effect of OTC occurred with three HIV-1 strains (two laboratory-adapted strains and one primary isolate). Addition of OTC to chronically HIV-1-infected MDM cultures also suppressed RT activity by 40 to 50% in comparison to untreated controls. The inhibitory effects of OTC on HIV-1 were not caused by toxicity to MDM or lymphocytes because there was no change in cell viability or cellular DNA synthesis, as evaluated by trypan blue dye exclusion and [3H]thymidine incorporation, at doses of OTC that inhibit virus replication. These observations indicate that OTC has the potential to limit HIV-1 replication in mononuclear phagocytes and lymphocytes and may be useful in the treatment of HIV-1 infection and AIDS.

Full Text

The Full Text of this article is available as a PDF (227.7 KB).

Selected References

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

  1. Bergamini A., Capozzi M., Ghibelli L., Dini L., Salanitro A., Milanese G., Wagner T., Beninati S., Pesce C. D., Amici C. Cystamine potently suppresses in vitro HIV replication in acutely and chronically infected human cells. J Clin Invest. 1994 May;93(5):2251–2257. doi: 10.1172/JCI117223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brodeur J., Goyal R. Effect of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid, on the metabolism and toxicity of bromobenzene: an acute study. Can J Physiol Pharmacol. 1987 May;65(5):816–822. doi: 10.1139/y87-131. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Collman R., Hassan N. F., Walker R., Godfrey B., Cutilli J., Hastings J. C., Friedman H., Douglas S. D., Nathanson N. Infection of monocyte-derived macrophages with human immunodeficiency virus type 1 (HIV-1). Monocyte-tropic and lymphocyte-tropic strains of HIV-1 show distinctive patterns of replication in a panel of cell types. J Exp Med. 1989 Oct 1;170(4):1149–1163. doi: 10.1084/jem.170.4.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dimitrov D. H., Hollinger F. B., Baker C. J., Kline M. W., Doyle M., Bremer J. W., Shearer W. T. Study of human immunodeficiency virus resistance to 2'-3'-dideoxyinosine and zidovudine in sequential isolates from pediatric patients on long-term therapy. J Infect Dis. 1993 Apr;167(4):818–823. doi: 10.1093/infdis/167.4.818. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Erice A., Balfour H. H., Jr Resistance of human immunodeficiency virus type 1 to antiretroviral agents: a review. Clin Infect Dis. 1994 Feb;18(2):149–156. doi: 10.1093/clinids/18.2.149. [DOI] [PubMed] [Google Scholar]
  8. Erice A., Mayers D. L., Strike D. G., Sannerud K. J., McCutchan F. E., Henry K., Balfour H. H., Jr Brief report: primary infection with zidovudine-resistant human immunodeficiency virus type 1. N Engl J Med. 1993 Apr 22;328(16):1163–1165. doi: 10.1056/NEJM199304223281605. [DOI] [PubMed] [Google Scholar]
  9. Eylar E., Rivera-Quinones C., Molina C., Báez I., Molina F., Mercado C. M. N-acetylcysteine enhances T cell functions and T cell growth in culture. Int Immunol. 1993 Jan;5(1):97–101. doi: 10.1093/intimm/5.1.97. [DOI] [PubMed] [Google Scholar]
  10. Fidelus R. K., Tsan M. F. Enhancement of intracellular glutathione promotes lymphocyte activation by mitogen. Cell Immunol. 1986 Jan;97(1):155–163. doi: 10.1016/0008-8749(86)90385-0. [DOI] [PubMed] [Google Scholar]
  11. Fitzgibbon J. E., Gaur S., Frenkel L. D., Laraque F., Edlin B. R., Dubin D. T. Transmission from one child to another of human immunodeficiency virus type 1 with a zidovudine-resistance mutation. N Engl J Med. 1993 Dec 16;329(25):1835–1841. doi: 10.1056/NEJM199312163292502. [DOI] [PubMed] [Google Scholar]
  12. Gendelman H. E., Orenstein J. M., Baca L. M., Weiser B., Burger H., Kalter D. C., Meltzer M. S. The macrophage in the persistence and pathogenesis of HIV infection. AIDS. 1989 Aug;3(8):475–495. doi: 10.1097/00002030-198908000-00001. [DOI] [PubMed] [Google Scholar]
  13. Hassan N. F., Campbell D. E., Douglas S. D. Purification of human monocytes on gelatin-coated surfaces. J Immunol Methods. 1986 Dec 24;95(2):273–276. doi: 10.1016/0022-1759(86)90415-1. [DOI] [PubMed] [Google Scholar]
  14. Hassan N. F., Cutilli J. R., Douglas S. D. Isolation of highly purified human blood monocytes for in vitro HIV-1 infection studies of monocyte/macrophages. J Immunol Methods. 1990 Jul 3;130(2):283–285. doi: 10.1016/0022-1759(90)90058-4. [DOI] [PubMed] [Google Scholar]
  15. Ho W. Z., Douglas S. D. Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte/macrophages in vitro. AIDS Res Hum Retroviruses. 1992 Jul;8(7):1249–1253. doi: 10.1089/aid.1992.8.1249. [DOI] [PubMed] [Google Scholar]
  16. Ho W. Z., Kaufman D., Song L., Cutillii J. R., Douglas S. D. Cystamine inhibits human immunodeficiency virus-1 replication in cord blood-derived mononuclear phagocytes and lymphocytes. Blood. 1996 Aug 1;88(3):928–933. [PubMed] [Google Scholar]
  17. Ho W. Z., Zhu X. H., Song L., Lee H. R., Cutilli J. R., Douglas S. D. Cystamine inhibits HIV type 1 replication in cells of monocyte/macrophage and T cell lineages. AIDS Res Hum Retroviruses. 1995 Apr;11(4):451–459. doi: 10.1089/aid.1995.11.451. [DOI] [PubMed] [Google Scholar]
  18. Kalayjian R. C., Skowron G., Emgushov R. T., Chance M., Spell S. A., Borum P. R., Webb L. S., Mayer K. H., Jackson J. B., Yen-Lieberman B. A phase I/II trial of intravenous L-2-oxothiazolidine-4-carboxylic acid (procysteine) in asymptomatic HIV-infected subjects. J Acquir Immune Defic Syndr. 1994 Apr;7(4):369–374. [PubMed] [Google Scholar]
  19. Lederman M. M., Georges D., Dando S., Schmelzer R., Averill L., Goldberg D. L-2-oxothiazolidine-4-carboxylic acid (procysteine) inhibits expression of the human immunodeficiency virus and expression of the interleukin-2 receptor alpha chain. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Feb 1;8(2):107–115. [PubMed] [Google Scholar]
  20. Lioy J., Ho W. Z., Cutilli J. R., Polin R. A., Douglas S. D. Thiol suppression of human immunodeficiency virus type 1 replication in primary cord blood monocyte-derived macrophages in vitro. J Clin Invest. 1993 Feb;91(2):495–498. doi: 10.1172/JCI116227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. McKinney R. E., Jr, Pizzo P. A., Scott G. B., Parks W. P., Maha M. A., Lehrman S. N., Riggs M., Eddy J., Lane B. A., Eppes S. C. Safety and tolerance of intermittent intravenous and oral zidovudine therapy in human immunodeficiency virus-infected pediatric patients. Pediatric Zidovudine Phase I Study Group. J Pediatr. 1990 Apr;116(4):640–647. doi: 10.1016/s0022-3476(05)81619-1. [DOI] [PubMed] [Google Scholar]
  22. Moslen M. T., Whitehead R. F., Ferguson A. E., Kanz M. F. Protection by L-2-oxothiazolidine-4-carboxylate, a cysteine prodrug, against 1,1-dichloroethylene hepatotoxicity in rats is associated with decreases in toxin metabolism and cytochrome P-450. J Pharmacol Exp Ther. 1989 Jan;248(1):157–163. [PubMed] [Google Scholar]
  23. Ogino M. T., Dankner W. M., Spector S. A. Development and significance of zidovudine resistance in children infected with human immunodeficiency virus. J Pediatr. 1993 Jul;123(1):1–8. doi: 10.1016/s0022-3476(05)81529-x. [DOI] [PubMed] [Google Scholar]
  24. Pizzo P. A., Wilfert C. Antiretroviral therapy for infection due to human immunodeficiency virus in children. Clin Infect Dis. 1994 Jul;19(1):177–196. doi: 10.1093/clinids/19.1.177. [DOI] [PubMed] [Google Scholar]
  25. Porta P., Aebi S., Summer K., Lauterburg B. H. L-2-oxothiazolidine-4-carboxylic acid, a cysteine prodrug: pharmacokinetics and effects on thiols in plasma and lymphocytes in human. J Pharmacol Exp Ther. 1991 Apr;257(1):331–334. [PubMed] [Google Scholar]
  26. Potts B. J., Maury W., Martin M. A. Replication of HIV-1 in primary monocyte cultures. Virology. 1990 Apr;175(2):465–476. doi: 10.1016/0042-6822(90)90431-p. [DOI] [PubMed] [Google Scholar]
  27. Raju P. A., Herzenberg L. A., Herzenberg L. A., Roederer M. Glutathione precursor and antioxidant activities of N-acetylcysteine and oxothiazolidine carboxylate compared in in vitro studies of HIV replication. AIDS Res Hum Retroviruses. 1994 Aug;10(8):961–967. doi: 10.1089/aid.1994.10.961. [DOI] [PubMed] [Google Scholar]
  28. Richman D. D., Meng T. C., Spector S. A., Fischl M. A., Resnick L., Lai S. Resistance to AZT and ddC during long-term combination therapy in patients with advanced infection with human immunodeficiency virus. J Acquir Immune Defic Syndr. 1994 Feb;7(2):135–138. [PubMed] [Google Scholar]
  29. Roederer M., Ela S. W., Staal F. J., Herzenberg L. A., Herzenberg L. A. N-acetylcysteine: a new approach to anti-HIV therapy. AIDS Res Hum Retroviruses. 1992 Feb;8(2):209–217. doi: 10.1089/aid.1992.8.209. [DOI] [PubMed] [Google Scholar]
  30. Roederer M., Staal F. J., Ela S. W., Herzenberg L. A., Herzenberg L. A. N-acetylcysteine: potential for AIDS therapy. Pharmacology. 1993;46(3):121–129. doi: 10.1159/000139037. [DOI] [PubMed] [Google Scholar]
  31. Staal F. J., Ela S. W., Roederer M., Anderson M. T., Herzenberg L. A., Herzenberg L. A. Glutathione deficiency and human immunodeficiency virus infection. Lancet. 1992 Apr 11;339(8798):909–912. doi: 10.1016/0140-6736(92)90939-z. [DOI] [PubMed] [Google Scholar]
  32. Staal F. J., Roederer M., Israelski D. M., Bubp J., Mole L. A., McShane D., Deresinski S. C., Ross W., Sussman H., Raju P. A. Intracellular glutathione levels in T cell subsets decrease in HIV-infected individuals. AIDS Res Hum Retroviruses. 1992 Feb;8(2):305–311. doi: 10.1089/aid.1992.8.305. [DOI] [PubMed] [Google Scholar]
  33. Tsan M. F., Danis E. H., Del Vecchio P. J., Rosano C. L. Enhancement of intracellular glutathione protects endothelial cells against oxidant damage. Biochem Biophys Res Commun. 1985 Feb 28;127(1):270–276. doi: 10.1016/s0006-291x(85)80154-6. [DOI] [PubMed] [Google Scholar]
  34. Willey R. L., Smith D. H., Lasky L. A., Theodore T. S., Earl P. L., Moss B., Capon D. J., Martin M. A. In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity. J Virol. 1988 Jan;62(1):139–147. doi: 10.1128/jvi.62.1.139-147.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Williamson J. M., Boettcher B., Meister A. Intracellular cysteine delivery system that protects against toxicity by promoting glutathione synthesis. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6246–6249. doi: 10.1073/pnas.79.20.6246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Williamson J. M., Meister A. Stimulation of hepatic glutathione formation by administration of L-2-oxothiazolidine-4-carboxylate, a 5-oxo-L-prolinase substrate. Proc Natl Acad Sci U S A. 1981 Feb;78(2):936–939. doi: 10.1073/pnas.78.2.936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Witschi A., Reddy S., Stofer B., Lauterburg B. H. The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992;43(6):667–669. doi: 10.1007/BF02284971. [DOI] [PubMed] [Google Scholar]

Articles from Clinical and Diagnostic Laboratory Immunology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES