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. 1994 May;93(5):2251–2257. doi: 10.1172/JCI117223

Cystamine potently suppresses in vitro HIV replication in acutely and chronically infected human cells.

A Bergamini 1, M Capozzi 1, L Ghibelli 1, L Dini 1, A Salanitro 1, G Milanese 1, T Wagner 1, S Beninati 1, C D Pesce 1, C Amici 1, et al.
PMCID: PMC294379  PMID: 8182157

Abstract

We have investigated the effects of cystamine on the replication of human immunodeficiency virus (HIV) in human lymphocytes and macrophages, the natural targets of HIV in vivo. Treatment of chronically infected macrophages with cystamine, at a concentration (500 microM) that did not show any cytotoxic or cytostatic effects, strongly decreased (> 80%) HIV-p24 antigen production and completely abolished the production of infectious viral particles. Cystamine does not affect viral transcription, translation or protein processing; indeed, all HIV proteins are present in a pattern similar to that of nontreated cells. Instead, cystamine interferes with the orderly assembly of HIV virions, as shown by electron microscopy analysis, that reveals only defective viral particles in treated cells. Moreover, suppression of HIV replication, due to the inhibition of proviral DNA formation was observed in acutely infected lymphocytes and macrophages pretreated with cystamine. These results show that cystamine potently suppresses HIV replication in human cells by contemporaneously blocking at least two independent steps of the viral life cycle, without affecting cell viability, suggesting that this compound may represent a new possibility towards the treatment of HIV-1 infection.

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Selected References

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

  1. Amici C., Santoro M. G. Suppression of virus replication by prostaglandin A is associated with heat shock protein synthesis. J Gen Virol. 1991 Aug;72(Pt 8):1877–1885. doi: 10.1099/0022-1317-72-8-1877. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. 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]
  4. Djurhuus R., Svardal A. M., Mansoor M. A., Ueland P. M. Modulation of glutathione content and the effect on methionine auxotrophy and cellular distribution of homocysteine and cysteine in mouse cell lines. Carcinogenesis. 1991 Feb;12(2):241–247. doi: 10.1093/carcin/12.2.241. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  7. Fitzgibbon J. E., Howell R. M., Haberzettl C. A., Sperber S. J., Gocke D. J., Dubin D. T. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. Antimicrob Agents Chemother. 1992 Jan;36(1):153–157. doi: 10.1128/aac.36.1.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  10. Gendelman H. E., Baca L. M., Turpin J., Kalter D. C., Hansen B., Orenstein J. M., Dieffenbach C. W., Friedman R. M., Meltzer M. S. Regulation of HIV replication in infected monocytes by IFN-alpha. Mechanisms for viral restriction. J Immunol. 1990 Oct 15;145(8):2669–2676. [PubMed] [Google Scholar]
  11. Gendelman H. E., Friedman R. M., Joe S., Baca L. M., Turpin J. A., Dveksler G., Meltzer M. S., Dieffenbach C. A selective defect of interferon alpha production in human immunodeficiency virus-infected monocytes. J Exp Med. 1990 Nov 1;172(5):1433–1442. doi: 10.1084/jem.172.5.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ho D. D., Rota T. R., Hirsch M. S. Infection of monocyte/macrophages by human T lymphotropic virus type III. J Clin Invest. 1986 May;77(5):1712–1715. doi: 10.1172/JCI112491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kalebic T., Kinter A., Poli G., Anderson M. E., Meister A., Fauci A. S. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):986–990. doi: 10.1073/pnas.88.3.986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kim S. Y., Byrn R., Groopman J., Baltimore D. Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: evidence for differential gene expression. J Virol. 1989 Sep;63(9):3708–3713. doi: 10.1128/jvi.63.9.3708-3713.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Kozubík A., Pospísil M., Netíková J. Possibilities of the combined use of non-steroidal anti-inflammatory drugs and sulfhydryl compounds in radioprotection. Strahlenther Onkol. 1991 Mar;167(3):186–190. [PubMed] [Google Scholar]
  17. Kubota S., el-Farrash M. A., Maki M., Harada S., Hatanaka M. 2,3 Dimercapto-1-propanol inhibits HIV-1 tat activity, viral production, and infectivity in vitro. AIDS Res Hum Retroviruses. 1990 Jul;6(7):919–927. doi: 10.1089/aid.1990.6.919. [DOI] [PubMed] [Google Scholar]
  18. Lu J., Baase W. A., Muchmore D. C., Dahlquist F. W. Protein folding: assignment of the energetic changes of reversible chemical modifications to the folded or unfolded states. Biochemistry. 1992 Sep 1;31(34):7765–7772. doi: 10.1021/bi00149a004. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Markello T. C., Bernardini I. M., Gahl W. A. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. 1993 Apr 22;328(16):1157–1162. doi: 10.1056/NEJM199304223281604. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Meltzer M. S., Skillman D. R., Gomatos P. J., Kalter D. C., Gendelman H. E. Role of mononuclear phagocytes in the pathogenesis of human immunodeficiency virus infection. Annu Rev Immunol. 1990;8:169–194. doi: 10.1146/annurev.iy.08.040190.001125. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Mitsuya H., Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1911–1915. doi: 10.1073/pnas.83.6.1911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mitsuya H., Weinhold K. J., Furman P. A., St Clair M. H., Lehrman S. N., Gallo R. C., Bolognesi D., Barry D. W., Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096–7100. doi: 10.1073/pnas.82.20.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nagiel-Ostaszewski I., Lau-Cam C. A. Protection by pantethine, pantothenic acid and cystamine against carbon tetrachloride-induced hepatotoxicity in the rat. Res Commun Chem Pathol Pharmacol. 1990 Feb;67(2):289–292. [PubMed] [Google Scholar]
  27. Pal R., Hoke G. M., Sarngadharan M. G. Role of oligosaccharides in the processing and maturation of envelope glycoproteins of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1989 May;86(9):3384–3388. doi: 10.1073/pnas.86.9.3384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Perno C. F., Baseler M. W., Broder S., Yarchoan R. Infection of monocytes by human immunodeficiency virus type 1 blocked by inhibitors of CD4-gp120 binding, even in the presence of enhancing antibodies. J Exp Med. 1990 Apr 1;171(4):1043–1056. doi: 10.1084/jem.171.4.1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Perno C. F., Yarchoan R., Cooney D. A., Hartman N. R., Gartner S., Popovic M., Hao Z., Gerrard T. L., Wilson Y. A., Johns D. G. Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2',3'-dideoxynucleosides. J Exp Med. 1988 Sep 1;168(3):1111–1125. doi: 10.1084/jem.168.3.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Roederer M., Staal F. J., Raju P. A., Ela S. W., Herzenberg L. A., Herzenberg L. A. Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4884–4888. doi: 10.1073/pnas.87.12.4884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Salahuddin S. Z., Rose R. M., Groopman J. E., Markham P. D., Gallo R. C. Human T lymphotropic virus type III infection of human alveolar macrophages. Blood. 1986 Jul;68(1):281–284. [PubMed] [Google Scholar]
  32. 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]
  33. Scott J. S., Lakin C. A., Oliver J. R. The effect of cysteamine, cystamine, and the structurally related compounds taurine, N-acetyl-cysteine, and D-penicillamine on plasma prolactin levels in normal and estrogen-primed hyperprolactinemic rats. Endocrinology. 1987 Aug;121(2):812–818. doi: 10.1210/endo-121-2-812. [DOI] [PubMed] [Google Scholar]
  34. St Clair M. H., Martin J. L., Tudor-Williams G., Bach M. C., Vavro C. L., King D. M., Kellam P., Kemp S. D., Larder B. A. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991 Sep 27;253(5027):1557–1559. doi: 10.1126/science.1716788. [DOI] [PubMed] [Google Scholar]
  35. Staal F. J., Roederer M., Herzenberg L. A., Herzenberg L. A. Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9943–9947. doi: 10.1073/pnas.87.24.9943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Vasin M. V., Chernov Iu N., Semenova L. A. Protivoluchevye svoistva radioprotektorov, immunomoduliatorov i sredstv, vliiaiushchikh na tkanevoi obmen, pri fraktsionirovannom obluchenii. Radiobiologiia. 1991 Mar-Apr;31(2):271–275. [PubMed] [Google Scholar]
  37. Yarchoan R., Klecker R. W., Weinhold K. J., Markham P. D., Lyerly H. K., Durack D. T., Gelmann E., Lehrman S. N., Blum R. M., Barry D. W. Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet. 1986 Mar 15;1(8481):575–580. doi: 10.1016/s0140-6736(86)92808-4. [DOI] [PubMed] [Google Scholar]
  38. Yarchoan R., Mitsuya H., Thomas R. V., Pluda J. M., Hartman N. R., Perno C. F., Marczyk K. S., Allain J. P., Johns D. G., Broder S. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science. 1989 Jul 28;245(4916):412–415. doi: 10.1126/science.2502840. [DOI] [PubMed] [Google Scholar]
  39. Yeh T. J., McBride P. T., Overall J. C., Jr, Green J. A. Automated, quantitative cytopathic effect reduction assay for interferon. J Clin Microbiol. 1982 Aug;16(2):413–415. doi: 10.1128/jcm.16.2.413-415.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]

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