Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Jul 1;180(1):359–363. doi: 10.1084/jem.180.1.359

Opposing regulatory effects of thioredoxin and eosinophil cytotoxicity- enhancing factor on the development of human immunodeficiency virus 1

PMCID: PMC2191566  PMID: 8006594

Abstract

Exogenous recombinant human thioredoxin (rTRX, > or = 500 nM), a dithiol reductase enzyme, inhibited the expression of human immunodeficiency virus (HIV) 1BaL in human macrophages (M phi) by 71% (range, 26-100%), as evaluated by p24 antigen production and the integration of provirus at 14 d after infection. The stoichiometric reducing agent N-acetylcysteine (NAC) also inhibited HIV production, but to a lesser degree, and only at 30,000-fold higher concentrations. Exogenous rTRX is cleaved by M phi to generate the inflammatory cytokine, eosinophil cytotoxicity-enhancing factor (ECEF). In contrast to rTRX, rECEF (concentrations from 50 pM to 2 microM) enhanced the production of HIV by 67% (range, 33-92%). Thus, whereas TRX is a potent inhibitor of the expression of HIV in human M phi, cleavage of TRX to ECEF creates a mediator with the opposite effect. TRX also inhibited the expression of integrated provirus in the chronically infected OM 10.1 cell line, showing that it can act at a step subsequent to viral infection and integration.

Full Text

The Full Text of this article is available as a PDF (586.8 KB).

Selected References

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

  1. Balcewicz-Sablinska M. K., Wollman E. E., Gorti R., Silberstein D. S. Human eosinophil cytotoxicity-enhancing factor. II. Multiple forms synthesized by U937 cells and their relationship to thioredoxin/adult T cell leukemia-derived factor. J Immunol. 1991 Oct 1;147(7):2170–2174. [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. Butera S. T., Perez V. L., Wu B. Y., Nabel G. J., Folks T. M. Oscillation of the human immunodeficiency virus surface receptor is regulated by the state of viral activation in a CD4+ cell model of chronic infection. J Virol. 1991 Sep;65(9):4645–4653. doi: 10.1128/jvi.65.9.4645-4653.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chomczynski P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques. 1993 Sep;15(3):532-4, 536-7. [PubMed] [Google Scholar]
  5. Dröge W., Eck H. P., Mihm S. HIV-induced cysteine deficiency and T-cell dysfunction--a rationale for treatment with N-acetylcysteine. Immunol Today. 1992 Jun;13(6):211–214. doi: 10.1016/0167-5699(92)90156-2. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Fauci A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. doi: 10.1126/science.3277274. [DOI] [PubMed] [Google Scholar]
  8. Holmgren A. Thioredoxin and glutaredoxin systems. J Biol Chem. 1989 Aug 25;264(24):13963–13966. [PubMed] [Google Scholar]
  9. 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]
  10. Newman G. W., Kelley T. G., Gan H., Kandil O., Newman M. J., Pinkston P., Rose R. M., Remold H. G. Concurrent infection of human macrophages with HIV-1 and Mycobacterium avium results in decreased cell viability, increased M. avium multiplication and altered cytokine production. J Immunol. 1993 Aug 15;151(4):2261–2272. [PubMed] [Google Scholar]
  11. 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]
  12. Ou C. Y., Kwok S., Mitchell S. W., Mack D. H., Sninsky J. J., Krebs J. W., Feorino P., Warfield D., Schochetman G. DNA amplification for direct detection of HIV-1 in DNA of peripheral blood mononuclear cells. Science. 1988 Jan 15;239(4837):295–297. doi: 10.1126/science.3336784. [DOI] [PubMed] [Google Scholar]
  13. Rayfield M., De Cock K., Heyward W., Goldstein L., Krebs J., Kwok S., Lee S., McCormick J., Moreau J. M., Odehouri K. Mixed human immunodeficiency virus (HIV) infection in an individual: demonstration of both HIV type 1 and type 2 proviral sequences by using polymerase chain reaction. J Infect Dis. 1988 Dec;158(6):1170–1176. doi: 10.1093/infdis/158.6.1170. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Rozell B., Hansson H. A., Luthman M., Holmgren A. Immunohistochemical localization of thioredoxin and thioredoxin reductase in adult rats. Eur J Cell Biol. 1985 Jul;38(1):79–86. [PubMed] [Google Scholar]
  17. Rubartelli A., Bajetto A., Allavena G., Wollman E., Sitia R. Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J Biol Chem. 1992 Dec 5;267(34):24161–24164. [PubMed] [Google Scholar]
  18. Scadden D. T., Wang Z., Groopman J. E. Quantitation of plasma human immunodeficiency virus type 1 RNA by competitive polymerase chain reaction. J Infect Dis. 1992 Jun;165(6):1119–1123. doi: 10.1093/infdis/165.6.1119. [DOI] [PubMed] [Google Scholar]
  19. Schreck R., Rieber P., Baeuerle P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. doi: 10.1002/j.1460-2075.1991.tb07761.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Silberstein D. S., Ali M. H., Baker S. L., David J. R. Human eosinophil cytotoxicity-enhancing factor. Purification, physical characteristics, and partial amino acid sequence of an active polypeptide. J Immunol. 1989 Aug 1;143(3):979–983. [PubMed] [Google Scholar]
  21. Silberstein D. S., McDonough S., Minkoff M. S., Balcewicz-Sablinska M. K. Human eosinophil cytotoxicity-enhancing factor. Eosinophil-stimulating and dithiol reductase activities of biosynthetic (recombinant) species with COOH-terminal deletions. J Biol Chem. 1993 Apr 25;268(12):9138–9142. [PubMed] [Google Scholar]
  22. Tagaya Y., Maeda Y., Mitsui A., Kondo N., Matsui H., Hamuro J., Brown N., Arai K., Yokota T., Wakasugi H. ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J. 1989 Mar;8(3):757–764. doi: 10.1002/j.1460-2075.1989.tb03436.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tagaya Y., Okada M., Sugie K., Kasahara T., Kondo N., Hamuro J., Matsushima K., Dinarello C. A., Yodoi J. IL-2 receptor(p55)/Tac-inducing factor. Purification and characterization of adult T cell leukemia-derived factor. J Immunol. 1988 Apr 15;140(8):2614–2620. [PubMed] [Google Scholar]
  24. Wollman E. E., d'Auriol L., Rimsky L., Shaw A., Jacquot J. P., Wingfield P., Graber P., Dessarps F., Robin P., Galibert F. Cloning and expression of a cDNA for human thioredoxin. J Biol Chem. 1988 Oct 25;263(30):15506–15512. [PubMed] [Google Scholar]
  25. Zhu T., Mo H., Wang N., Nam D. S., Cao Y., Koup R. A., Ho D. D. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science. 1993 Aug 27;261(5125):1179–1181. doi: 10.1126/science.8356453. [DOI] [PubMed] [Google Scholar]
  26. de Quay B., Malinverni R., Lauterburg B. H. Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS. 1992 Aug;6(8):815–819. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES