Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
Effects of glutathione precursors on human immunodeficiency virus replication.
Chem Biol Interact. 1994 Jun;91(2-3):217-24. Unique Identifier : AIDSLINE MED/94251848 Simon G; Moog C; Obert G; Laboratoire common Universite Louis Pasteur/Synthelabo,; Strasbourg, France.
Abstract:
Asymptomatic human immunodeficiency virus (HIV)-seropositive individuals have reduced glutathione (GSH) levels. This has led to the suggestion that elevated intracellular thiols levels may inhibit HIV replication and progression of the disease. We confirmed that N-acetyl-L-cysteine (NAC), a cysteine prodrug which maintains intracellular GSH levels during oxidative stress, inhibits in the chronically infected U1 cells, the stimulation of HIV replication induced by phorbol 12-myristate 13-acetate (PMA), interleukin-6 (IL-6) or granulocyte-macrophage colony stimulating factor (GM-CSF). However, we found no significant inhibition of PMA-mediated long terminal repeat (LTR)-directed beta-galactosidase expression in transiently transfected Jurkat T-cells. We have compared NAC effects with the effects of other GSH precursors on HIV expression. Treatment of the U1 cell line by L-2-oxo-4-thiazolidine carboxylic acid (OTC), which is converted to cysteine by 5-oxoprolinase, or by homocysteine (HC), a natural cysteine precursor, reduced the PMA-induced HIV expression, but surprisingly, markedly stimulated the expression mediated by IL-6 and GM-CSF. Several experiments to investigate the effect of OTC on LTR transactivation were carried out, but beta-galactosidase activity was never modified in a significant fashion in PMA-induced Jurkat T-cells after OTC treatment. Furthermore, HC stimulated the PMA-mediated HIV-LTR transactivation in Jurkat T-cells. GSH assays showed that treatment of U937 and Jurkat T-cells with NAC and OTC moderately increased the GSH level, while HC led to a significantly higher increase of the thiol level. In conclusion, it appeared that an increase of the GSH intracellular level did not lead solely to an inhibition of HIV replication but could also lead to an activation of viral expression. This seemed the case when HIV replication was stimulated by compounds which act mainly at a post-transcriptional level.
Keywords: beta-Galactosidase/BIOSYNTHESIS Acetylcysteine/*PHARMACOLOGY Cell Line Colorimetry Comparative Study Gene Expression Regulation, Viral/DRUG EFFECTS Glutathione/*METABOLISM Granulocyte-Macrophage Colony-Stimulating Factor/PHARMACOLOGY Homocysteine/*PHARMACOLOGY Human HIV/*DRUG EFFECTS/GENETICS/PHYSIOLOGY HIV Long Terminal Repeat/DRUG EFFECTS Interleukin-6/PHARMACOLOGY Prodrugs/PHARMACOLOGY Tetradecanoylphorbol Acetate/PHARMACOLOGY Thiazoles/*PHARMACOLOGY Tumor Cells, Cultured Virus Replication/DRUG EFFECTS JOURNAL ARTICLE
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Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
