title: Effects of glutathione precursors on human immunodeficiency virus replication.
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.
authors.affiliation: Laboratoire common Université Louis Pasteur/Synthélabo, Strasbourg, France.
authors.forename: G
authors.initials: G
authors.lastname: Simon
authors.forename: C
authors.initials: C
authors.lastname: Moog
authors.forename: G
authors.initials: G
authors.lastname: Obert
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D002460:Cell Line; D003124:Colorimetry; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: D015850:Interleukin-6; D011355:Prodrugs; D013844:Thiazoles; D053778:Thiazolidines; D006710:Homocysteine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D001616:beta-Galactosidase; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine; C029536:2-oxothiazolidine-4-carboxylic acid