EFFECTS OF GLUTATHIONE PRECURSORS ON HUMAN-IMMUNODEFICIENCY-VIRUS REPLICATION

Asymptomatic human immunodeficiency virus (HIV)-seropositive individua ls have reduced glutathione (GSH) levels. This has led to the suggesti on that elevated intracellular thiols levels may inhibit HIV replicati on and progression of the disease. We confirmed that N-acetyl-L-cystei ne (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 1 3-acetate (PMA), interleukin-6 (IL-6) or granulocyte-macrophage colony stimulating factor (GM-CSF). However, we found no significant inhibit ion of PMA-mediated long terminal repeat (LTR)-directed beta-galactosi dase expression in transiently transfected Jurkat T-cells. We have com pared NAC effects with the effects of other GSH precursors on HIV expr ession. Treatment of the U1 cell line by L-2-oxo-4-thiazolidine carbox ilic acid (OTC), which is converted to cysteine by 5-oxoprolinase, or by homocysteine (HC), a natural cysteine precursor, reduced the PMA-in duced HIV expression, but surprisingly, markedly stimulated the expres sion mediated by IL-6 and GM-CSF. Several experiments to investigate t he effect of OTC on LTR transactivation were carried out, but beta-gal actosidase activity was never modified in a significant fashion in PMA -induced Jurkat T-cells after OTC treatment. Furthermore, HC stimulate d the PMA-mediated HIV-LTR transactivation in Jurkat T-cells. GSH assa ys showed that treatment of U937 and Jurkat T-cells with NAC and OTC m oderately increased the GSH level, while HC led to a significantly hig her increase of the thiol level. In conclusion, it appeared that an in crease of the GSH intracellular level did not lead solely to an inhibi tion of HIV replication but could also lead to an activation of viral expression. This seemed the case when HIV replication was stimulated b y compounds which act mainly at a posttranscriptional level.