G. Simon et al., EFFECTS OF GLUTATHIONE PRECURSORS ON HUMAN-IMMUNODEFICIENCY-VIRUS REPLICATION, Chemico-biological interactions, 91(2-3), 1994, pp. 217-224
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.