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M9470132.TXT
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1994-07-02
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Document 0132
DOCN M9470132
TI Effects of glutathione precursors on human immunodeficiency virus
replication.
DT 9409
AU Simon G; Moog C; Obert G; Laboratoire common Universite Louis
Pasteur/Synthelabo,; Strasbourg, France.
SO Chem Biol Interact. 1994 Jun;91(2-3):217-24. Unique Identifier :
AIDSLINE MED/94251848
AB 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.
DE 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
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).