Valproic acid reduces the intracellular level of glutathione and stimulates human immunodeficiency virus.
Modifications of the glutathione (GSH) intracellular level have been implicated in the regulation of human immunodeficiency virus (HIV) transcription and expression. In regard to this hypothesis, we have investigated the effects of valproic acid (VPA) on HIV replication. Indeed, it has been recently reported that VPA inhibits the human red blood cell glutathione reductase. In the supernatant of a CEM-SS T-lymphocytic cell line infected with the LAI strain of HIV-1, we observed an increase, in a dose-dependent fashion, of the reverse transcriptase activity after treatment of cells with VPA. VPA also induced HIV expression in the chronically infected monocytic U1 cell line which constitutively expresses low levels of virus, enhanced the HIV-long terminal repeat (LTR)-directed expression of beta-galactosidase in transiently transfected Jurkat T-cells, and potentiated the PMA effect on the LTR transactivation. GSH assays showed that VPA treatment led to a decrease in the intracellular level of this thiol compound in U937 (U1 parent-cell line) and in Jurkat T-cells. Work to understand the molecular mechanism of VPA-induced HIV transcription and expression are now in progress. VPA seems to be an adequate molecule to study the implications of a GSH decrease in the stimulation of HIV replication. However, a modification of the intracellular balance between reduced and oxidized glutathione, rather than a simple reduction of the intracellular glutathione level, could be of importance in the regulation of HIV replication and we are now testing this hypothesis. Finally, these findings already suggest that VPA, which is an anticonvulsive drug frequently prescribed for the management of various seizure disorders, should not be recommended for treatment of epilepsy or other related illnesses in HIV-positive individuals.
Simon
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Laboratoire commun Université Louis Pasteur/Synthélabo, Strasbourg, France.
Moog
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Obert
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D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D010084:Oxidation-Reduction; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D001616:beta-Galactosidase / Q000235:genetics
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D014635:Valproic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D001616:beta-Galactosidase; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate