Sodium valproate, an anticonvulsant drug, stimulates human immunodeficiency virus type 1 replication independently of glutathione levels.
Since modulation of the glutathione (GSH) level has been implicated in the regulation of human immunodeficiency virus (HIV) transcription and expression, we have undertaken an analysis of the effect of sodium valproate (VPA) on HIV-1 replication. VPA, which is an anti-epileptic drug in widespread use in clinical medicine, has been shown to depress the activity of GSH reductase, an enzyme required for maintaining high cellular levels of reduced GSH. The effect of this drug on HIV-1 replication has been studied in primary infected cells, i.e. peripheral blood mononuclear cells (PBMC) and monocyte/macrophages, in the CEM-SS cell line, and in chronically infected stimulated and non-stimulated U1 cells. We have shown that VPA markedly enhanced viral replication in all infected cells tested. Virus production was induced in U1 cells by VPA treatment and the stimulatory effects of tumour necrosis factor-alpha, interleukin-6 and granulocyte/macrophage colony-stimulating factor were augmented. The LTR-driven gene expression in Jurkat T cells was increased. However, the elevated viral production did not correlate with the effect of VPA on the intracellular GSH level. Thus, VPA stimulated in vitro HIV-1 replication in acutely and chronically infected cells and enhanced LTR-driven gene expression. These effects were observed for concentrations that are reached in the plasma of VPA-treated patients. Therefore, although the clinical significance of these data remains to be demonstrated, these results should be considered in the choice of an anticonvulsant drug in HIV-infected individuals.
Moog
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Laboratoire de Virologie de la Faculté de Médecine et U74 de I'INSERM, Université Louis Pasteur, Strasbourg, France. c.moog@vir.u-strasbg.fr
Kuntz-Simon
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Caussin-Schwemling
C
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Obert
G
G
D000927:Anticonvulsants / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors*; D016325:HIV Long Terminal Repeat; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007763:Lac Operon; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000821:virology; D008264:Macrophages / Q000166:cytology / Q000821:virology; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D014635:Valproic Acid; D005980:Glutathione Reductase; D054303:HIV Reverse Transcriptase; D001616:beta-Galactosidase; D005978:Glutathione