Moog C, Kuntz-Simon G, Caussin-Schwemling C, Obert G
Laboratoire de Virologie de la Faculté de Médecine et U74 de I'INSERM, Université Louis Pasteur, Strasbourg, France.
J Gen Virol. 1996 Sep;77 ( Pt 9):1993-9. doi: 10.1099/0022-1317-77-9-1993.
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.
由于谷胱甘肽（GSH）水平的调节与人类免疫缺陷病毒（HIV）转录和表达的调控有关，我们对丙戊酸钠（VPA）对HIV-1复制的影响进行了分析。VPA是临床医学中广泛使用的抗癫痫药物，已被证明可抑制GSH还原酶的活性，该酶是维持细胞内高还原型GSH水平所必需的。在原代感染细胞，即外周血单核细胞（PBMC）和单核细胞/巨噬细胞、CEM-SS细胞系以及慢性感染的受刺激和未受刺激的U1细胞中，研究了这种药物对HIV-1复制的影响。我们已经表明，VPA在所有测试的感染细胞中均显著增强病毒复制。通过VPA处理在U1细胞中诱导病毒产生，并且肿瘤坏死因子-α、白细胞介素-6和粒细胞/巨噬细胞集落刺激因子的刺激作用增强。Jurkat T细胞中LTR驱动的基因表达增加。然而，病毒产生的增加与VPA对细胞内GSH水平的影响无关。因此，VPA在急性和慢性感染细胞中刺激体外HIV-1复制，并增强LTR驱动的基因表达。在VPA治疗患者的血浆中达到的浓度下观察到了这些效应。因此，尽管这些数据的临床意义仍有待证明，但在为HIV感染个体选择抗惊厥药物时应考虑这些结果。
