Simon G, Moog C, Obert G
Laboratoire commun Université Louis Pasteur/Synthélabo, Strasbourg, France.
Chem Biol Interact. 1994 Jun;91(2-3):111-21. doi: 10.1016/0009-2797(94)90031-0.
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.
细胞内谷胱甘肽（GSH）水平的改变与人类免疫缺陷病毒（HIV）转录和表达的调控有关。关于这一假说，我们研究了丙戊酸（VPA）对HIV复制的影响。事实上，最近有报道称VPA可抑制人类红细胞谷胱甘肽还原酶。在用HIV-1 LAI株感染的CEM-SS T淋巴细胞系的上清液中，我们观察到用VPA处理细胞后，逆转录酶活性呈剂量依赖性增加。VPA还可诱导慢性感染的单核细胞U1细胞系（该细胞系组成性表达低水平病毒）中的HIV表达，增强瞬时转染的Jurkat T细胞中HIV长末端重复序列（LTR）指导的β-半乳糖苷酶表达，并增强佛波酯（PMA）对LTR反式激活的作用。谷胱甘肽检测显示，VPA处理导致U937（U1亲本细胞系）和Jurkat T细胞中这种硫醇化合物的细胞内水平降低。目前正在开展工作以了解VPA诱导HIV转录和表达的分子机制。VPA似乎是研究谷胱甘肽减少对HIV复制刺激影响的合适分子。然而，还原型和氧化型谷胱甘肽之间细胞内平衡的改变，而非细胞内谷胱甘肽水平的简单降低，可能在HIV复制调控中具有重要意义，我们目前正在验证这一假说。最后，这些发现已经表明，VPA作为一种常用于治疗各种癫痫疾病的抗惊厥药物，不应该被推荐用于治疗HIV阳性个体的癫痫或其他相关疾病。
