Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells.
Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells.
复制标题
甲基苯丙胺激活活化 B 细胞 (NF-κB) 的核因子 kappa 轻链增强子，并诱导人类小胶质细胞中的人类免疫缺陷病毒 (HIV) 转录。
DOI：
10.1007/s13365-012-0103-4
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发表时间：
2012
影响因子：
3.2
通讯作者：
Harvey,BrandonK
中科院分区：
文献类型：
--
作者：
Wires,EmilyS;Alvarez,David;Dobrowolski,Curtis;Wang,Yun;Morales,Marisela;Karn,Jonathan;Harvey,BrandonK
人类免疫缺陷病毒（HIV）主要感染中枢神经系统（CNS）的神经胶质细胞。最近的证据表明，滥用甲基苯丙胺（METH）等药物的艾滋病毒感染者比不滥用药物的艾滋病毒感染者病毒载量更高，神经系统并发症更严重。本研究的目的是确定METH对HIV长末端重复序列（LTR）启动子的HIV表达以及对小胶质细胞（CNS中HIV的主要宿主细胞）中HIV整合前病毒的影响。用HIV LTR报告基因和HIV达特基因（病毒复制和基因表达的关键调节因子）共转染用SV 40 T抗原永生化的原代人小胶质细胞（CHME-5细胞），并暴露于METH。我们的研究结果表明，METH处理诱导LTR激活，在达特的存在下增强的效果。我们还发现，METH增加了核因子κ B（NF-κB）的核转位，这是LTR启动子的关键细胞转录调节因子，并增加了CHME-5细胞中NF-κ B特异性报告质粒的活性。NF-κB的显性负调控因子的存在阻断了HIV LTR的MET相关活化。此外，用METH处理HIV潜伏感染的CHME-5（CHME-5/HIV）细胞诱导HIV表达和NF-κB的p65亚基的核转位。这些结果表明，METH可以通过激活NF-κB信号通路刺激小胶质细胞中的HIV基因表达。这种机制可能概述了导致使用METH的HIV阳性个体中观察到的神经退行性变增加的最初生化事件。
Human immunodeficiency virus (HIV) primarily infects glial cells in the central nervous system (CNS). Recent evidence suggests that HIV-infected individuals who abuse drugs such as methamphetamine (METH) have higher viral loads and experience more severe neurological complications than HIV-infected individuals who do not abuse drugs. The aim of this study was to determine the effect of METH on HIV expression from the HIV long terminal repeat (LTR) promoter and on an HIV integrated provirus in microglial cells, the primary host cells for HIV in the CNS. Primary human microglial cells immortalized with SV40 T antigen (CHME-5 cells) were cotransfected with an HIV LTR reporter and the HIV Tat gene, a key regulator of viral replication and gene expression, and exposed to METH. Our results demonstrate that METH treatment induced LTR activation, an effect potentiated in the presence of Tat. We also found that METH increased the nuclear translocation of the nuclear factor kappa B (NF-κB), a key cellular transcriptional regulator of the LTR promoter, and the activity of an NF-κB-specific reporter plasmid in CHME-5 cells. The presence of a dominant-negative regulator of NF-κB blocked METH-related activation of the HIV LTR. Furthermore, treatment of HIV-latently infected CHME-5 (CHME-5/HIV) cells with METH induced HIV expression and nuclear translocation of the p65 subunit of NF-κB. These results suggest that METH can stimulate HIV gene expression in microglia cells through activation of the NF-κB signaling pathway. This mechanism may outline the initial biochemical events leading to the observed increased neurodegeneration in HIV-positive individuals who use METH.