Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression.
Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression.
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DOI：
10.1016/j.ajpath.2013.09.011
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
C. Mantri;J. V. Mantri;Jui Pandhare;C. Dash
中科院分区：
文献类型：
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作者：
C. Mantri;J. V. Mantri;Jui Pandhare;C. Dash
甲基苯丙胺是美国使用频率第二高的非法药物。滥用甲基苯丙胺与HIV-1感染风险增加、病毒载量增加以及HIV-1致病作用增强有关。尽管甲基苯丙胺滥用与HIV-1致病机制之间的直接联系在患者中仍未确定，但甲基苯丙胺已被证明可增加HIV-1在巨噬细胞、树突状细胞和HIV转基因小鼠细胞中的复制。有趣的是，甲基苯丙胺对人类CD4+T细胞中HIV-1复制的影响尚不清楚，这些细胞是活体感染的主要目标。因此，我们以剂量依赖的方式研究了在甲基苯丙胺存在的情况下，HIV-1在原代CD4+T细胞中的复制。结果表明，甲基苯丙胺在1~50μ/L浓度范围内对HIV-1复制的抑制作用最小，而在浓度为&100μ/L时，对HIV-1复制的抑制作用呈剂量依赖关系。我们还发现，甲基苯丙胺上调了CD4+T细胞中细胞内抗HIV-1microRNAs(miR-125b、miR-150和miR-28-5p)的表达。基因敲除实验表明，上调抗HIV-1 miRNAs抑制了HIV-1的复制。这些结果与甲基苯丙胺通过增加HIV-1复制而加剧HIV-1发病的范式相反。因此，我们的发现强调了药物使用和HIV-1之间的复杂相互作用，并需要全面了解甲基苯丙胺在HIV-1发病机制中的作用。
Methamphetamine is the second most frequently used illicit drug in the United States. Methamphetamine abuse is associated with increased risk of HIV-1 acquisition, higher viral loads, and enhanced HIV-1 pathogenesis. Although a direct link between methamphetamine abuse and HIV-1 pathogenesis remains to be established in patients, methamphetamine has been shown to increase HIV-1 replication in macrophages, dendritic cells, and cells of HIV transgenic mice. Intriguingly, the effects of methamphetamine on HIV-1 replication in human CD4+T cells that serve as the primary targets of infectionin vivoare not clearly understood. Therefore, we examined HIV-1 replication in primary CD4+T cells in the presence of methamphetamine in a dose-dependent manner. Our results demonstrate that methamphetamine had a minimal effect on HIV-1 replication at concentrations of 1 to 50 μmol/L. However, at concentrations >100 μmol/L, it inhibited HIV-1 replication in a dose-dependent manner. We also discovered that methamphetamine up-regulated the cellular anti–HIV-1 microRNAs (miR-125b, miR-150, and miR-28-5p) in CD4+T cells. Knockdown experiments illustrated that up-regulation of the anti-HIV miRNAs inhibited HIV-1 replication. These results are contrary to the paradigm that methamphetamine accentuates HIV-1 pathogenesis by increasing HIV-1 replication. Therefore, our findings underline the complex interaction between drug use and HIV-1 and necessitate comprehensive understanding of the effects of methamphetamine on HIV-1 pathogenesis.