The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication
The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication
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DOI：
10.1128/aac.46.11.3447-3455.2002
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发表时间：
2002-11-01
影响因子：
4.9
通讯作者：
Tremblay, MJ
中科院分区：
文献类型：
--
作者：
Roy, J;Paquette, JS;Tremblay, MJ
免疫抑制性大环内酯雷帕霉素用于人类预防移植排斥。该药物通过选择性抑制由带有 5'-聚嘧啶束的 mRNA 编码的蛋白质（例如核糖体蛋白质、延伸因子）的翻译来发挥作用。人类免疫缺陷病毒 1 型 (HIV-1) 携带位于 tat 外显子 2 内的聚嘧啶基序。当用荧光素酶报道 T 向性和巨噬细胞向性病毒感染时，用雷帕霉素处理人 T 淋巴细胞会导致 HIV-1 转录显着减少。雷帕霉素治疗消除了完全感染性 HIV-1 颗粒的复制。 FK506 逆转了雷帕霉素介导的 HIV-1 产生抑制作用。雷帕霉素的抗 HIV-1 作用也在来自不同健康捐赠者的原代人类细胞（即外周血淋巴细胞）中观察到。雷帕霉素被证明可以减少基础 HIV-1 长末端重复基因表达，并且观察到的雷帕霉素对 HIV-1 复制的影响似乎与病毒特异性反式激活 Tat 蛋白无关。基于β-肌动蛋白启动子的组成型报告基因载体不受雷帕霉素处理的影响。动力学病毒感染研究和接触用异源包膜蛋白假型化的报告病毒（即双嗜性鼠白血病病毒和水泡性口炎病毒 G）表明雷帕霉素主要在转录水平影响 HIV-1 的生命周期。 Northern 印迹分析证实该化合物选择性地靶向 HIV-1 mRNA 合成。
The immunosuppressive macrolide rapamycin is used in humans to prevent graft rejection. This drug acts by selectively repressing the translation of proteins that are encoded by an mRNA bearing a 5'-polypyrimidine tract (e.g., ribosomal proteins, elongation factors). The human immunodeficiency virus type 1 (HIV-1) carries a polypyrimidine motif that is located within the tat exon 2. Treatment of human T lymphoid cells with rapamycin resulted in a marked diminution of HIV-1 transcription when infection was performed with luciferase reporter T-tropic and macrophage-tropic viruses. Replication of fully infectious HIV-1 particles was abolished by rapamycin treatment. The rapamycin-mediated inhibitory effect on HIV-1 production was reversed by FK506. The anti-HIV-1 effect of rapamycin was also seen in primary human cells (i.e., peripheral blood lymphocytes) from different healthy donors. Rapamycin was shown to diminish basal HIV-1 long terminal repeat gene expression, and the observed effect of rapamycin on HIV-1 replication seems to be independent of the virus-specific transactivating Tat protein. A constitutive beta-actin promoter-based reporter gene vector was unaffected by rapamycin treatment. Kinetic virus infection studies and exposure to reporter viruses pseudotyped with heterologous envelope proteins (i.e., amphotropic murine leukemia virus and vesicular stomatitis virus G) suggested that rapamycin is primarily affecting the life cycle of HIV-1 at a transcriptional level. Northern blot analysis confirmed that this compound is selectively targeting HIV-1 mRNA synthesis.