BET bromodomain inhibition as a novel strategy for reactivation of HIV-1
BET bromodomain inhibition as a novel strategy for reactivation of HIV-1
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DOI：
10.1189/jlb.0312165
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发表时间：
2012-12-01
影响因子：
5.5
通讯作者：
Montano, Monty
中科院分区：
文献类型：
--
作者：
Banerjee, Camellia;Archin, Nancie;Montano, Monty
潜伏的HIV-1的持续存在仍然是根除感染的治疗努力中的一个主要挑战。我们报告了BET家族溴结构域的选择性小分子抑制剂JQ 1对HIV再活化的能力，JQ 1是一种具有抗癌特性的有前途的治疗剂。JQ 1在潜伏性T细胞感染和潜伏性单核细胞感染模型中重新激活HIV转录。我们还测试了暴露于JQ 1的效果，以允许从HIV感染的ART治疗患者分离的静息CD 4（+）T细胞库中恢复具有复制能力的HIV。在三名患者中的一名中，JQ 1允许以高于未刺激条件的频率恢复病毒。JQ 1以最小的细胞毒性作用有效地抑制T细胞增殖。用JQ 1对T细胞的转录谱分析显示，与HDAC抑制剂类似，JQ 1对T细胞活化基因（包括CD 3、CD 28和CXCR 4）的有效下调，但JQ 1还对染色质修饰基因（包括SIRT 1、HDAC 6和多种赖氨酸脱甲基酶（KDM））的有效上调。因此，JQ 1重新激活HIV-1，同时抑制T细胞活化基因和上调组蛋白修饰基因，预计有利于增加达特活性。因此，JQ 1可能是有用的，在研究潜在的新机制的转录控制，以及在翻译的努力，以确定治疗分子，以实现病毒根除。J. Leukoc. 92：1147-1154; 2012.
The persistence of latent HIV-1 remains a major challenge in therapeutic efforts to eradicate infection. We report the capacity for HIV reactivation by a selective small molecule inhibitor of BET family bromodomains, JQ1, a promising therapeutic agent with antioncogenic properties. JQ1 reactivated HIV transcription in models of latent T cell infection and latent monocyte infection. We also tested the effect of exposure to JQ1 to allow recovery of replication-competent HIV from pools of resting CD4(+) T cells isolated from HIV-infected, ART-treated patients. In one of three patients, JQ1 allowed recovery of virus at a frequency above unstimulated conditions. JQ1 potently suppressed T cell proliferation with minimal cytotoxic effect. Transcriptional profiling of T cells with JQ1 showed potent down-regulation of T cell activation genes, including CD3, CD28, and CXCR4, similar to HDAC inhibitors, but JQ1 also showed potent up-regulation of chromatin modification genes, including SIRT1, HDAC6, and multiple lysine demethylases (KDMs). Thus, JQ1 reactivates HIV-1 while suppressing T cell activation genes and up-regulating histone modification genes predicted to favor increased Tat activity. Thus, JQ1 may be useful in studies of potentially novel mechanisms for transcriptional control as well as in translational efforts to identify therapeutic molecules to achieve viral eradication. J. Leukoc. Biol. 92: 1147-1154; 2012.