Thiostrepton Reactivates Latent HIV-1 through the p-TEFb and NF-κB Pathways Mediated by Heat Shock Response
Thiostrepton Reactivates Latent HIV-1 through the p-TEFb and NF-κB Pathways Mediated by Heat Shock Response
复制标题
硫链丝菌素通过热休克反应介导的 p-TEFb 和 NF-kappaB 途径重新激活潜伏的 HIV-1
DOI：
10.1128/aac.02328-19
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发表时间：
2020-05-01
影响因子：
4.9
通讯作者：
Deng, Kai
中科院分区：
文献类型：
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作者：
Peng, Wen;Hong, Zhongsi;Deng, Kai
抗逆转录病毒疗法（ART）抑制HIV-1复制，但未能治愈感染。一个非常稳定的病毒潜伏库的存在，主要是在静息记忆CD 4（+）T细胞，仍然是病毒根除的主要障碍。“休克和杀死”策略靶向这些潜伏感染的细胞并增强免疫识别和清除，因此，它是HIV-1功能性治愈的一种有前途的方法。尽管已有一些潜伏期逆转剂（LRA）的报道，但其临床应用尚未取得明显进展，因此寻找新型有效的LRA仍是当务之急。在这里，我们报告了硫链丝菌肽（TSR），一种蛋白酶体抑制剂，在细胞模型和ART抑制个体的原代CD 4（+）T细胞中有效地重新激活潜伏的HIV-1。TSR不会诱导整体T细胞活化、严重细胞毒性或CD 8（+）T细胞功能障碍，使其成为潜在的LRA候选药物。我们还观察到当TSR与JQ 1、prostratin或苔藓抑素-1组合时，再活化的显著协同效应。有趣的是，六个TSR类似物也显示出类似于或比TSR更有效的再激活能力。我们进一步证实，TSR上调了CD 4（+）T细胞中热休克蛋白（HSP）的表达，随后激活了正转录延伸因子B（p-TEF B）和NF-κ B B信号，导致病毒再活化。总之，我们确定TSR作为一种新的LRA，这可能具有重要意义的应用程序，在未来的HIV-1的功能性治疗。
Antiretroviral therapy (ART) suppresses HIV-1 replication but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4(+) T cells, remains a major obstacle to viral eradication. The "shock and kill" strategy targets these latently infected cells and boosts immune recognition and clearance, and thus, it is a promising approach for an HIV-1 functional cure. Although some latency-reversing agents (LRAs) have been reported, no apparent clinical progress has been made, so it is still vital to seek novel and effective LRAs. Here, we report that thiostrepton (TSR), a proteasome inhibitor, reactivates latent HIV-1 effectively in cellular models and in primary CD4(+) T cells from ART-suppressed individuals ex vivo. TSR does not induce global T cell activation, severe cytotoxicity, or CD8(+) T cell dysfunction, making it a prospective LRA candidate. We also observed a significant synergistic effect of reactivation when TSR was combined with JQ1, prostratin, or bryostatin-1. Interestingly, six TSR analogues also show reactivation abilities that are similar to or more effective than that of TSR. We further verified that TSR upregulated expression of heat shock proteins (HSPs) in CD4(+) T cells, which subsequently activated positive transcriptional elongation factor b (p-TEFb) and NF-kappa B signals, leading to viral reactivation. In summary, we identify TSR as a novel LRA which could have important significance for applications to an HIV-1 functional cure in the future.