Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation.
Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation.
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DOI：
10.1016/j.celrep.2017.01.022
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发表时间：
2017-01-31
期刊：
影响因子：
8.8
通讯作者：
Planelles V
中科院分区：
文献类型：
--
作者：
Bosque A;Nilson KA;Macedo AB;Spivak AM;Archin NM;Van Wagoner RM;Martins LJ;Novis CL;Szaniawski MA;Ireland CM;Margolis DM;Price DH;Planelles V
感染者体内潜伏的 HIV-1 的存在是阻止病毒根除的主要障碍。因此，在抗逆转录病毒治疗方案存在的情况下重新激活潜伏病毒已被提议作为实现缓解的治疗策略。我们筛选了小分子并鉴定了几种具有重新激活潜伏 HIV-1 能力的苯并三唑衍生物。在 IL-2 存在的情况下，苯并三唑重新激活并减少原代细胞中的潜在储存库，并且值得注意的是，病毒重新激活是在不诱导细胞增殖、T 细胞激活或细胞因子释放的情况下实现的。机理研究表明，苯并三唑可阻断磷酸化 STAT5 的 SUMO 化，从而增加 STAT5 的活性和 HIV-1 LTR 的占据。我们的结果确定苯并三唑为潜伏期逆转剂，STAT5 信号传导和 SUMOylation 为 HIV-1 根除策略的目标。这些化合物代表了寻找“休克和杀死”疗法的不同方向。潜伏的 HIV-1 是根除 HIV-1 的障碍。博斯克等人。鉴定出一系列能够重新激活和减少潜伏 HIV-1 的化合物。这些化合物可阻断 STAT5 的 SUMOylation，并代表 HIV-1 根除策略的目标。
The presence of latent HIV-1 in infected individuals represents a major barrier preventingviral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules and identified several benzotriazole derivatives with the ability to reactivate latent HIV-1. In the presence of IL-2, benzotriazoles reactivated and reduced the latent reservoir in primary cells, and, remarkably, viral reactivation was achieved without inducing cell proliferation, T cell activation, or cytokine release. Mechanistic studies showed that benzotriazoles block SUMOylation of phosphorylated STAT5, increasing STAT5’s activity and occupancy of the HIV-1 LTR. Our results identify benzotriazoles as latency reversing agents and STAT5 signaling and SUMOylation as targets for HIV-1 eradication strategies. These compounds represent a different direction in the search for “shock and kill” therapies. Latent HIV-1 represents a barrier toward HIV-1 eradication. Bosque et al. identify a family of compounds that have the ability to reactivate and decrease latent HIV-1. These compounds block SUMOylation of STAT5 and represent a target for HIV-1 eradication strategies.