Bosque Alberto, Nilson Kyle A, Macedo Amanda B, Spivak Adam M, Archin Nancie M, Van Wagoner Ryan M, Martins Laura J, Novis Camille L, Szaniawski Matthew A, Ireland Chris M, Margolis David M, Price David H, Planelles Vicente
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
Cell Rep. 2017 Jan 31;18(5):1324-1334. doi: 10.1016/j.celrep.2017.01.022.
The presence of latent HIV-1 in infected individuals represents a major barrier preventing viral 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.
潜伏的HIV-1在受感染个体中的存在是阻碍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出几种具有重新激活潜伏HIV-1能力的苯并三唑衍生物。在白细胞介素-2存在的情况下，苯并三唑重新激活并减少了原代细胞中的潜伏库，而且值得注意的是，在不诱导细胞增殖、T细胞活化或细胞因子释放的情况下实现了病毒重新激活。机制研究表明，苯并三唑阻断磷酸化STAT5的SUMO化，增加STAT5的活性以及其在HIV-1长末端重复序列上的占有率。我们的结果将苯并三唑鉴定为潜伏逆转剂，并将STAT5信号传导和SUMO化鉴定为HIV-1根除策略的靶点。这些化合物代表了寻找“激活并清除”疗法的一个不同方向。
