Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
Institute of Human Genetics (IGH), CNRS-University of Montpelier, Montpelier, France.
FASEB J. 2019 Jul;33(7):8280-8293. doi: 10.1096/fj.201801165R. Epub 2019 Apr 25.
The HIV-1 transactivation protein (Tat) binds the HIV mRNA transactivation responsive element (TAR), regulating transcription and reactivation from latency. Drugs against Tat are unfortunately not clinically available. We reported that didehydro-cortistatin A (dCA) inhibits HIV-1 Tat activity. In human CD4 T cells isolated from aviremic individuals and in the humanized mouse model of latency, combining dCA with antiretroviral therapy accelerates HIV-1 suppression and delays viral rebound upon treatment interruption. This drug class is amenable to block-and-lock functional cure approaches, aimed at a durable state of latency. Simian immunodeficiency virus (SIV) infection of rhesus macaques (RhMs) is the best-characterized model for AIDS research. Here, we demonstrate, using and cell-based assays, that dCA directly binds to SIV Tat's basic domain. dCA specifically inhibits SIV Tat binding to TAR, but not a Tat-Rev fusion protein, which activates transcription when Rev binds to its cognate RNA binding site replacing the apical region of TAR. Tat-TAR inhibition results in loss of RNA polymerase II recruitment to the SIV promoter. Importantly, dCA potently inhibits SIV reactivation from latently infected Hut78 cells and from primary CD4 T cells explanted from SIV239-infected RhMs. In sum, dCA's remarkable breadth of activity encourages SIV-infected RhM use for dCA preclinical evaluation.-Mediouni, S., Kessing, C. F., Jablonski, J. A., Thenin-Houssier, S., Clementz, M., Kovach, M. D., Mousseau, G., de Vera, I.M.S., Li, C., Kojetin, D. J., Evans, D. T., Valente, S. T. The Tat inhibitor didehydro-cortistatin A suppresses SIV replication and reactivation.
HIV-1 转录激活蛋白（Tat）结合 HIV mRNA 转录激活反应元件（TAR），调节转录和潜伏状态的重新激活。不幸的是，目前没有针对 Tat 的药物。我们曾报道二去氢皮质甾酮 A（dCA）可抑制 HIV-1 Tat 活性。在来自无病毒血症个体的人 CD4 T 细胞和潜伏状态的人源化小鼠模型中，dCA 与抗逆转录病毒疗法联合使用可加速 HIV-1 的抑制，并延迟治疗中断后的病毒反弹。此类药物可用于阻断-锁定功能性治愈方法，旨在实现持久的潜伏状态。恒河猴（RhMs）感染猴免疫缺陷病毒（SIV）是艾滋病研究中最具特征的模型。在这里，我们通过和细胞测定法证实，dCA 可直接与 SIV Tat 的碱性结构域结合。dCA 特异性抑制 SIV Tat 与 TAR 的结合，但不抑制 Tat-Rev 融合蛋白与 TAR 的结合，后者通过 Rev 与其同源 RNA 结合位点结合，取代 TAR 的顶端区域，从而激活转录。Tat-TAR 抑制导致 RNA 聚合酶 II 募集到 SIV 启动子的丧失。重要的是，dCA 可有效抑制潜伏感染的 Hut78 细胞和从 SIV239 感染的 RhMs 中分离出的原代 CD4 T 细胞中的 SIV 重新激活。总之，dCA 显著的广泛活性鼓励使用 SIV 感染的 RhM 进行 dCA 临床前评估。-Mediouni，S.，Kessing，C. F.，Jablonski，J. A.，Thenin-Houssier，S.，Clementz，M.，Kovach，M. D.，Mousseau，G.，de Vera，I. M. S.，Li，C.，Kojetin，D. J.，Evans，D. T.，Valente，S. T. 抑制因子 dCA 抑制 SIV 复制和重新激活。
