Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, NC, USA.
Cell Rep. 2017 Oct 17;21(3):600-611. doi: 10.1016/j.celrep.2017.09.080.
HIV-1 Tat activates viral transcription and limited Tat transactivation correlates with latency establishment. We postulated a "block-and-lock" functional cure approach based on properties of the Tat inhibitor didehydro-Cortistatin A (dCA). HIV-1 transcriptional inhibitors could block ongoing viremia during antiretroviral therapy (ART), locking the HIV promoter in persistent latency. We investigated this hypothesis in human CD4 T cells isolated from aviremic individuals. Combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound after treatment interruption, even during strong cellular activation. We show that dCA mediates epigenetic silencing by increasing nucleosomal occupancy at Nucleosome-1, restricting RNAPII recruitment to the HIV-1 promoter. The efficacy of dCA was studied in the bone marrow-liver-thymus (BLT) mouse model of HIV latency and persistence. Adding dCA to ART-suppressed mice systemically reduces viral mRNA in tissues. Moreover, dCA significantly delays and reduces viral rebound levels upon treatment interruption. Altogether, this work demonstrates the potential of block-and-lock cure strategies.
HIV-1 Tat 激活病毒转录，有限的 Tat 反式激活与潜伏期建立相关。我们基于 Tat 抑制剂去氢考地他辛 (dCA) 的特性，提出了一种“阻断-锁定”功能性治愈方法。HIV-1 转录抑制剂可以在抗逆转录病毒治疗 (ART) 期间阻断持续的病毒血症，将 HIV 启动子锁定在持续的潜伏状态。我们在从无病毒血症个体中分离的人 CD4 T 细胞中研究了这一假设。dCA 与 ART 联合使用可加速 HIV-1 的抑制，并防止治疗中断后的病毒反弹，即使在强烈的细胞激活期间也是如此。我们表明，dCA 通过增加核小体-1 的核小体占有率来介导表观遗传沉默，限制 RNAPII 募集到 HIV-1 启动子。我们在骨髓-肝-胸腺 (BLT) 小鼠 HIV 潜伏和持续模型中研究了 dCA 的疗效。在 ART 抑制的小鼠中添加 dCA 可系统性地降低组织中的病毒 mRNA。此外，dCA 显著延迟和减少治疗中断后的病毒反弹水平。总之，这项工作证明了阻断-锁定治愈策略的潜力。
