Yu Kaixin, Liu Hanxin, Pan Ting
Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China.
Int J Mol Sci. 2025 Jun 30;26(13):6311. doi: 10.3390/ijms26136311.
HIV-1 Tat acts as a central molecular switch governing the transition between viral latency and active replication, making it a pivotal target for HIV-1 functional cure strategies. By binding to the viral long terminal repeat (LTR) and hijacking host transcriptional machinery, Tat dynamically regulates RNA polymerase II processivity to alter viral transcription states. Recent studies reveal its context-dependent variability: while Tat recruits chromatin modifiers and scaffolds non-coding RNAs to stabilize epigenetic silencing in latently infected cells, it also triggers rapid transcriptional amplification upon cellular activation. This review systematically analyzes the bistable regulatory mechanism of Tat and investigates advanced technologies for reprogramming this switch to eliminateviral reservoirs and achieve functional cures. Conventional approaches targeting Tat are limited by compensatory viral evolution and poor bioavailability. Next-generation interventions will employ precision-engineered tools, such as AI-optimized small molecules blocking Tat-P-TEFb interfaces and CRISPR-dCas9/Tat chimeric systems, for locus-specific LTR silencing or reactivation ("block and lock" or "shock and kill"). Advanced delivery platforms, including brain-penetrant lipid nanoparticles (LNPs), enable the targeted delivery of Tat-editing mRNA or base editors to microglial reservoirs. Single-cell multiomics elucidates Tat-mediated clonal heterogeneity, identifying "switchable" subpopulations for timed interventions. By integrating systems-level Tat interactomics, epigenetic engineering, and spatiotemporally controlled delivery, this review proposes a roadmap to disrupt HIV-1 persistence by hijacking the Tat switch, ultimately bridging mechanistic insights to clinical applications.
HIV-1反式激活因子（Tat）作为一个核心分子开关，控制着病毒潜伏与活跃复制之间的转换，使其成为HIV-1功能性治愈策略的关键靶点。通过与病毒长末端重复序列（LTR）结合并劫持宿主转录机制，Tat动态调节RNA聚合酶II的持续合成能力，以改变病毒转录状态。最近的研究揭示了其依赖于背景的变异性：虽然Tat招募染色质修饰因子并搭建非编码RNA支架，以稳定潜伏感染细胞中的表观遗传沉默，但它也会在细胞激活时触发快速的转录扩增。本综述系统分析了Tat的双稳态调节机制，并研究了重新编程此开关以消除病毒储存库并实现功能性治愈的先进技术。针对Tat的传统方法受到代偿性病毒进化和低生物利用度的限制。下一代干预措施将采用精准设计的工具，如人工智能优化的小分子阻断Tat-P-TEFb界面和CRISPR-dCas9/Tat嵌合系统，用于位点特异性LTR沉默或重新激活（“阻断并锁定”或“激活并清除”）。先进的递送平台，包括可穿透大脑的脂质纳米颗粒（LNP），能够将编辑Tat的mRNA或碱基编辑器靶向递送至小胶质细胞储存库。单细胞多组学阐明了Tat介导的克隆异质性，识别出可进行定时干预的“可切换”亚群。通过整合系统水平的Tat相互作用组学、表观遗传工程和时空控制递送，本综述提出了一条通过劫持Tat开关来破坏HIV-1持续存在的路线图，最终将机制性见解与临床应用联系起来。
