An Ounce of Tat Prevention Is Worth a Pound of Functional Cure.
An Ounce of Tat Prevention Is Worth a Pound of Functional Cure.
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一盎司的预防胜过一磅的功能性治疗。
DOI：
10.1128/mbio.01269-15
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发表时间：
2015
期刊：
影响因子：
6.4
通讯作者：
Planelles,Vicente
中科院分区：
文献类型：
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作者：
Planelles,Vicente
通过抗逆转录病毒治疗（ART）可以有效地抑制HIV-1感染。然而，一个小的潜伏病毒库的持续存在阻碍了病毒的根除。因此，大多数感染者必须终生接受抗逆转录病毒治疗。虽然人们正在努力寻找一种能够根除病毒的消毒治疗方法，但一种被认为是功能性治疗的替代方法仍然很少被探索。设想对艾滋病毒的功能性治愈是在没有抗逆转录病毒治疗的情况下长期控制病毒复制（见参考文献1和2）。这种功能性治愈可能包括有效的免疫干预，将储库减少到高度“可控”的大小，和/或诱导对病毒基因表达的长期抑制。Tat病毒蛋白是病毒基因表达的强反激活因子，缺乏它病毒复制受到严重限制；因此，它是一个合乎逻辑的抗病毒靶标。Mousseau等人最近发表的一篇文章报道了一种新的Tat抑制剂，作者认为这种抑制剂具有诱导“永久潜伏期”的不同寻常的能力。双脱氢皮质抑素A （dCA）不同于目前fda批准的抗逆转录病毒药物，因为它可以抑制整合病毒的病毒基因表达。基于上述原因，dCA代表了一种新型抑制剂。皮质抑素A （CA）是一种甾体生物碱，来自于一种海洋海绵，由于其抗增殖作用而引起了人们的兴趣(4)。dCA是CA的衍生物，据报道与母体化合物具有同等效力(5)，并且相对容易通过化学合成获得。CA的一个显著特征是它能够以纳米摩尔亲和力结合并抑制细胞周期蛋白依赖性激酶11 (CDK11)(6)。最近Valente和同事发现CDK11对HIV-1基因的表达至关重要，因为磷酸化因子是病毒mrna正常加工所需的(7)。基于这些发现，Mousseau和Valente实验室的同事们预测dCA通过阻断CDK11的活性，反过来会阻碍HIV-1的转录(8)。dCA被证明是HIV复制的有效抑制剂(8)。有趣的是，Mousseau等人在测试dCA时无法重现ca介导的CDK11抑制，而是证明了dCA抗病毒作用的不同机制。Mousseau及其同事认为，dCA结合Tat的基本结构域，该结构域介导核核定位并结合转激活反应元件（TAR）(8)。因此，dCA阻止Tat向TAR茎环结构募集，可能阻碍了P-TEFb（正转录延伸因子-b）的募集和转录延伸（见图1）。
Infection by HIV-1 can effectively be suppressed by antiretroviral therapy (ART). However, the persistence of a small, latent virus reservoir impedes viral eradication. Thus, most infected individuals must be treated with ART for life. While efforts to find a sterilizing cure that eradicates the virus are ongoing, an alternative approach deemed a functional cure has remained less explored. A functional cure for HIV is envisioned as long-term control of virus replication in the absence of ART (reviewed in references 1 and 2). Such a functional cure might encompass effective immune interventions, reduction of the reservoir to a highly “controllable” size, and/or induction of a long-lasting suppression of viral gene expression. The Tat viral protein is a strong transactivator of viral gene expression, and viral replication is severely restricted in its absence; thus, it makes a logical antiviral target. A recent article by Mousseau et al.(3) reports on a novel Tat inhibitor that the authors show has the unusual ability to induce a “permanent state of latency.” Didehydro-cortistatin A (dCA) is a departure from current FDA-approved antiretroviral drugs in that it inhibits viral gene expression from integrated viruses. For the above reasons, dCA represents a novel inhibitor class. Cortistatin A (CA) is a steroidal alkaloid from Corticium simplex, a marine sponge, which has raised interest based on its antiproliferative effects (4). dCA is a derivative of CA that was reported to be equipotent (5) to the parent compound as well as relatively easy to obtain by chemical synthesis. One of the salient features of CA is its ability to bind to and inhibit cyclin-dependent kinase 11 (CDK11) with nanomolar affinity (6). CDK11 was recently shown by Valente and colleagues to be essential for HIV-1 gene expression by phosphorylating factors required for proper 3= processing of viral mRNAs (7). Based on these findings, Mousseau and colleagues in the Valente laboratory predicted that dCA, by blocking the activity of CDK11, would in turn hinder HIV-1 transcription (8). dCA proved to be a potent inhibitor of HIV replication (8).Intriguingly, Mousseau et al. were unable to reproduce CA-mediated CDK11 inhibition when testing dCA and instead demonstrated a different mechanism for dCA’s antiviral effects. Mousseau and colleagues suggest that dCA binds to Tat’s basic domain, the same domain that mediates localization to the nucleolus and binding to the transactivation response element (TAR)(8). dCA thus prevents recruitment of Tat to the TAR stem-loop structure, presumably hindering the recruitment of P-TEFb (positive transcription elongation factor-b) and transcription elongation (see Fig. 1).