潜在的HIV-1激活子代表了对感染治愈的障碍，并且依赖于宿主RNA聚合酶（Pol）II机制进行重新出现。在这里，我们发现RNA Pol II介质激酶CDK8/19的抑制剂Senexin A和BRD6989抑制了激活剂和T细胞信号激动剂诱导的HIV-1表达。发现这些抑制剂阻碍了RNA Pol II对HIV-1 LTR的招募。此外，通过shRNA或基因敲除干扰CDK8后，多种激活潜伏病毒逆转剂引起的HIV-1表达受到了影响。然而，CDK8缺乏并未完全模拟CDK8/19激酶抑制，这表明介质激酶并非功能冗余。此外，对与HIV-1感染和接受抗逆转录病毒疗法的人类外周血单核细胞（CD4+）进行Senexin A处理，抑制了PMA和ionomycin引起的T细胞刺激对病毒复制的诱导。这些观察结果表明，介质激酶CDK8和CDK19在调控HIV-1转录中起着重要作用，并且这些酶的小分子抑制剂可能有助于推动持久性潜伏状态下病毒表达的疗法的发展。意义一种HIV-1感染的治愈将需要能够迫使含有病毒基因组拷贝插入细胞染色体但被关闭或沉默的细胞的新型疗法。这些称为潜伏感染细胞，它们是目前治疗HIV/艾滋病无法治愈感染的主要原因，因为这些细胞中的病毒不受目前药物的影响。我们的结果表明，Cdk8的化学抑制剂也抑制了潜伏的HIV亲病毒表达。Cdk8是一个重要的酶，它调节基因在细胞需要对信号作出反应时的表达，并由一个在癌症中经常发生突变的基因产生。我们的观察结果表明，Cdk8抑制剂可以用于新型治疗，以防止潜伏病毒的表达，最终可能使得感染者停止抗逆转录病毒药物治疗。

Latent HIV-1 provirus represents the barrier toward a cure for infection and is dependent upon the host RNA Polymerase (Pol) II machinery for reemergence. Here, we find that inhibitors of the RNA Pol II mediator kinases CDK8/19, Senexin A and BRD6989, inhibit induction of HIV-1 expression in response to latency-reversing agents and T cell signaling agonists. These inhibitors were found to impair recruitment of RNA Pol II to the HIV-1 LTR. Furthermore, HIV-1 expression in response to several latency reversal agents was impaired upon disruption of CDK8 by shRNA or gene knockout. However, the effects of CDK8 depletion did not entirely mimic CDK8/19 kinase inhibition suggesting that the mediator kinases are not functionally redundant. Additionally, treatment of CD4+ peripheral blood mononuclear cells isolated from people living with HIV-1 and who are receiving antiretroviral therapy with Senexin A inhibited induction of viral replication in response to T cell stimulation by PMA and ionomycin. These observations indicate that the mediator kinases, CDK8 and CDK19, play a significant role for regulation of HIV-1 transcription and that small molecule inhibitors of these enzymes may contribute to therapies designed to promote deep latency involving the durable suppression of provirus expression. IMPORTANCE A cure for HIV-1 infection will require novel therapies that can force elimination of cells that contain copies of the virus genome inserted into the cell chromosome, but which is shut off, or silenced. These are known as latently-infected cells, which represent the main reason why current treatment for HIV/AIDS cannot cure the infection because the virus in these cells is unaffected by current drugs. Our results indicate that chemical inhibitors of Cdk8 also inhibit the expression of latent HIV provirus. Cdk8 is an important enzyme that regulates the expression of genes in response to signals to which cells need to respond and which is produced by a gene that is frequently mutated in cancers. Our observations indicate that Cdk8 inhibitors may be employed in novel therapies to prevent expression from latent provirus, which might eventually enable infected individuals to cease treatment with antiretroviral drugs.