Thompson Landon, Jamal Imran, Das Juthika, Dang Casey, Hong Zhenzi, Katz Doran, Bosque Alberto, Singh Vir B
Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA.
School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA.
Viruses. 2025 Sep 20;17(9):1278. doi: 10.3390/v17091278.
The elimination of HIV latent reservoirs is an extremely challenging task due to the interplay of multiple mechanisms regulating latency. Thus, we need to identify novel strategies to target heterogeneous reservoirs uniformly. Recent reports have provided intriguing evidence for the novel antiviral function of RNA Polymerase III (RNAP III), which remains to be further explored. In this study, we evaluated the role of RNA Pol III in regulating HIV latency and replication. We first demonstrated that the pharmacological inhibition of RNAP III can lead to a strong reactivation of latency in cell lines representing both T and monocytic cellular reservoirs. Next, we investigated the involvement of RNA Pol III in regulating HIV-1 replication using HIV-1 pseudotyped (DuoFluo) virus and HIV-1-Bal in THP-1 and Sup-T1 cells. We show that the pharmacological inhibition of RNAP III significantly induced HIV transcription. These findings were further confirmed in physiologically relevant primary CD4 T cells, and a consistent increase in HIV transcription was observed up to 72 h. Collectively, our study suggests that inhibition of RNAP III can increase the rate of HIV transcription, while the total HIV DNA remains unchanged. Overall, our study identifies a previously unknown role of RNA Pol III in restricting HIV transcription and advocates that targeting RNAP III-driven mechanisms could be a novel strategy to reactivate HIV latent reservoirs.
由于多种调节潜伏期的机制相互作用，消除HIV潜伏库是一项极具挑战性的任务。因此，我们需要确定新的策略来统一靶向异质性潜伏库。最近的报告为RNA聚合酶III（RNAP III）的新型抗病毒功能提供了有趣的证据，这仍有待进一步探索。在本研究中，我们评估了RNA Pol III在调节HIV潜伏期和复制中的作用。我们首先证明，RNAP III的药理学抑制可导致代表T细胞和单核细胞潜伏库的细胞系中潜伏期的强烈重新激活。接下来，我们使用HIV-1假型（DuoFluo）病毒和HIV-1-Bal在THP-1和Sup-T1细胞中研究了RNA Pol III在调节HIV-1复制中的作用。我们表明，RNAP III的药理学抑制显著诱导HIV转录。这些发现在生理相关的原代CD4 T细胞中得到进一步证实，并且在长达72小时内观察到HIV转录持续增加。总体而言，我们的研究表明，抑制RNAP III可以提高HIV转录速率，而HIV总DNA保持不变。总之，我们的研究确定了RNA Pol III在限制HIV转录方面以前未知的作用，并主张靶向RNAP III驱动的机制可能是重新激活HIV潜伏库的新策略。
