Schlösser Verena, Lightfoot Helen Louise, Leemann Christine, Bejoy Aathma Merin, Tiwari Shashank, Schloßhauer Jeffrey L, Vongrad Valentina, Brunschweiger Andreas, Hall Jonathan, Metzner Karin J, Imig Jochen
Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.
Noncoding RNA. 2025 Jan 20;11(1):8. doi: 10.3390/ncrna11010008.
Despite tremendous advances in antiretroviral therapy (ART) against HIV-1 infections, no cure or vaccination is available. Therefore, discovering novel therapeutic strategies remains an urgent need. In that sense, miRNAs and miRNA therapeutics have moved intensively into the focus of recent HIV-1-related investigations. A strong reciprocal interdependence has been demonstrated between HIV-1 infection and changes of the intrinsic cellular miRNA milieu. This interrelationship may direct potential alterations of the host cells' environment beneficial for the virus or its suppression of replication. Whether this tightly balanced and controlled battle can be exploited therapeutically remains to be further addressed. In this context, the fluoroquinolone antibiotic Enoxacin has been demonstrated as a potent modulator of miRNA processing. Here, we test the hypothesis that this applies also to selected HIV-1-related miRNAs.
We studied the effect of Enoxacin on HIV-1 replication coupled with miRNA qRT-PCR analysis of HIV-1-related miRNAs in CEM-SS and MT-4 T-cells. The effects of miRNA mimic transfections combined with Enoxacin treatment on HIV-1 replication were assessed. Finally, we employed an in vitro DICER1 cleavage assay to study the effects of Enoxacin on a pro-HIV-1 miRNA hsa-miR-132 processing.
We established that Enoxacin, but not the structurally similar compound nalidixic acid, exhibits strong anti-HIV-1 effects in the T-cell line CEM-SS, but not MT-4. We provide experimental data that this effect of Enoxacin is partly attributed to the specific downregulation of mature hsa-miR-132-3p, but not other tested pro- or anti-HIV-1 miRNAs, which is likely due to affecting DICER1 processing.
Our findings show an anti-retroviral activity of Enoxacin at least in part by downregulation of hsa-miR-132-3p, which may be relevant for future antiviral therapeutic applications by modulation of the RNA interference pathway.
尽管抗逆转录病毒疗法（ART）在治疗HIV-1感染方面取得了巨大进展，但仍没有治愈方法或疫苗可用。因此，发现新的治疗策略仍然是当务之急。从这个意义上说，微小RNA（miRNA）和miRNA疗法已成为近期HIV-1相关研究的焦点。HIV-1感染与内在细胞miRNA环境的变化之间已证明存在强烈的相互依存关系。这种相互关系可能会导致宿主细胞环境发生潜在改变，有利于病毒或抑制其复制。这种紧密平衡和受控的斗争是否可以用于治疗仍有待进一步探讨。在此背景下，氟喹诺酮类抗生素依诺沙星已被证明是miRNA加工的有效调节剂。在此，我们测试了这一假设，即这也适用于选定的与HIV-1相关的miRNA。
我们研究了依诺沙星对HIV-1复制的影响，并结合CEM-SS和MT-4 T细胞中与HIV-1相关的miRNA的miRNA qRT-PCR分析。评估了miRNA模拟物转染与依诺沙星治疗相结合对HIV-1复制的影响。最后，我们采用体外DICER1切割试验来研究依诺沙星对促HIV-1的miRNA hsa-miR-132加工的影响。
我们确定依诺沙星而非结构相似的化合物萘啶酸在T细胞系CEM-SS中表现出强烈的抗HIV-1作用，但在MT-4中则不然。我们提供的实验数据表明，依诺沙星的这种作用部分归因于成熟的hsa-miR-132-3p的特异性下调，而不是其他测试的促HIV-1或抗HIV-1的miRNA，这可能是由于影响了DICER1加工。
我们的研究结果表明依诺沙星至少部分通过下调hsa-miR-132-3p具有抗逆转录病毒活性，这可能与未来通过调节RNA干扰途径进行抗病毒治疗应用相关。
