Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA.
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Viruses. 2020 Sep 23;12(10):1067. doi: 10.3390/v12101067.
Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA-approved modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription, while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators.
人类免疫缺陷病毒 1（HIV-1）是最常见的人类逆转录病毒。最近的数据显示，全球有 3400 万人感染了 HIV-1。HIV-1 感染可导致艾滋病，仅在美国每年就导致近 2 万人死亡。由于这种逆转录病毒导致高发病率和死亡率，因此必须开发更有效的治疗方案来治疗这些病毒感染。目前还没有获得 FDA 批准的调节剂来干预的一个关键靶点是前病毒转录。一种用于鉴定治疗传染病的新型治疗方法的成功方法是重新利用 FDA 批准用于其他适应症的药物。使用 FDA 批准药物的主要好处包括化合物具有良好的毒性特征、已批准的制造工艺以及对患者的即时商业可用性。在这里，我们证明了先前批准用于其他适应症的药物可用于激活或抑制 HIV-1 前病毒转录。具体来说，我们发现非布司他、依曲泊帕和白藜芦醇可激活 HIV-1 转录，而霉酚酸酯是我们抑制 HIV-1 转录的主要抑制剂。此外，我们观察到淋巴样和髓样谱系的感染细胞对我们的主要转录调节剂有不同的反应。最后，我们证明了使用多剂量方案可以增强我们的转录激活剂的激活作用。
