Ilyushina Natalia A, Donnelly Raymond P
Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
Antiviral Res. 2014 Nov;111:112-20. doi: 10.1016/j.antiviral.2014.09.008. Epub 2014 Sep 20.
Influenza viruses, which can cross species barriers and adapt to new hosts, pose a constant potential threat to human health. The influenza pandemic of 2009 highlighted the rapidity with which an influenza virus can spread worldwide. Currently available antivirals have a number of limitations against influenza, and novel antiviral strategies, including novel drugs and drug combinations, are urgently needed. Here, we evaluated the in vitro effects of interferon (IFN)-β, IFN-λ1, oseltamivir carboxylate (a neuraminidase (NA) inhibitor), and combinations of these agents against two seasonal (i.e., H1N1 and H3N2) influenza A viruses. We observed that A/California/04/09 (H1N1) and A/Panama/2007/99 (H3N2) isolates were equally sensitive to the antiviral activity of IFN-β and oseltamivir carboxylate in A549 and Calu-3 cells. In contrast, IFN-λ1 exhibited substantially lower protective potential against the H1N1 strain (64-1030-fold ↓, P<0.05), and was ineffective against H3N2 virus in both cell lines. Three dimensional analysis of drug-drug interactions revealed that IFN-λ1 interacted with IFN-β and oseltamivir carboxylate in an additive or synergistic manner, respectively, to inhibit influenza A virus replication in human airway epithelial cells. Overall, the present study demonstrated that anti-influenza agents with different mechanisms of action (e.g., a NA inhibitor combined with IFN-λ1) exerted a significantly greater (P<0.05) synergistic effect compared to co-treatment with drugs that target the same signaling pathway (i.e., IFN-β plus IFN-λ1) in vitro. Our findings provide support for the combined use of interferon plus oseltamivir as a potential means for treating influenza infections.
流感病毒能够跨越物种屏障并适应新宿主，对人类健康构成持续的潜在威胁。2009年的流感大流行凸显了流感病毒在全球范围内传播的速度之快。目前可用的抗病毒药物对流感存在诸多局限性，因此迫切需要新的抗病毒策略，包括新型药物和药物组合。在此，我们评估了干扰素（IFN）-β、IFN-λ1、奥司他韦羧酸盐（一种神经氨酸酶（NA）抑制剂）以及这些药物组合对两种季节性甲型流感病毒（即H1N1和H3N2）的体外作用。我们观察到，A/California/04/09（H1N1）和A/Panama/2007/99（H3N2）毒株在A549和Calu-3细胞中对IFN-β和奥司他韦羧酸盐的抗病毒活性同样敏感。相比之下，IFN-λ1对H1N1毒株的保护潜力显著较低（降低64 - 1030倍，P<0.05），并且在两种细胞系中对H3N2病毒均无作用。药物 - 药物相互作用的三维分析表明，IFN-λ1分别与IFN-β和奥司他韦羧酸盐以相加或协同的方式相互作用，以抑制甲型流感病毒在人气道上皮细胞中的复制。总体而言，本研究表明，与在体外联合使用靶向相同信号通路的药物（即IFN-β加IFN-λ1）相比，具有不同作用机制的抗流感药物（例如NA抑制剂与IFN-λ1联合）发挥了显著更强（P<0.05）的协同作用。我们的研究结果为联合使用干扰素和奥司他韦作为治疗流感感染的潜在手段提供了支持。
