Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL 32827, USA.
Center for Personalized Nanomedicine, Institute of Neuroimmune Pharmacology, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA.
Viruses. 2018 Jun 9;10(6):317. doi: 10.3390/v10060317.
Dengue virus (DENV) is the most prevalent mosquito-borne viral illness in humans. Currently, there are no therapeutic agents available to prevent or treat DENV infections. Our objective was to fill this unmet medical need by evaluating the antiviral activity of interferon-α (IFN) and ribavirin (RBV) as a combination therapy against DENV. DENV-infected Vero and Huh-7 cells were exposed to RBV and/or IFN, and the viral burden was quantified over time by plaque assay. Drug-drug interactions for antiviral effect were determined by fitting a mathematical model to the data. We then assessed clinically-relevant exposures of IFN plus RBV using the hollow fiber infection model (HFIM) system. RBV monotherapy was only effective against DENV at toxic concentrations in Vero and Huh-7 cells. IFN, as a single agent, did inhibit DENV replication at physiological concentrations and viral suppression was substantial in Huh-7 cells (Half maximal effective concentration () = 58.34 IU/mL). As a combination therapy, RBV plus IFN was additive for viral suppression in both cell lines; however, enhancement of antiviral activity at clinically-achievable concentrations was observed only in Huh-7 cells. Finally, clinical exposures of RBV plus IFN suppressed DENV replication by 99% even when treatment was initiated 24 h post-infection in the HFIM. Further evaluation revealed that the antiviral effectiveness of the combination regimen against DENV is mostly attributed to activity associated with IFN. These findings suggest that IFN is a potential therapeutic strategy for the treatment of DENV.
登革热病毒（DENV）是人类中最普遍的蚊媒病毒病。目前，尚无可用于预防或治疗 DENV 感染的治疗药物。我们的目标是通过评估干扰素-α（IFN）和利巴韦林（RBV）联合治疗作为 DENV 的抗病毒疗法来填补这一未满足的医疗需求。用 RBV 和/或 IFN 处理感染 DENV 的 Vero 和 Huh-7 细胞，并通过噬斑测定法随时间定量病毒载量。通过拟合数学模型来确定抗病毒作用的药物-药物相互作用。然后，我们使用中空纤维感染模型（HFIM）系统评估 IFN 加 RBV 的临床相关暴露。RBV 单药治疗仅在 Vero 和 Huh-7 细胞中在毒性浓度下对 DENV 有效。IFN 作为单一药物，在生理浓度下确实抑制 DENV 复制，并且在 Huh-7 细胞中病毒抑制作用很大（半数有效浓度 () = 58.34 IU/mL）。作为联合治疗，RBV 加 IFN 在两种细胞系中均具有相加的病毒抑制作用；然而，仅在 Huh-7 细胞中观察到在临床可达到的浓度下增强抗病毒活性。最后，即使在 HFIM 中在感染后 24 小时开始治疗，RBV 加 IFN 的临床暴露也能使 DENV 复制抑制 99%。进一步的研究结果表明，该联合方案对 DENV 的抗病毒作用主要归因于 IFN 相关的活性。这些发现表明 IFN 是治疗 DENV 的一种有潜力的治疗策略。
