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首页> 外文期刊>Viruses >Antiviral Effects of Clinically-Relevant Interferon-α and Ribavirin Regimens against Dengue Virus in the Hollow Fiber Infection Model (HFIM)
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Antiviral Effects of Clinically-Relevant Interferon-α and Ribavirin Regimens against Dengue Virus in the Hollow Fiber Infection Model (HFIM)

机译：在空心纤维感染模型（HFIM）中，临床相关干扰素-α和利巴韦林疗法对登革热病毒的抗病毒作用

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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 ( EC 50 ) = 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.
机译：登革热病毒（DENV）是人类中最普遍的蚊媒病毒性疾病。当前，没有可用于预防或治疗DENV感染的治疗剂。我们的目标是通过评估干扰素-α（IFN）和利巴韦林（RBV）联合抗DENV的抗病毒活性来满足这一尚未满足的医疗需求。将DENV感染的Vero和Huh-7细胞暴露于RBV和/或IFN，并通过噬菌斑测定对病毒载量进行定量分析。通过将数学模型拟合到数据来确定抗病毒作用的药物相互作用。然后，我们使用中空纤维感染模型（HFIM）系统评估了IFN和RBV的临床相关暴露。 RBV单一疗法仅在Vero和Huh-7细胞中的毒性浓度下对DENV有效。干扰素作为单一药物确实在生理浓度下抑制DENV复制，并且在Huh-7细胞中有明显的病毒抑制作用（半数最大有效浓度（EC 50）= 58.34 IU / mL）。作为一种联合疗法，RBV + IFN可以在两种细胞系中抑制病毒。然而，仅在Huh-7细胞中观察到了在临床上可达到的浓度下抗病毒活性的增强。最后，即使在HFIM中感染后24小时开始治疗，RBV和IFN的临床暴露也能使DENV复制抑制99％。进一步的评估表明，联合方案对DENV的抗病毒效力主要归因于与IFN相关的活性。这些发现表明，IFN是治疗DENV的潜在治疗策略。

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