Cell type mediated resistance of vesicular stomatitis virus and Sendai virus to ribavirin.
Cell type mediated resistance of vesicular stomatitis virus and Sendai virus to ribavirin.
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DOI：
10.1371/journal.pone.0011265
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发表时间：
2010-06-22
期刊：
影响因子：
3.7
通讯作者：
Grdzelishvili VZ
中科院分区：
文献类型：
--
作者：
Shah NR;Sunderland A;Grdzelishvili VZ
利巴韦林 (RBV) 是一种合成核苷类似物，具有广谱抗病毒活性。尽管RBV被批准用于治疗丙型肝炎病毒、呼吸道合胞病毒和拉沙热病毒感染，但其作用机制和治疗效果仍存在很大争议。最近的报告表明，连续 RBV 治疗后由于 RBV 摄取减少而产生的基于细胞的耐药性会极大地限制其疗效。在这里，我们检查了某些细胞类型是否对 RBV 具有天然抵抗力，即使事先没有接触过药物。比较了来自不同宿主物种的七种不同细胞系的 RBV 对两种非节段负链 RNA 病毒、水泡性口炎病毒（VSV，弹状病毒）和仙台病毒（SeV，副粘病毒）的抗病毒活性。我们的结果显示，细胞类型对 RBV 的反应存在显着差异，从几乎没有抗病毒作用到非常有效地抑制病毒复制。尽管这七种细胞系中 VSV 和 SeV 的病毒复制动力学存在差异，但观察到的两种病毒的 RBV 耐药模式非常相似，这表明细胞而不是病毒决定因素在这种耐药性中发挥着主要作用。虽然所测试的细胞系均不存在 RBV 摄取缺陷，但在不同细胞类型中观察到 RBV 的长期积累存在巨大差异，并且这与 RBV 的抗病毒功效相关。虽然添加鸟苷仅在已经高度抵抗 RBV 的细胞中中和 RBV，但放线菌素 D 几乎完全逆转了所有细胞系中的 RBV 效应（但不是摄取）。总之，我们的数据表明，RBV 可能通过不同细胞类型中的不同机制抑制同一病毒，具体取决于细胞内 RBV 代谢。我们的结果强烈指出，在体外检查新药和已建立药物的抗病毒功效和效力时，使用不同来源的多种细胞系的重要性。
Ribavirin (RBV) is a synthetic nucleoside analog with broad spectrum antiviral activity. Although RBV is approved for the treatment of hepatitis C virus, respiratory syncytial virus, and Lassa fever virus infections, its mechanism of action and therapeutic efficacy remains highly controversial. Recent reports show that the development of cell-based resistance after continuous RBV treatment via decreased RBV uptake can greatly limit its efficacy. Here, we examined whether certain cell types are naturally resistant to RBV even without prior drug exposure. Seven different cell lines from various host species were compared for RBV antiviral activity against two nonsegmented negative-strand RNA viruses, vesicular stomatitis virus (VSV, a rhabdovirus) and Sendai virus (SeV, a paramyxovirus). Our results show striking differences between cell types in their response to RBV, ranging from virtually no antiviral effect to very effective inhibition of viral replication. Despite differences in viral replication kinetics for VSV and SeV in the seven cell lines, the observed pattern of RBV resistance was very similar for both viruses, suggesting that cellular rather than viral determinants play a major role in this resistance. While none of the tested cell lines was defective in RBV uptake, dramatic variations were observed in the long-term accumulation of RBV in different cell types, and it correlated with the antiviral efficacy of RBV. While addition of guanosine neutralized RBV only in cells already highly resistant to RBV, actinomycin D almost completely reversed the RBV effect (but not uptake) in all cell lines. Together, our data suggest that RBV may inhibit the same virus via different mechanisms in different cell types depending on the intracellular RBV metabolism. Our results strongly point out the importance of using multiple cell lines of different origin when antiviral efficacy and potency are examined for new as well as established drugs in vitro.
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DOI：
10.1124/jpet.108.145854
发表时间：
2009-04-01
影响因子：
3.5
作者：
Endres, Christopher J.;Moss, Aaron M.;Unadkat, Jashvant D.
通讯作者：
Unadkat, Jashvant D.
影响因子：
5.4
作者：
Leyssen, P;Balzarini, J;Neyts, J
通讯作者：
Neyts, J
影响因子：
5
作者：
Parker, WB
通讯作者：
Parker, WB
影响因子：
5.4
作者：
Das, Subash C.;Nayak, Debasis;Pattnaik, Asit K.
通讯作者：
Pattnaik, Asit K.
影响因子：
3.7
作者：
Airaksinen, A;Pariente, N;Domingo, E
通讯作者：
Domingo, E