Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain.
J Virol. 2011 Jul;85(14):7246-55. doi: 10.1128/JVI.00614-11. Epub 2011 May 11.
Arenaviruses include several important human pathogens, and there are very limited options of preventive or therapeutic interventions to combat these viruses. An off-label use of the purine nucleoside analogue ribavirin (1-β-d-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) is the only antiviral treatment currently available for arenavirus infections. However, the ribavirin antiviral mechanism action against arenaviruses remains unknown. Here we document that ribavirin is mutagenic for the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) in cell culture. The mutagenic activity of ribavirin on LCMV was observed under single- and multiple-passage regimes and could not be accounted for by a decrease of the intracellular GTP pool promoted by ribavirin-mediated inhibition of inosine monophosphate dehydrogenase (IMPDH). Our findings suggest that the antiviral activity of ribavirin on arenaviruses might be exerted, at least partially, by lethal mutagenesis. Implications for antiarenavirus therapy are discussed.
沙粒病毒包括几种重要的人类病原体，目前对抗这些病毒的预防或治疗干预措施非常有限。嘌呤核苷类似物利巴韦林（1-β-d-核糖呋喃基-1-H-1,2,4-三唑-3-羧酰胺）的标签外使用是目前对抗沙粒病毒感染的唯一抗病毒治疗方法。然而，利巴韦林对沙粒病毒的抗病毒机制作用尚不清楚。在这里，我们记录到利巴韦林在细胞培养中对原型沙粒病毒淋巴细胞性脉络丛脑膜炎病毒（LCMV）具有诱变作用。在单次和多次传代的情况下都观察到利巴韦林对 LCMV 的诱变活性，并且不能通过利巴韦林介导的肌苷单磷酸脱氢酶（IMPDH）抑制所促进的细胞内 GTP 池减少来解释。我们的研究结果表明，利巴韦林对沙粒病毒的抗病毒活性至少部分是通过致死性诱变发挥的。讨论了对抗沙粒病毒治疗的影响。
