Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, Madrid, Spain.
Antimicrob Agents Chemother. 2023 Jul 18;67(7):e0039423. doi: 10.1128/aac.00394-23. Epub 2023 Jun 27.
The concept of a mild mutagen was coined to describe a minor mutagenic activity exhibited by some nucleoside analogues that potentiated their efficacy as antiretroviral agents. In the present study, we report the mild mutagen activity of sofosbuvir (SOF) for hepatitis C virus (HCV). Serial passages of HCV in human hepatoma cells, in the presence of SOF at a concentration well below its cytotoxic concentration 50 (CC) led to pre-extinction populations whose mutant spectra exhibited a significant increase of C→U transitions, relative to populations passaged in the absence of SOF. This was reflected in an increase in several diversity indices that were used to characterize viral quasispecies. The mild mutagenic activity of SOF was largely absent when it was tested with isogenic HCV populations that displayed high replicative fitness. Thus, SOF can act as a mild mutagen for HCV, depending on HCV fitness. Possible mechanisms by which the SOF mutagenic activity may contribute to its antiviral efficacy are discussed.
温和诱变剂的概念是为了描述某些核苷类似物所表现出的轻微诱变活性，这些活性增强了它们作为抗逆转录病毒药物的疗效。在本研究中，我们报告了索非布韦（SOF）对丙型肝炎病毒（HCV）的温和诱变活性。在低于细胞毒性浓度 50（CC）的浓度下，在人肝癌细胞中对 HCV 进行连续传代，导致在不存在 SOF 的情况下传代的种群的前灭绝种群，其突变谱相对于不存在 SOF 的种群显示出 C→U 转换的显著增加。这反映在用于表征病毒准种的多个多样性指数的增加。当用显示高复制适应性的同基因 HCV 群体进行测试时，SOF 的温和诱变活性基本上不存在。因此，SOF 可以根据 HCV 的适应性成为 HCV 的温和诱变剂。讨论了 SOF 诱变活性可能有助于其抗病毒疗效的可能机制。
