miR-122-based therapies select for three distinct resistance mechanisms based on alterations in RNA structure.
miR-122-based therapies select for three distinct resistance mechanisms based on alterations in RNA structure.
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DOI：
10.1073/pnas.2103671118
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发表时间：
2021-08-17
影响因子：
11.1
通讯作者：
Sagan SM
中科院分区：
文献类型：
--
作者：
Chahal J;Gebert LFR;Camargo C;MacRae IJ;Sagan SM
基于microRNA（miRNA）的药物正在迅速席卷临床。在此，我们分析了第一个miRNA抑制剂的耐药相关变体（RAV），使其进入临床，即用于慢性丙型肝炎病毒（HCV）感染的miR-122抑制剂。我们发现了三种不同的耐药机制，这些机制基于病毒RNA结构的独特改变。具体而言，RAV改变了病毒RNA的结构，以促进核糖开关活性，基因组稳定性或正链病毒RNA合成。我们的发现支持了miR-122介导的HCV RNA积累的最新模型，并提供了抗病毒治疗耐药的机制。随着更多的miRNA靶向治疗进入临床，这些对基于miRNA的治疗的耐药机制的早期见解可能具有重要意义。丙型肝炎病毒（HCV）是一种正义RNA病毒，与肝脏特异性microRNA（称为miR-122）相互作用。miR-122与病毒基因组5′非翻译区的两个位点结合，促进HCV RNA积累。这种相互作用对于细胞培养物中的病毒RNA积累是重要的，并且miR-122抑制剂已被证明可有效降低慢性HCV感染患者中的病毒滴度。在本文中，我们分析了在细胞培养物中分离的或从接受基于miR-122的治疗的患者中分离的耐药相关变体，并发现了三种不同的耐药机制，所有这些机制都基于病毒RNA结构的变化。具体而言，抗性相关变体促进核糖开关活性、基因组稳定性或正链病毒RNA合成，所有这些都是在缺乏miR-122的情况下。总之，这些发现提供了对miR-122介导的病毒RNA积累机制的深入了解，并提供了由RNA结构变化介导的抗病毒耐药机制。
MicroRNA (miRNA)–based drugs are quickly taking the clinic by storm. Herein, we analyzed resistance-associated variants (RAVs) to the first miRNA inhibitors to make it to the clinic, namely miR-122 inhibitors for chronic hepatitis C virus (HCV) infection. We uncovered three distinct resistance mechanisms based on unique alterations to the structure of the viral RNA. Specifically, RAVs altered the structure of the viral RNA in a manner that promotes riboswitch activity, genome stability, or positive-strand viral RNA synthesis. Our findings support recent models of miR-122–mediated HCV RNA accumulation and provide mechanism(s) of resistance to antiviral therapy. These early insights into the mechanism(s) of resistance to miRNA-based therapies may be of importance as more miRNA-targeted therapies enter into the clinic. Hepatitis C virus (HCV) is a positive-sense RNA virus that interacts with a liver-specific microRNA called miR-122. miR-122 binds to two sites in the 5′ untranslated region of the viral genome and promotes HCV RNA accumulation. This interaction is important for viral RNA accumulation in cell culture, and miR-122 inhibitors have been shown to be effective at reducing viral titers in chronic HCV-infected patients. Herein, we analyzed resistance-associated variants that were isolated in cell culture or from patients who underwent miR-122 inhibitor–based therapy and discovered three distinct resistance mechanisms all based on changes to the structure of the viral RNA. Specifically, resistance-associated variants promoted riboswitch activity, genome stability, or positive-strand viral RNA synthesis, all in the absence of miR-122. Taken together, these findings provide insight into the mechanism(s) of miR-122–mediated viral RNA accumulation and provide mechanisms of antiviral resistance mediated by changes in RNA structure.
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DOI：
10.3390/v3091739
发表时间：
2011-09
期刊：
Viruses
影响因子：
--
作者：
Gebhard LG;Filomatori CV;Gamarnik AV
通讯作者：
Gamarnik AV
影响因子：
14.9
作者：
Amador-Cañizares Y;Panigrahi M;Huys A;Kunden RD;Adams HM;Schinold MJ;Wilson JA
通讯作者：
Wilson JA
影响因子：
56.9
作者：
Jopling, CL;Yi, MK;Sarnow, P
通讯作者：
Sarnow, P
影响因子：
4.5
作者：
Karabiber, Fethullah;McGinnis, Jennifer L.;Weeks, Kevin M.
通讯作者：
Weeks, Kevin M.
DOI：
10.1073/pnas.1012464108
发表时间：
2011-02-22
影响因子：
11.1
作者：
Machlin, Erica S.;Sarnow, Peter;Sagan, Selena M.
通讯作者：
Sagan, Selena M.