Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with miR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems.
Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with miR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems.
复制标题
DOI：
10.1038/srep30939
复制
发表时间：
2016-08-03
影响因子：
4.6
通讯作者：
Kaneko S
中科院分区：
文献类型：
--
作者：
Liu F;Shimakami T;Murai K;Shirasaki T;Funaki M;Honda M;Murakami S;Yi M;Tang H;Kaneko S
抗丙型肝炎病毒（HCV）的直接作用抗病毒药物（DAA）显示出有效的抗病毒活性，副作用少。然而，DAA抗性突变体的选择是一个日益增长的问题，需要解决。相比之下，miR-122拮抗作用在所有HCV基因型中显示出广泛的抗病毒作用，并且对耐药性具有高屏障。在本研究中，我们评估了三种DAA（西米普韦、达卡他韦和索非布韦）与抗miR-122治疗的联合作用，以对抗细胞培养物中的HCV基因型1a。我们发现，抗miR-122和DAA联合治疗具有累加或协同抗病毒作用。Simeprevir与anti-miR-122联合使用可显著降低Simeprevir耐药突变体中Simeprevir的EC 50值。通过将达卡他韦与抗miR-122组合，在达卡他韦耐药突变体中实现了类似的EC 50降低。在HCV复制细胞中用DAA和抗miR-122的组合治疗急剧降低HCV RNA量。相反，用simeprevir或daclatasvir单次治疗DAA最初降低了HCV RNA水平，但随后水平反弹。DAA抗性突变体在组合处理中比在DAA单一处理中观察到的频率低。总之，在DAA单一治疗中加入miR-122拮抗作用具有累加或协同抗病毒作用，有助于有效抑制HCV复制和DAA耐药突变体的出现。
Direct-acting antivirals (DAAs) against Hepatitis C virus (HCV) show effective antiviral activity with few side effects. However, the selection of DAA-resistance mutants is a growing problem that needs to be resolved. In contrast, miR-122 antagonism shows extensive antiviral effects among all HCV genotypes and a high barrier to drug resistance. In the present study, we evaluated three DAAs (simeprevir, daclatasvir, and sofosbuvir) in combination with anti-miR-122 treatment against HCV genotype 1a in cell cultures. We found that combination treatments with anti-miR-122 and a DAA had additive or synergistic antiviral effects. The EC50 values of simeprevir in simeprevir-resistant mutants were significantly decreased by combining simeprevir with anti-miR-122. A similar reduction in EC50 in daclatasvir-resistant mutants was achieved by combining daclatasvir with anti-miR-122. Combination treatment in HCV-replicating cells with DAA and anti-miR-122 sharply reduced HCV RNA amounts. Conversely, DAA single treatment with simeprevir or daclatasvir reduced HCV RNA levels initially, but the levels later rebounded. DAA-resistant mutants were less frequently observed in combination treatments than in DAA single treatments. In summary, the addition of miR-122 antagonism to DAA single treatments had additive or synergistic antiviral effects and helped to efficiently suppress HCV replication and the emergence of DAA-resistant mutants.