Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice.
Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice.
复制标题
靶向宿主细胞进入因子可阻止人肝小鼠治疗中突破性的抗病毒耐药丙型肝炎病毒变异体。
DOI：
10.1136/gutjnl-2014-309045
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发表时间：
2016
期刊：
影响因子：
24.5
通讯作者：
Vercauteren K
中科院分区：
文献类型：
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作者：
Vercauteren K
目的直接作用抗病毒药物 (DAA) 通过靶向在复制过程中发挥重要作用的病毒蛋白来抑制丙型肝炎病毒 (HCV) 感染。然而，DAA 治疗期间耐药相关变异 (RAV) 的选择一直是治疗失败的一个原因。在本研究中，我们希望解决此类RAV是否可以通过联合施用宿主靶向进入抑制剂来控制，以防止肝内病毒传播。设计我们研究了在慢性感染基因型1b HCV的人肝小鼠中，在DAA单一疗法（蛋白酶抑制剂西卢普韦）中添加进入抑制剂（抗清道夫受体B型I mAb1671）的效果。使用临床相关的非实验室毒株来实现由相关病毒变体（准种）组成的病毒血症，并使用新一代测序以高分辨率监测 RAV 的出现。结果接受 DAA 单一疗法的 HCV 感染人肝小鼠迅速经历了治疗中病毒突破。 HCV 蛋白酶结构域的深度测序证实了病毒反弹时耐药突变体的表现。相比之下，尽管在一些动物中检测到了 RAV 的出现，但接受 DAA 和进入抑制剂联合治疗的小鼠均未经历治疗中病毒突破。 结论 这项研究提供了临床前体内证据，表明在抗 HCV DAA 方案中添加进入抑制剂可限制 DAA 抗性病毒的突破。我们的方法是预防 DAA-RAV 治疗反弹引起的治疗失败的绝佳策略。在最新的 DAA 联合疗法中加入进入抑制剂可能会进一步提高缓解率，特别是在难以治疗的患者群体中。
ObjectiveDirect-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread.DesignWe investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing.ResultsHCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals.ConclusionsThis study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.