Nucleic Acid Polymers Are Active against Hepatitis Delta Virus Infection In Vitro
Nucleic Acid Polymers Are Active against Hepatitis Delta Virus Infection In Vitro
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DOI：
10.1128/jvi.01416-17
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发表时间：
2018-02-01
影响因子：
5.4
通讯作者：
Sureau, Camille
中科院分区：
文献类型：
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作者：
Beilstein, Frauke;Blanchet, Matthieu;Sureau, Camille
在这项研究中，在丁型肝炎病毒（HDV）的体外感染模型，用于评估硫代磷酸酯核酸聚合物（NAP）的抗病毒作用，并探讨其作用机制。结果表明，在分化的人肝癌细胞培养物中，NAP在低于4 μ M的浓度下抑制HDV感染。NAP在病毒进入时显示出活性，但在HDV RNA复制后无活性。抑制是独立的NAP核苷酸序列，但依赖于大小和两亲性的聚合物。NAP抗病毒活性对携带主要B肝炎病毒（HBV）免疫逃逸取代（D144 A和G145 R）的HDV病毒粒子有效，并且就HBV包膜蛋白而言是泛基因组的。此外，类似于固定化肝素，固定化NAP可以结合HDV颗粒，这表明进入抑制是由于，至少部分地，防止病毒附着到细胞表面糖胺聚糖。结果证明NAP是一类新型的抗病毒化合物，可以防止HDV传播。重要提示HDV感染是人类最严重的病毒性肝炎，也是最难治愈的病毒性肝炎之一。目前，治疗仅限于长期给予高剂量的干扰素，其仅提供部分疗效。因此，迫切需要创新的方法来鉴定针对HDV的新的抗病毒药物。我们的研究的意义在于证明核酸聚合物（NAP）通过靶向HDV病毒粒子的包膜而具有抗HDV的活性。在体外感染试验中，在不存在细胞毒性的情况下，在小于4 μ M的浓度下记录NAP活性。此外，NAP可以在病毒进入时阻断HDV的事实表明它们有可能控制HDV在慢性HBV感染的肝脏中的传播。此外，NAP抗HDV活性是HBV包膜蛋白的泛基因组学，并且不被与HBV免疫逃逸相关的HBsAg取代所规避。
In this study, an in vitro infection model for the hepatitis delta virus (HDV) was used to evaluate the antiviral effects of phosphorothioate nucleic acid polymers (NAPs) and investigate their mechanism of action. The results show that NAPs inhibit HDV infection at concentrations less than 4 mu M in cultures of differentiated human hepatoma cells. NAPs were shown to be active at viral entry but inactive postentry on HDV RNA replication. Inhibition was independent of the NAP nucleotide sequence but dependent on both size and amphipathicity of the polymer. NAP antiviral activity was effective against HDV virions bearing the main hepatitis B virus (HBV) immune escape substitutions (D144A and G145R) and was pangenomic with regard to HBV envelope proteins. Furthermore, similar to immobilized heparin, immobilized NAPs could bind HDV particles, suggesting that entry inhibition was due, at least in part, to preventing attachment of the virus to cell surface glycosaminoglycans. The results document NAPs as a novel class of antiviral compounds that can prevent HDV propagation.IMPORTANCE HDV infection causes the most severe form of viral hepatitis in humans and one of the most difficult to cure. Currently, treatments are limited to long-term administration of interferon at high doses, which provide only partial efficacy. There is thus an urgent need for innovative approaches to identify new antiviral against HDV. The significance of our study is in demonstrating that nucleic acid polymers (NAPs) are active against HDV by targeting the envelope of HDV virions. In an in vitro infection assay, NAP activity was recorded at concentrations less than 4 mu M in the absence of cell toxicity. Furthermore, the fact that NAPs could block HDV at viral entry suggests their potential to control the spread of HDV in a chronically HBV-infected liver. In addition, NAP anti-HDV activity was pangenomic with regard to HBV envelope proteins and not circumvented by HBsAg substitutions associated with HBV immune escape.