核酸聚合物对体外肝炎三角洲病毒感染有活性。

StephenW

J Virol. 2017 Dec 6. pii: JVI.01416-17. doi: 10.1128/JVI.01416-17. [Epub ahead of print]
Nucleic acid polymers are active against Hepatitis Delta Virus infection in vitro.Beilstein F1, Blanchet M2, Vaillant A3, Sureau C4.
Author information
1Institut National de la Transfusion Sanguine (INTS), CNRS-INSERM U1134, Paris, France.2Replicor Inc. Montreal, Canada.3Replicor Inc. Montreal, Canada [email protected] [email protected].4Institut National de la Transfusion Sanguine (INTS), CNRS-INSERM U1134, Paris, France [email protected] [email protected].

AbstractIn 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 less than 4 micromolar concentrations in cultures of differentiated human hepatoma cells. NAPs were shown to be active at viral entry, but inactive post entry on HDV RNA replication. Inhibition was independent of the NAPs nucleotide sequence, but dependent on both size and amphipathicity of the polymer. NAPs 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.IMPORTANCEHDV 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, NAPs activity was recorded at less than 4 micromolar concentrations in the absence of cell toxicity. Furthermore, the fact that NAPs could block HDV at viral entry, suggest their potential to control the spread of HDV in a chronically HBV-infected liver. In addition, NAPs anti-HDV activity was pangenomic with regard to HBV envelope proteins and not circumvented by HBsAg substitutions associated with HBV immune escape.


PMID:29212929DOI:10.1128/JVI.01416-17

StephenW

J Virol。 2017年12月6日。pii：JVI.01416-17。 doi：10.1128 / JVI.01416-17。 [电子版提前打印]
核酸聚合物对体外肝炎三角洲病毒感染有活性。
Beilstein F1，Blanchet M2，Vaillant A3，Sureau C4。
作者信息

1
    法国巴黎CNRS-INSERM U1134国家输血协会（INTS）。
2
    Replicor Inc.加拿大蒙特利尔。
3
    Replicor Inc.加拿大蒙特利尔[email protected] [email protected]。
4
    法国巴黎输血协调研究所（INTS），CNRS-INSERM U1134，[email protected] [email protected]。

抽象

在这项研究中，用甲型肝炎病毒（HDV）的体外感染模型来评估硫代磷酸核酸聚合物（NAPs）的抗病毒作用并研究其作用机制。结果显示NAP在分化的人肝细胞瘤细胞的培养物中以低于4微摩尔浓度抑制HDV感染。显示NAP在病毒进入时是活跃的，但是在HDV RNA复制后进入非活动状态。抑制独立于NAP核苷酸序列，但依赖于聚合物的大小和两亲性。 NAPs抗病毒活性对携带主要乙型肝炎病毒（HBV）免疫逃逸替代物（D144A和G145R）的HDV病毒粒子是有效的，并且对于HBV包膜蛋白是pangenomic。此外，类似于固定的肝素，固定化的NAP可以结合HDV颗粒，表明进入抑制至少部分是由于防止病毒附着到细胞表面葡糖胺聚糖上。结果证明NAPs是一类新型抗病毒化合物，可以预防HDV的传播.IMVORTANCEHDV感染是人类最严重的病毒性肝炎，也是最难治愈的病毒之一。目前，治疗局限于高剂量长期使用干扰素，只能提供部分疗效。因此迫切需要创新的方法来鉴定抗HDV的新型抗病毒药物。我们研究的意义在于证明核酸聚合物（NAP）通过靶向HDV病毒体的包膜而对HDV具有活性。在体外感染测定中，在不存在细胞毒性的情况下，在小于4微摩尔浓度下记录NAP活性。此外，NAPs在病毒进入时可阻断HDV的事实表明，它们有潜力控制HDV在慢性HBV感染肝脏中的传播。此外，NAP抗乙肝病毒包膜蛋白的抗HDV活性是泛基因组的，而不是由HBV免疫逃避相关的乙肝表面抗原取代所规避。

结论：
    29212929
DOI：
    10.1128 / JVI.01416-17

windu

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