抑制HepaRG细胞和原代人肝细胞中核酸聚合物的乙型肝炎病毒

StephenW

PLoS One. 2017 Jun 21;12(6):e0179697. doi: 10.1371/journal.pone.0179697. eCollection  2017.
Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes.Guillot C1, Martel N1, Berby F1, Bordes I1, Hantz O1, Blanchet M2, Sureau C3, Vaillant A2, Chemin I1.
Author information
1Centre de Recherche en Cancérologie de Lyon INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France.2Replicor Inc. Montréal, Canada.3Molecular Virology Laboratory, Institut National de la Transfusion Sanguine (INTS), CNRS INSERM U1134, Paris, France.

AbstractHepatitis B virus (HBV) infection remains a major public health concern worldwide with 240 million individuals chronically infected and at risk of developing cirrhosis and hepatocellular carcinoma. Current treatments rarely cure chronic hepatitis B infection, highlighting the need for new anti-HBV drugs. Nucleic acid polymers (NAPs) are phosphorothioated oligonucleotides that have demonstrated a great potential to inhibit infection with several viruses. In chronically infected human patients, NAPs administration lead to a decline of blood HBsAg and HBV DNA and to HBsAg seroconversion, the expected signs of functional cure. NAPs have also been shown to prevent infection of duck hepatocytes with the Avihepadnavirus duck hepatitis B virus (DHBV) and to exert an antiviral activity against established DHBV infection in vitro and in vivo. In this study, we investigated the specific anti-HBV antiviral activity of NAPs in the HepaRG human hepatoma cell line and primary cultures of human hepatocytes. NAPs with different chemical features (phosphorothioation, 2'O-methyl ribose, 5-methylcytidine) were assessed for antiviral activity when provided at the time of HBV inoculation or post-inoculation. NAPs dose-dependently inhibited HBV entry in a phosphorothioation-dependent, sequence-independent and size-dependent manner. This inhibition of HBV entry by NAPs was impaired by 2'O-methyl ribose modification. NAP treatment after viral inoculation did not elicit any antiviral activity.


PMID:28636622DOI:10.1371/journal.pone.0179697

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StephenW

PLoS One。 2017年6月21日; 12（6）：e0179697。 doi：10.1371 / journal.pone.0179697。 eCollection 2017。
抑制HepaRG细胞和原代人肝细胞中核酸聚合物的乙型肝炎病毒进入。
Guillot C1，Martel N1，Berby F1，Bordes I1，Hantz O1，Blanchet M2，Sureau C3，Vaillant A2，Chemin I1。
作者信息

1
    Centre de Recherche enCancérologiede Lyon INSERM U1052，CNRS UMR5286，里昂大学，里昂，法国。
2
    Replicor Inc.Montréal，加拿大。
3
    分子病毒学实验室，国家输血管理研究所（INTS），CNRS INSERM U1134，巴黎，法国。

抽象

乙型肝炎病毒（HBV）感染仍然是全球主要的公共卫生问题，其中2.4亿人长期感染并发生肝硬化和肝细胞癌的风险。目前的治疗很少治愈慢性乙型肝炎感染，强调需要新的抗HBV药物。核酸聚合物（NAP）是硫代磷酸化的寡核苷酸，其已经证明具有抑制几种病毒感染的巨大潜力。在长期感染的人类患者中，NAPs导致血液HBsAg和HBV DNA的下降以及HBsAg血清学转换，预期功能治愈的迹象。 NAP也被证明可以防止禽流感病毒鸭乙型肝炎病毒（DHBV）感染鸭肝细胞，并在体外和体内对已建立的DHBV感染发挥抗病毒活性。在本研究中，我们调查了HepaRG人肝癌细胞系和人肝细胞原代培养物中NAP的特异性抗HBV抗病毒活性。在HBV接种或接种后提供时，评估具有不同化学特征（硫代磷酸化，2'O-甲基核糖，5-甲基胞苷）的NAP的抗病毒活性。 NAP以硫代磷酸依赖性，与序列无关和大小依赖的方式剂量依赖地抑制HBV进入。 NAPs对HBV进入的抑制受到2'O-甲基核糖修饰的损害。病毒接种后的NAP治疗未引起任何抗病毒活性。

结论：
    28636622
DOI：
    10.1371 / journal.pone.0179697

StephenW

"Altogether, our study demonstrates the ability of NAPs to block HBV entry into hepatocytes. A NAP structure/activity relationship similar to that documented with other enveloped viruses is observed, with the exception of the 2’O-Me modification having a detrimental effect on antiviral activity against HBV. Results from the present study, along with previous in vivo and clinical studies, highlight the potential of NAPs as therapeutic antiviral agents in general, and as anti-HBV drug in particular. Combination of NAPs with currently available therapies may represent a new relevant step toward an HBV cure."

"总之，我们的研究表明NAP阻断HBV进入肝细胞的能力。 观察到与其他包膜病毒相似的NAP结构/活性关系，除了对HBV的抗病毒活性有不利影响的2'O-Me修饰外。 本研究结果与以往的体内和临床研究结果一起突出表明NAP作为治疗性抗病毒药物的潜力，特别是抗HBV药物。 NAP与目前可用的治疗方法的结合可能代表了HBV治愈的新的相关步骤"

http://journals.plos.org/plosone ... ournal.pone.0179697