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首页> 外文OA文献 >Inhibitory Effect of Adefovir on Viral DNA Synthesis and Covalently Closed Circular DNA Formation in Duck Hepatitis B Virus-Infected Hepatocytes In Vivo and In Vitro
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Inhibitory Effect of Adefovir on Viral DNA Synthesis and Covalently Closed Circular DNA Formation in Duck Hepatitis B Virus-Infected Hepatocytes In Vivo and In Vitro

机译：阿德福韦对鸭乙型肝炎病毒感染的肝细胞体内和体外病毒DNA合成和共价闭合环状DNA形成的抑制作用。

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The elimination of viral covalently closed circular DNA (CCC DNA) from the nucleus of infected hepatocytes is an obstacle to achieving sustained viral clearance during antiviral therapy of chronic hepatitis B virus (HBV) infection. The aim of our study was to determine whether treatment with adefovir, a new acyclic nucleoside phosphonate, the prodrug of which, adefovir dipivoxil, is in clinical evaluation, is able to suppress viral CCC DNA both in vitro and in vivo using the duck HBV (DHBV) model. First, the effect of adefovir on viral CCC DNA synthesis was examined with primary cultures of DHBV-infected fetal hepatocytes. Adefovir was administered for six consecutive days starting one day before or four days after DHBV inoculation. Dose-dependent inhibition of both virion release in culture supernatants and synthesis of intracellular viral DNA was observed. Although CCC DNA amplification was inhibited by adefovir, CCC DNA was not eliminated by antiviral treatment and the de novo formation of CCC DNA was not prevented by pretreatment of the cells. Next, preventive treatment of experimentally infected ducklings with lamivudine or adefovir revealed that both efficiently suppressed viremia and intrahepatic DNA. However, persistence of viral DNA even when detectable only by PCR was associated with a recurrence of viral replication following drug withdrawal. Taken together, our results demonstrate that adefovir is a potent inhibitor of DHBV replication that inhibits CCC DNA amplification but does not effectively prevent the formation of CCC DNA from incoming viral genomes.
机译：从被感染的肝细胞核中消除病毒共价封闭的环状DNA（CCC DNA）是在慢性乙型肝炎病毒（HBV）感染的抗病毒治疗期间实现持续病毒清除的障碍。我们研究的目的是确定使用阿德福韦（一种新的无环核苷膦酸酯）的治疗是否在临床评估中，该药物的前药阿德福韦酯（difivoxil）正在临床评估中，能够使用鸭HBV抑制体内和体外的病毒CCC DNA（ DHBV）模型。首先，用DHBV感染的胎儿肝细胞的原代培养检查了阿德福韦对病毒CCC DNA合成的影响。从DHBV接种前一天或接种后四天开始，连续六天服用阿德福韦。观察到了剂量依赖性抑制病毒在培养上清液中的释放以及细胞内病毒DNA的合成。尽管阿德福韦抑制了CCC DNA的扩增，但抗病毒处理并不能消除CCC DNA，并且通过细胞预处理不能阻止CCC DNA从头形成。接下来，用拉米夫定或阿德福韦对实验感染的小鸭进行预防性治疗表明，二者均能有效抑制病毒血症和肝内DNA。但是，病毒DNA的持久性即使仅通过PCR即可检测到，也与停药后病毒复制的复发有关。两者合计，我们的结果表明，阿德福韦是DHBV复制的有效抑制剂，可抑制CCC DNA扩增，但不能有效防止来自传入病毒基因组的CCC DNA的形成。

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