新的联合疗法为治愈乙型肝炎提供了机会

StephenW

New combination therapy offers chance of healing hepatitis B

German Center for Infection Research

Research News
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IMAGE: The digitally-colourized transmission electron microscopic image reveals the presence of Hepatitis B virions (orange coloured). view more

Credit: CDC/Dr. Erskine Palmer

The new therapeutic approach is based on shutting down the viral hepatitis B genome located in the nucleus of infected liver cells. Upon infection of the liver cell, the viral genome is transformed inside the nucleus into a closed circular DNA molecule. This deoxyribonucleic acid is a stable molecule known as covalently closed circular DNA (cccDNA) and serves as the template for the production of new viruses. The cccDNA represents the central reservoir of the hepatitis B viruses and enables their persistence in the liver. The virologist Prof. Dr. Maura Dandri and her team at the UKE managed to prevent the HBV-cccDNA from producing further viruses in the animal model.

The point of attack of their therapy is the viral HBx protein, which protects the cccDNA in the cell nucleus from silencing by preventing a host factor (SMC complex) from binding to it. The team treated the animals on the one hand with the antiviral cytokine interferon-alpha, which was already shown to reduce viral RNA, and on the other they suppressed the formation of the HBx protein by RNA interference, a method in which the translation from RNA to protein is inhibited. In both cases, they were able to abrogate HBx production in most infected cells, and thus to deactivate the cccDNA through reappearance of the host restriction factor. In addition, they combined this treatment with the administration of bulevirtide, able to prevent the entry of HBV into the cells and thus a reinfection. In this way, the effect of the cccDNA deactivation could be maintained even beyond the end of treatment. Bulevirtide, better known by the research name myrcludex, was co-developed in the DZIF and has recently been approved for the European market as an active substance in the treatment of hepatitis D.

"This combination therapy was able to achieve the sustained shutting down of the cccDNA in infected cells," Prof. Dandri explains. She directs the "HBV Cure" project in the DZIF and the "Virushepatitis" working group in the UKE. Even though it has as yet only been tested in the mouse model, Prof. Dandri is convinced of the combination: "The results show that the HBV genome can be shut down with certain combination treatments. These approaches can now be applied in clinical studies in order to achieve a functional cure of chronic hepatitis B."

StephenW

新的联合疗法为治愈乙型肝炎提供了机会

德国感染研究中心

研究新闻
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图像：数字彩色的透射电子显微镜图像显示了乙型肝炎病毒粒子（橙色）的存在。查看更多

图片来源：CDC / Dr。厄斯金·帕尔默（Erskine Palmer）

新的治疗方法是基于关闭位于被感染的肝细胞核内的病毒性乙型肝炎基因组。感染肝细胞后，病毒基因组在细胞核内转化为封闭的环状DNA分子。这种脱氧核糖核酸是一种稳定的分子，被称为共价闭合环状DNA（cccDNA），并用作生产新病毒的模板。 cccDNA代表了乙型肝炎病毒的中央储存库，并使其在肝脏中得以持久存在。病毒学家Maura Dandri博士及其在UKE的研究小组设法防止HBV-cccDNA在动物模型中产生其他病毒。

他们疗法的攻击点是病毒HBx蛋白，它通过阻止宿主因子（SMC复合物）与其结合，从而保护细胞核中的cccDNA免受沉默。该团队一方面用抗病毒细胞因子干扰素-α（已显示可减少病毒RNA）对动物进行治疗，另一方面，他们通过RNA干扰抑制了HBx蛋白的形成，该方法是从RNA进行翻译对蛋白质有抑制作用。在这两种情况下，它们都能够消除大多数感染细胞中的HBx产生，从而通过宿主限制因子的重新出现而使cccDNA失活。此外，他们将这种治疗方法与bulevirtide联合使用，能够防止HBV进入细胞，从而防止再次感染。这样，甚至在治疗结束后，也可以保持cccDNA失活的效果。 Bulevirtide，以研究名称myrcludex更广为人知，是在DZIF中共同开发的，最近被批准作为治疗D型肝炎的活性物质进入欧洲市场。

丹德里教授解释说：“这种联合疗法能够实现被感染细胞中cccDNA的持续关闭。”她负责DZIF的“ HBV治愈”项目和UKE的“病毒性肝炎”工作组。即使仅在小鼠模型中进行了测试，Dandri教授还是相信这种组合：“结果表明，通过某些组合治疗可以关闭HBV基因组。这些方法现在可以用于临床研究中。以达到治愈慢性乙型肝炎的目的。”