使用淋巴毒素-β-受体激动剂，以消除乙肝病毒

StephenW

                http://www.hepatitiscommunity.com/index.php?target=news&option=composants&itemId=141&PHPSESSID=c2l1k8v9mhhvmggq5dcoofkl34

Using lymphotoxin-beta-receptor agonists to eradicate the HBV virus
       
                        Data from animal studies presented during the EASL meeting showed that it is possible to eradicate the HBV virus from infected cells by targeting its replication template, the so-called covalently closed circular DNA (cccDNA). These findings raise hope for an alternative therapeutic approach to cure chronic HBV infection.
       
                        The discovery of compounds directly targeting HBV cccDNA has recently become one of the major challenges in hepatitis B research. Indeed, while current treatments are very potent to reduce patients’ viremia, these agents are not capable of eliminating the virus’s cccDNA. Thus, patients cannot be cured and require life-long treatments that may cause side effects.
       
                        During the EASL meeting, several early phase studies were presented suggesting different approaches to target HBV cccDNA. One of these approaches, presented by Julie Lucifora, from the team of Ulrike Protzer in Munich, Germany, showed it is possible to destroy cccDNA in infected cells by using agonists of the lymphtoxin beta receptor (LTbR).
       
                        LTbR-agonists trigger cccDNA degradation in vitro and in vivo
       
                        The researchers led their experiments in vitro in different cell culture models, including HBV-infected HepaRG cells and primary human hepatocytes, but also in vivo in mouse LTbR transgenic models. They observed that LTbR activation led to a strong dose-dependent anti-HBV effect both in vitro and in vivo, without inducing cell-toxicity. All HBV replication markers were decreased upon treatment, including cccDNA (Slide 13).
       
                        Importantly, the team showed that there was no rebound in HBV replication after stopping the LTbR treatment (Slide 14). Such a rebound is observed when using nucleos(t)ide analogues such as lamivudine.
       
                        cccDNA degradation depends on the overexpression of APOBEC3B
       
                        The team further identified the mechanism at play. LTbR-activation results in the overexpression of a protein called APOBEC3B, known for its deaminase activity. “In our experiments, the deactivation of APOBEC3B led to a full rescue of cccDNA in cells treated with the agonist,” explained Lucifora.
       
                        Dr. Lucifora proposed a model in which a signaling pathway activated by LTbR agnonists leads to the overexpression of APOBEC3B, triggering hypermutations in the cccDNA and its subsequent degradation by endonucleases.
       
                        “This is one of the first studies showing that by activating a signaling cascade we can destabilize and degrade HBV cccDNA. This provides new hopes for developing therapies which might one day be able to cure the infection,” said Dr. Lucifora, who added that one of the agonists used in her team’s experiments, CBE11, initially developed for anti-cancer therapy, has already been used in clinical phase I trials without inducing any adverse effect.
       
                        Written by Clementine Wallace, based on abstract 59, presented by Julie Lucifora, from Munich, Germany, also interviewed during the EASL congress 2013 in Amsterdam.
                        May 3rd, 2013

StephenW

使用淋巴毒素-β-受体激动剂，以消除乙肝病毒



EASL会议期间提出的从动物研究的数据表明，它有可能根除乙肝病毒感染的细胞，通过靶向复制模板，所谓的共价闭合环状DNA（cccDNA的）。这些发现提出替代治疗的方法来治疗慢性HBV感染者的希望。



最近发现直接针对HBV cccDNA的化合物成为B型肝炎的研究中面临的主要挑战之一。事实上，虽然目前的治疗是非常有效的，以减少患者的病毒血症，这些药物能够消除病毒的cccDNA的。因此，患者不能治愈，需要终身治疗，可能会引起副作用。



EASL会议期间，几个不同的方法提出建议，针对HBV cccDNA的早期阶段研究。这些方法之一，由朱莉Lucifora，在德国慕尼黑，从球队乌尔里克Protzer的，表明它有可能使用了lymphtoxinβ受体激动剂（LTBR）的cccDNA摧毁受感染的细胞。



LTBR-受体激动剂触发cccDNA的体外和体内的降解



研究者在体外导致他们的实验在不同的细胞培养模型，包括HBV感染HepaRG细胞和初级的人类肝细胞，而且在体内转基因模型鼠LTBR。他们观察到LTBR的活化导致一个强有力的剂量依赖性的抗-HBV的效果，无论是在体外和体内，而诱导的细胞毒性。所有HBV复制的标记减少治疗后，包括cccDNA的（幻灯片13）。



重要的是，研究小组发现，有（幻灯片14）的LTBR治疗停药后没有反弹HBV复制。使用核苷（酸）类似物如拉米夫定这样的反弹时观察。



cccDNA的降解取决于过度APOBEC3B



该团队进一步确定在发挥作用的机制。过度表达的一种蛋白质称为LTBR激活结果，被称为APOBEC3B其脱氨酶的活性。 “解释说：”在我们的实验中，停用APOBEC3B导致cccDNA的一个完整的救援细胞激动剂治疗，Lucifora。



博士Lucifora提出信号通路激活由LTBR agnonists导致过度的APOBEC3B一个模型，其中，触发hypermutations，在共价闭合环状DNA及其随后的核酸内切酶的降解。



“这是第一个研究表明，我们可以通过激活信号级联的稳定，降低HBV cccDNA的之一。博士说：“Lucifora开发的疗法可能有一天能够治愈的感染提供了新的希望，他补充说，她的小组的实验中，最初开发用于抗肿瘤治疗，CBE11使用激动剂，已经有人用于临床Ⅰ期临床试验，并没有引起任何不利影响。



写华莱士，由克莱门汀的基础上，由Julie Lucifora摘要59，从慕尼黑，德国EASL代表大会2013期间，还采访了在阿姆斯特丹。

2013年5月3日

jsmscym

攻克乙肝是不会超过10年了