cccDNA在HBV维持中的作用

StephenW

          Viruses      2017,      9(6),      156;      doi:10.3390/v9060156   
  
      Review  
  The Role of cccDNA in HBV Maintenance
       Lena Allweiss 1         and    Maura Dandri 1,2,*           
            1   
    I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany
  
            2   
    German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel Site, Germany
  

                    *      
      Correspondence: Tel.: +49-40-7410-52949; Fax: +49-40-7410-57232
   
  
        Academic Editors:      Ulrike Protzer      and      Michael Nassal        
      Received: 4 May 2017 / Accepted: 19 June 2017 / Published: 21 June 2017  
        Abstract:      Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide; it can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma. The molecular mechanisms determining HBV persistence are not fully understood, but these appear to be multifactorial and the unique replication strategy employed by HBV enables its maintenance in infected hepatocytes. Both the stability of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the hepatocyte nucleus, and the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. Since a true cure of HBV requires clearance of intranuclear cccDNA from infected hepatocytes, understanding the mechanisms involved in cccDNA biogenesis, regulation and stability is mandatory to achieve HBV eradication. This review will summarize the state of knowledge on these mechanisms including the impact of current treatments on the cccDNA stability and activity. We will focus on events challenging cccDNA persistence in dividing hepatocytes.
        Keywords:
    hepatitis B virus; cccDNA; animal models; human liver chimeric mice; cell proliferation
  

StephenW

病毒2017，9（6），156; DOI：10.3390 / v9060156
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cccDNA在HBV维持中的作用
Lena Allweiss 1和Maura Dandri 1,2，*
1
汉堡 - 埃本多夫大学医学中心内科医学系内科医师Martinistr。 52，D-20246 Hamburg，Germany
2
德国感染研究中心（DZIF），德国汉堡吕贝克 - 博尔斯堡遗址
*
通讯：电话：+ 49-40-7410-52949;传真：+ 49-40-7410-57232
学术编辑：Ulrike Protzer和Michael Nassal
收到：2017年5月4日/接受：2017年6月19日/发布时间：2017年6月21日
摘要：慢性乙型肝炎病毒（HBV）感染继续是全球重要的健康负担;可引起肝脏各种程度的损害，并与肝硬化和肝细胞癌的发展密切相关。确定HBV持续性的分子机制尚未完全了解，但这些似乎是多因素的，HBV采用的独特复制策略使其能够在感染肝细胞中维持。形成稳定的微染色体的HBV基因组的稳定性，肝细胞核中共价闭合的环状DNA（cccDNA）和免疫系统不能解决慢性HBV感染的两者被认为是HBV慢性的关键机制。由于真正治愈HBV需要清除感染肝细胞的核内cccDNA，因此了解cccDNA生物发生机制，调节和稳定性的机制是实现HBV消除的必要条件。本综述将总结这些机制的知识状况，包括当前治疗对cccDNA稳定性和活性的影响。我们将重点关注cccDNA在分裂肝细胞方面的持久性。
关键词：
乙肝病毒; cccDNA的;动物模型;人肝嵌合小鼠;细胞增殖

StephenW

"
Such findings point out the important role that immune modulating factors play in reducing cccDNA loads and activity. We speculate that both direct killing of infected cells and compensatory proliferation of HBV-infected hepatocytes play a key synergistic role in the process of resolving acute hepatitis. This process might have also been functional in chronically HBV infected patients, which were reported to achieve more beneficial treatment outcomes when the stopping of long-term NA therapy was accompanied with a transitory hepatic flare [50,51,80].
6. Conclusions
In sum, even if elimination of the cccDNA from the infected liver remains challenging and more research is needed to develop therapeutic approaches boosting HBV-specific immune responses or agents directly targeting the cccDNA, cell division appears to be a natural Achilles’ heel in HBV persistence. At the same time, key factors produced by immune cells, like IFNs and tumor necrosis factor α, can further promote non-cytolytic inhibition of HBV replication and contribute to cccDNA destabilization [56]. The fact that even after a resolved acute infection low amounts of cccDNA molecules are detected in the liver of patients [81], raises hope that not the entire intrahepatic cccDNA reservoir needs to be eliminated to gain immunological control and resolve the infection. We hypothesize that if a sufficient amount of HBV-infected cells will be eliminated and even more cccDNA will be degraded through compensatory proliferation and non-cytolytic immune factors, the immune system should be able to resolve chronic HBV infection."

StephenW

这些发现指出免疫调节因子在减少cccDNA负荷和活性中起重要作用。我们推测，感染细胞的直接杀伤和HBV感染肝细胞的代偿性增殖在解决急性肝炎的过程中起着关键的协同作用。慢性乙型肝炎病毒感染患者的这一过程也可能发挥作用，据报道，当长期NA治疗停止时伴有短暂的肝脏炎症，据报道其可以获得更有益的治疗效果[50,51,80]。
6。结论
总之，即使从感染的肝脏中消除cccDNA依然存在挑战，需要更多的研究来开发提高HBV特异性免疫应答的治疗方法或直接针对cccDNA的药物，细胞分裂似乎是HBV持久性中的天然跟腱。同时，免疫细胞产生的关键因子，如IFN和肿瘤坏死因子α，可进一步促进非细胞溶解抑制HBV复制，促进cccDNA不稳定[56]。即使在解决急性感染之后，在患者肝脏中检测到低量的cccDNA分子[81]，也希望不需要消除整个肝内cccDNA储层以获得免疫控制并解决感染。我们假设如果消除足够数量的HBV感染细胞，并且通过代偿性增殖和非细胞溶解免疫因子降低更多的cccDNA，则免疫系统应该能够解决慢性HBV感染。

StephenW

http://www.mdpi.com/1999-4915/9/6/156/htm

newchinabok

很重要文章。但是是一种假设，没有验证，也没有办法验证

StephenW

回复 newchinabok 的帖子

这些假设都是基于着名科学家的研究，如斯蒂芬·斯普森（Stephen Urban）.

如斯蒂芬·斯普森（Stephen Urban）研究显示单个肝细胞中cccDNA的数量有限, 没有多个copies.
George KK Lau的研究也显示NUC治疗后全肝的cccDNA数量非常低.

我想如果我们可以中和血清的HBsAg(从整合的HBV DNA，剩余的cccDNA), 我们可以实现功能治愈.

newchinabok

回复 StephenW 的帖子

免疫治疗是关键

newchinabok

回复 StephenW 的帖子

免疫治疗是关键

kite2002005

StephenW 发表于 2017-6-24 16:46
回复 newchinabok 的帖子

这些假设都是基于着名科学家的研究，如斯蒂芬·斯普森（Stephen Urban）.

请教文章是什么意思？意思是 长期核苷药患者，停药，会伴随肝炎症状，但更有益于消灭减少cccdna?