Can we eliminate cccDNA: some slides from Prof. Massimo Levrero

StephenW

a46346310

大意是？

StephenW

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我的理解:
cccDNA的活性是由表观遗传(epigenetics)因素控制. 如果我们不能毁灭cccDNA，我们可以尝试使cccDNA失去活性(例如使用干扰素).

表觀遺傳學又稱“擬遺傳學”、“表遺傳學”、“外遗传学”以及“後遺傳學”（英文epigenetics），是一門生物學學科，研究在沒有細胞核DNA序列改變的情況時，基因功能的可逆的、可遺傳的改變。这些改變包括DNA的修饰(如甲基化修饰)、组蛋白的各种修饰等。也指生物發育過程中包含的程序的研究。在這兩種情況下，研究的對象都包括在DNA序列中未包含的基因調控信息如何傳遞到（細胞或生物體的）下一代這個問題。在西方文字中epigenetics即指在DNA包含的遺傳信息以外附加的（希臘文前綴epi-）。
表观遗传学是20世纪80年代逐渐兴起的一门学科，是在研究与经典孟德尔遗传学遗传法则不相符的许多生命现象过程中逐步发展起来的。
表观遗传现象包括DNA甲基化、RNA干扰、组織蛋白修饰等。与经典遗传学以研究基因序列影响生物学功能为核心相比，表观遗传学主要研究这些“表观遗传现象”的建立和维持的机制。

咬牙硬挺

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使用干扰素使CCCDNA失去活性的可能性很小啊，还有其他方法吗

StephenW

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这位教授认为：
干扰素alpha诱导”积极的后生控制"HBV cccDNA的转录状况，可能有助于持久，但却是可逆的，”治疗后“抑制乙肝病毒复制.


The Professor thinks:
"IFN alpha induces a condition of "active epigenetic control" of HBV cccDNA transcriptions that likely contributes to the persistent, yet reversible,"off therapy" inhibition of HBV replication.

kennyu

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我记得原来有人说，只有inf gamma可以直接作用于cccDNA，为啥这个ppt里面，inf alpha也有效果？
PS1，你提到的“可逆”，指的是病情反复吗？
PS2，其中一页里面提到肝移植的病人，其cccDNA会被稀释，我不太理解，为啥没有重新建立感染？而是出现的cccDNA的稀释。

StephenW

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感谢您的问题。当然，我只有slides，没有演讲的文本。所以可能会产生误导。我深表歉意。
PS1，你提到的“可逆”，指的是病情反复吗？ - “可逆” (reversable)指后生控制(epigenetic control).如果我们失去了控制后生，cccDNA应再度活跃.
PS2，其中一页里面提到肝移植的病人，其cccDNA会被稀释，我不太理解，为啥没有重新建立感染？而是出现的cccDNA的稀释 - 这种“移植”，是指肝细胞从一只老鼠移植到另一个老鼠（我的理解）。移植后，这些细胞分裂，造成cccDNA的稀释. 见下面的文件的摘要。

许多这些研究​​是在动物身上进行. 我应该说清楚.

Abstract
Chronic hepatitis B virus (HBV) infection is maintained by the presence of covalently closed circular DNA (cccDNA), the template of viral transcription and replication. In quiescent hepatocytes, cccDNA is a stable molecule that can persist throughout the hepatocyte lifespan. However, in chronic HBV infection, immunomediated cell injury and compensatory hepatocyte proliferation may favor cccDNA decline and selection of cccDNA-free cells. To investigate the impact of liver regeneration on cccDNA stability and activity in vivo, we used the urokinase-type plasminogen activator (uPA)/severe combined immunodeficiency (SCID) mouse model. Primary tupaia hepatocytes (PTHs) chronically infected with woolly monkey HBV (WM-HBV) were isolated from one highly viremic uPA/SCID chimeric mouse and transplanted into 20 uPA recipients. Expansion of transplanted PTHs and viral load changes were determined by real-time polymerase chain reaction and immunohistochemistry. Transplantation of WM-HBV infected hepatocytes led to an average of 3.8 PTH doublings within 80 days, 75% reduction of virion productivity (relaxed circular DNA/cccDNA), and lower expression levels of pregenomic RNA and hepatitis B core antigen. Remarkably, a median 2-log decline of cccDNA per cell determined during PTH proliferation was due to both dilution of the cccDNA pool among daughter cells and a 0.5-log loss of intrahepatic cccDNA loads (P = 0.02). Intrahepatic viral DNA sequences persisting at the end of the study were mostly present as replicative intermediates and not as integrated virus. Conclusion: Cell division in the setting of liver regeneration and without administration of antiviral drugs induced strong destabilization of the cccDNA reservoir, resulting in cccDNA clearance in the great majority of chronically infected hepatocytes. (Hepatology 2010)

lifevendor

Our food could change the epigenetic states of HBV, also chinese herb medcine has the potential in change the epigenetic states of cccDNA, minichromosome.