Rapid Turnover of Hepatitis B Virus Covalently Closed Circular DNA Indicated by Monitoring Emergence and Reversion of Signature-Mutation in Treated Chronic Hepatitis B Patients.
Rapid Turnover of Hepatitis B Virus Covalently Closed Circular DNA Indicated by Monitoring Emergence and Reversion of Signature-Mutation in Treated Chronic Hepatitis B Patients.
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通过监测治疗的慢性乙型肝炎患者特征突变的出现和逆转表明乙型肝炎病毒共价闭合环状 DNA 的快速周转
DOI：
10.1002/hep.31240
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Huang Q;Zhou B;Cai D;Zong Y;Wu Y;Liu S;Mercier A;Guo H;Hou J;Colonno R;Sun J
乙肝病毒共价闭合环状DNA(CccDNA)在乙肝病毒感染的形成和持续中起着关键作用。了解预先存在的cccDNA池的周转时间将有助于设计策略，通过完全阻断cccDNA的从头生成来清除乙肝病毒。在这项研究中，我们对rtM204I/V突变的出现和逆转进行了回顾性监测，rtM204I/V突变是拉米夫定耐药(LAMR)的标志性突变，在两个临床试验的肝活检和纵向血清样本中被用作cccDNA周转的生物标志物。对方法进行了优化，以从临床样本中差异分离和测序HBVVrion DNA、cccDNA和HBVRNA。在配对肝和血清标本中，cccDNA的LAMR组成与血清和肝内HBVRNA的LAMR组成有很强的相关性(r值分别为0.96和0.90)，提示当肝活检不能进行时，血清HBVRNA可以作为cccDNA基因组成的替代标志物。在经历病毒学突破的替比夫定治疗患者的16-28周内，血清HBVRNA中出现了LAMR突变，并从无法检测到的突变增加到40%-90%。同样，在改用干扰素治疗的拉米夫定耐药患者中，携带100%LAMR突变的血清HBVRNA群体在24-48周内完全逆转为野生型。经治疗的乙肝患者的血清HBVRNA和活检组织中cccDNA的遗传组成动态表明，cccDNA的更新发生得相对较快(几个月)，这为完全阻断cccDNA的补充进行有限治疗提供了一种可能性。
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a pivotal role in the establishment and persistence of HBV infection. Understanding the turnover time of preexisting cccDNA pools would be helpful in designing strategies to clear HBV by fully blocking the de novo generation of cccDNA. In this study, we retrospectively monitored the emergence and reversion of the rtM204I/V mutant, a signature lamivudine resistance (LAMR) mutation serving as a biomarker of cccDNA turnover in liver biopsies and longitudinal serum samples from two clinical trials. Methodologies were optimized to differentially isolate and sequence HBV virion DNA, cccDNA, and HBV RNA from clinical samples. A strong correlation was observed between LAMR composition of cccDNA with that of serum and intrahepatic HBV RNA in paired liver and serum samples (r = 0.96 and 0.90, respectively), suggesting that serum HBV RNA can serve as a surrogate marker of cccDNA genetic composition when liver biopsies are unavailable. LAMR mutations emerged and increased from undetectable to 40%‐90% within 16‐28 weeks in serum HBV RNA from telbivudine‐treated patients experiencing virological breakthrough. Similarly, in lamivudine‐resistant patients who switched to interferon therapy, serum HBV‐RNA population bearing 100% LAMR mutations fully reversed back to wild type within 24‐48 weeks. The genetic composition dynamics of serum HBV RNA and biopsy cccDNA in treated HBV patients indicates that cccDNA turnover occurs relatively rapidly (several months), offering a possibility of HBV cure with finite therapy through completely blocking cccDNA replenishment.
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影响因子：
5.4
作者：
Mason, William S.;Xu, Chunxiao;Jilbert, Allison R.
通讯作者：
Jilbert, Allison R.
血清 HBV RNA：慢性乙型肝炎病毒感染的新的潜在生物标志物
DOI：
10.1002/hep.30325
发表时间：
2019-04
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Liu S;Zhou B;Valdes JD;Sun J;Guo H
通讯作者：
Guo H
影响因子：
25.7
作者：
Lai, Ching-Lung;Wong, Danny;Yuen, Man-Fung
通讯作者：
Yuen, Man-Fung
影响因子：
13.5
作者：
Sun, Jian;Xie, Qing;Hou, Jinlin
通讯作者：
Hou, Jinlin
影响因子：
13.5
作者：
Gordon, Stuart C.;Krastev, Zahary;Horban, Andrzej;Petersen, Joerg;Sperl, Jan;Dinh, Phillip;Martins, Eduardo B.;Yee, Leland J.;Flaherty, John F.;Kitrinos, Kathryn M.;Rustgi, Vinod K.;Marcellin, Patrick
通讯作者：
Marcellin, Patrick