hbsag来源的研究

newchinabok

http://stm.sciencemag.org/content/9/409/eaan0241

newchinabok

RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg
Christine I. Wooddell1,*,†, Man-Fung Yuen2,*, Henry Lik-Yuen Chan3, Robert G. Gish4, Stephen A. Locarnini5,6, Deborah Chavez7, Carlo Ferrari8,9, Bruce D. Given1, James Hamilton10, Steven B. Kanner1, Ching-Lung Lai2, Johnson Y. N. Lau11, Thomas Schluep10, Zhao Xu1, Robert E. Lanford7 and David L. Lewis1
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Science Translational Medicine  27 Sep 2017:
Vol. 9, Issue 409, eaan0241
DOI: 10.1126/scitranslmed.aan0241
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How hepatitis hangs around
Hepatitis B virus (HBV) infects the liver, and chronic infection can lead to cirrhosis or cancer. Wooddell et al. report the results of a phase 2 trial of a drug based on RNA interference, which was unable to reduce viral burden in certain subsets of patients. To determine the mechanism of this variable response, the researchers examined chronically infected chimpanzees that had been treated with the drug. They found evidence that viral antigen was being produced from integrated HBV transcripts that did not harbor the target sequence. This study uncovers a previously unappreciated source of viral antigen, which could inform disease pathogenesis and help guide development of future HBV treatments.
Abstract
Chronic hepatitis B virus (HBV) infection is a major health concern worldwide, frequently leading to liver cirrhosis, liver failure, and hepatocellular carcinoma. Evidence suggests that high viral antigen load may play a role in chronicity. Production of viral proteins is thought to depend on transcription of viral covalently closed circular DNA (cccDNA). In a human clinical trial with an RNA interference (RNAi)–based therapeutic targeting HBV transcripts, ARC-520, HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for HBV e antigen (HBeAg) but was reduced significantly less in patients who were HBeAg-negative or had received long-term therapy with nucleos(t)ide viral replication inhibitors (NUCs). HBeAg positivity is associated with greater disease risk that may be moderately reduced upon HBeAg loss. The molecular basis for this unexpected differential response was investigated in chimpanzees chronically infected with HBV. Several lines of evidence demonstrated that HBsAg was expressed not only from the episomal cccDNA minichromosome but also from transcripts arising from HBV DNA integrated into the host genome, which was the dominant source in HBeAg-negative chimpanzees. Many of the integrants detected in chimpanzees lacked target sites for the small interfering RNAs in ARC-520, explaining the reduced response in HBeAg-negative chimpanzees and, by extension, in HBeAg-negative patients. Our results uncover a heretofore underrecognized source of HBsAg that may represent a strategy adopted by HBV to maintain chronicity in the presence of host immunosurveillance. These results could alter trial design and endpoint expectations of new therapies for chronic HBV.

newchinabok

rnai药降hbsag的局限在于能否清除整合hbv

windu

希望在核衣壳上市之前能揭开更多HBV的秘密

涅槃2016

有大神翻译一下吧

kmustwjj

就是说，基于RNA干扰技术的靶向药物，比如ARC520等，对于HBeAg阴性患者比阳性患者，HBsAg下降更多一点。HBeAg高载量是导致肝癌等疾病的主要因素。

StephenW

回复 kmustwjj 的帖子

有点不同意.
这项研究是ARC520在黑猩猩 : HBeAg阴性比阳性黑猩猩，HBsAg下降更小一点.
这导致结论:产生HBsAg的整合型hbvdna的存在 (因为ARC520 RANi 针对整合型hbvdna产生的HBsAg没有效果).

antiHBVren

基于RNAi的慢性感染患者和黑猩猩的治疗表明，整合的乙型肝炎病毒DNA是HBsAg的来源
Christine I. Wooddell 1，袁文凤2，*，李显源3，罗伯特G。吉什4，斯蒂芬A.洛加尔尼尼5,6，德博拉查韦斯7，卡罗法拉利8,9，布鲁斯D.给定1，詹姆斯汉密尔顿10， Steven B. Kanner 1，黎清龙2，Johnson YN Lau11，Thomas Schluep 10，赵旭1，Robert E. Lanford7和David L. Lewis1
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科学转化医学2017年9月27日：
卷。 9，Issue 409，eaan0241
DOI：10.1126 / scitranslmed.aan0241
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肝炎如何徘徊
乙型肝炎病毒（HBV）感染肝脏，慢性感染可导致肝硬化或癌症。伍德戴尔等人报告基于RNA干扰的药物的第二阶段试验的结果，其不能减少某些患者亚群中的病毒负荷。为了确定这种可变反应的机制，研究人员检查了慢性感染的黑猩猩，这些黑猩猩已经接受了这种治疗。他们发现证据表明病毒抗原是由整合的HBV转录物产生的，而不含有靶序列。这项研究揭示了一个以前未被重视的病毒抗原来源，它可以告知疾病的发病机制，并有助于指导未来HBV治疗的发展。
抽象
慢性乙型肝炎病毒（HBV）感染是全世界主要的健康问题，经常导致肝硬化，肝功能衰竭和肝细胞癌。有证据表明高病毒抗原负荷可能在慢性病中起作用。病毒蛋白的产生被认为取决于病毒共价闭合环状DNA（cccDNA）的转录。在一项以RNA干扰（RNAi）为基础的治疗靶向HBV转录本的人类临床试验中，未治疗的HBV e抗原阳性患者（HBeAg）ARC-520，HBV S抗原（HBsAg）显着降低，但显着降低在HBeAg阴性或接受长期治疗的核苷（酸）ide病毒复制抑制剂（NUCs）的患者中。 HBeAg阳性与更大的疾病风险有关，可能在HBeAg消失后适度降低。在慢性感染HBV的黑猩猩中研究了这种意外的差别反应的分子基础。几条证据表明，HBsAg不仅来自附加型cccDNA微型染色体，而且来自HBV DNA整合到宿主基因组中的转录本，而宿主基因组是HBeAg阴性黑猩猩的主要来源。在黑猩猩中检测到的许多整合子缺乏ARC-520中小干扰RNA的靶位点，这解释了HBeAg阴性黑猩猩以及HBeAg阴性患者的应答减少。我们的研究结果揭示了迄今为止尚未被认识到的HBsAg来源，这可能代表了HBV在宿主免疫监视下维持慢性的策略。这些结果可能会改变慢性HBV新疗法的试验设计和终点预期。