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乙型肝炎病毒编码的微RNA控制病毒复制

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才高八斗

发表于 2017-4-29 19:13 |显示全部帖子
Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication

    Xi Yang, Hongfeng Li, Huahui Sun, Hongxia Fan, Yaqi Hu, Min Liu, Xin Li and Hua Tang

    Tianjin Life Science Research Center and Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    J.-H. James Ou, Editor

    University of Southern California

ABSTRACT

MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding, functional RNAs. Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR-3) by deep sequencing and Northern blotting. HBV-miR-3 is located at nucleotides (nt) 373 to 393 of the HBV genome and was generated from 3.5-kb, 2.4-kb, and 2.1-kb HBV in a classic miRNA biogenesis (Drosha-Dicer-dependent) manner. HBV-miR-3 was highly expressed in hepatoma cell lines with an integrated HBV genome and HBV+ hepatoma tumors. In patients with HBV infection, HBV-miR-3 was released into the circulation by exosomes and HBV virions, and HBV-miR-3 expression had a positive correlation with HBV titers in the sera of patients in the acute phase of HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg, and replication of HBV. HBV-miR-3 targets the unique site of the HBV 3.5-kb transcript to specifically reduce HBc protein expression, levels of pregenomic RNA (pgRNA), and HBV replication intermediate (HBV-RI) generation but does not affect the HBV DNA polymerase level, thus suppressing HBV virion production (replication). This may explain the low levels of HBV virion generation with abundant subviral particles lacking core during HBV replication, which may contribute to the development of persistent infection in patients. Taken together, our findings shed light on novel mechanisms by which HBV-encoded miRNA controls the process of self-replication by regulating HBV transcript during infection.

IMPORTANCE Hepatitis B is a liver infection caused by the hepatitis B virus (HBV) that can become a long-term, chronic infection and lead to cirrhosis or liver cancer. HBV is a small DNA virus that belongs to the hepadnavirus family, with virions and subviral forms of particles that lack a core. MicroRNA (miRNA), a small (∼22-nt) noncoding RNA, was recently found to be an important regulator of gene expression. We found that HBV encodes miRNA (HBV-miR-3). More importantly, we revealed that HBV-miR-3 targets its transcripts to attenuate HBV replication. This may contribute to explaining how HBV infection leads to mild damage in liver cells and the subsequent establishment/maintenance of persistent infection. Our findings highlight a mechanism by which HBV-encoded miRNA controls the process of self-replication by regulating the virus itself during infection and might provide new biomarkers for diagnosis and treatment of hepatitis B.
KEYWORDS

    miRNA hepatitis B virus pgRNA HBc

FOOTNOTES

        Received 22 September 2016.
        Accepted 23 January 2017.
        Accepted manuscript posted online 1 February 2017.
    Address correspondence to Hua Tang, htang2002{at}yahoo.com.

    Citation Yang X, Li H, Sun H, Fan H, Hu Y, Liu M, Li X, Tang H. 2017. Hepatitis B virus-encoded microRNA controls viral replication. J Virol 91:e01919-16. https://doi.org/10.1128/JVI.01919-16.


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才高八斗

发表于 2017-4-29 19:13 |显示全部帖子
乙型肝炎病毒编码的微RNA控制病毒复制

    西洋,李红凤,胡辉辉,红霞,胡雅琪,刘敏,新李,华唐

    天津医科大学基础医学院天津生命科学研究中心,病原生物学系,天津

    J.-H.詹姆斯·奥,编辑

    南加州大学

抽象

微小RNA(miRNA)是一类小型,单链,非编码的功能性RNA。乙型肝炎病毒(HBV)是具有病毒粒子和亚病毒形式的颗粒缺乏核心的包膜DNA病毒。不知道HBV是否编码miRNA。在这里,我们通过深度测序和Northern印迹鉴定了HBV编码的miRNA(称为HBV-miR-3)。 HBV-miR-3位于HBV基因组的核苷酸(nt)373至393处,并以经典的miRNA生物发生(Drosha-Dicer依赖)方式从3.5kb,2.4kb和2.1kb的HBV产生。 HBV-miR-3在具有综合HBV基因组和HBV +肝癌肿瘤的肝癌细胞系中高度表达。在HBV感染患者中,HBV-miR-3通过外来体和HBV病毒体释放到循环中,HBV-miR-3表达与HBV感染急性期患者血清HBV滴度呈正相关。更有趣的是,我们发现HBV-miR-3抑制HBsAg,HBeAg和HBV复制。 HBV-miR-3靶向HBV 3.5-kb转录本的独特位点,以特异性降低HBc蛋白表达,前基因组RNA(pgRNA)水平和HBV复制中间体(HBV-RI)产生水平,但不影响HBV DNA聚合酶水平,从而抑制HBV病毒体的产生(复制)。这可能解释HBV复制过程中缺乏核心的亚型病毒颗粒较多的HBV病毒粒子生成水平较低,这可能有助于患者持续感染的发展。综合起来,我们的研究结果揭示了HBV编码的miRNA通过调控HBV转录本在感染期间控制自我复制过程的新机制。

重要性乙型肝炎是由乙型肝炎病毒(HBV)引起的肝脏感染,可能会导致长期慢性感染并导致肝硬化或肝癌。 HBV是属于肝炎病毒科的小型DNA病毒,具有病毒粒子和亚病毒形式的颗粒缺乏核心。最近发现微小RNA(miRNA)是小(〜22 -nt)非编码RNA,是基因表达的重要调节因子。我们发现HBV编码miRNA(HBV-miR-3)。更重要的是,我们发现HBV-miR-3靶向其转录物以减弱HBV复制。这可能有助于解释HBV感染如何导致肝细胞轻度损伤以及随后的持续感染的建立/维持。我们的研究结果突出了HBV编码的miRNA通过在感染期间调节病毒本身来控制自我复制过程的机制,并且可能为乙型肝炎的诊断和治疗提供新的生物标志物。
关键词

    miRNA乙肝病毒pgRNA HBc



        收到2016年9月22日
        于2017年1月23日接受。
        接受稿在2017年2月1日发布。
    地址与华唐通讯,htang2002 {at} yahoo.com。

    引文Yang X,Li H,Sun H,Fan H,Hu Y,Liu M,Li X,Tang H. 2017.乙型肝炎病毒编码的microRNA控制病毒复制。 J Virol 91:e01919-16。 https://doi.org/10.1128/JVI.01919-16
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