乙型肝炎病毒编码的miRNA控制病毒复制

StephenW

J Virol. 2017 Feb 1. pii: JVI.01919-16. doi: 10.1128/JVI.01919-16. [Epub ahead of print]
Hepatitis B virus-encoded miRNA controls viral replication.Yang X1, Li H1, Sun H1, Fan H1, Hu Y1, Liu M1, Li X1, Tang H2.
Author information

• 1Tianjin Life Science Research Center and Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
• 2Tianjin Life Science Research Center and Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China [email protected] [email protected].
  

AbstractmicroRNAs (miRNAs) are a class of small single-stranded non-coding 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 blot. HBV-miR-3 is located at nts 373-393 of the HBV genome and was generated from 3.5Kb, 2,4Kb and 2.1Kb HBV in 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 to circulation by exosome and HBV viron, and HBV-miR-3 expression was a positive correlation with HBV titers in the serum in the acute phase of patients with HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg and replication of HBV. HBV-miR-3 represses HBV replication by targeting the region of HBV 3.5 kb mRNA encoding HBV core protein (HBc) to reduce HBc protein and HBV pregenomic RNA (pgRNA), which in turn led to attenuate HBV replication. Overall, these results indicate that HBV encodes miRNA which may provide new potential biomarkers for clinical HBV infection and shed lights on a new mechanism of HBV replication regulation by which HBV-encoded miRNAs control self-replication via targeting viral transcripts.
IMPORTANCE: Hepatitis B is a liver infection caused by the hepatitis B virus (HBV), which can become a long-term, chronic infection and lead to cirrhosis or liver cancer. Hepatitis B virus (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) non-coding RNA, is 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 itself transcripts to attenuate HBV replication. This may contribute to explain that HBV infection leads to mild damage in live cells and the subsequent establishment/maintenance of its 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 diagnostic and treatment of hepatitis B.

Copyright © 2017 American Society for Microbiology.

PMID:28148795DOI:10.1128/JVI.01919-16
[PubMed - as supplied by publisher]

StephenW

J Virol。 2017 Feb 1. pii：JVI.01919-16。 doi：10.1128 / JVI.01919-16。 [打印前的电子版]
乙型肝炎病毒编码的miRNA控制病毒复制。
Yang X1，Li H1，Sun H1，Fan H1，Hu Y1，Liu M1，Li X1，Tang H2。
作者信息

    天津医科大学基础医学院天津生命科学研究中心和病原生物学系，天津300070。
    天津医科大学基础医学院天津生命科学研究中心和病原生物学系，天津300070 [email protected] [email protected]。

抽象

微小RNA（miRNA）是一类小单链非编码功能性RNA。乙型肝炎病毒（HBV）是具有病毒粒子和缺少核心的亚病毒形式的颗粒的包膜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nts 373-393，并且由经典miRNA生物发生（Drosha-Dicer依赖）方式中的3.5Kb，2,4Kb和2.1Kb HBV产生。 HBV-miR-3在具有整合的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 viron释放到循环中，HBV-miR-3的表达与HBV感染急性期血清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的复制。 HBV-miR-3通过靶向编码HBV核心蛋白（HBc）的HBV 3.5kb mRNA区域以减少HBc蛋白和HBV前基因组RNA（pgRNA）来抑制HBV复制，这又导致HBV复制减弱。总体而言，这些结果表明，HBV编码miRNA，其可以为临床HBV感染提供新的潜在生物标志物，并阐明HBV复制调节的新机制，HBV编码的miRNA通过靶向病毒转录物控制自我复制。
重要性：

乙型肝炎是由乙型肝炎病毒（HBV）引起的肝脏感染，其可以成为长期的慢性感染并导致肝硬化或肝癌。乙型肝炎病毒（HBV）是属于肝炎病毒家族的小DNA病毒，具有缺少核心的病毒粒子和亚病毒形式的颗粒。最近发现微小RNA（miRNA）（一种小（〜22nt）非编码RNA）是基因表达的重要调节剂。我们发现HBV编码miRNA（HBV-miR-3）。更重要的是，我们揭示HBV-miR-3靶向本身转录本以减弱HBV复制。这可能有助于解释HBV感染导致活细胞轻度损伤和随后建立/维持其持续感染。我们的研究结果突出了一种机制，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，并且可能为乙型肝炎的诊断和治疗提供新的生物标志物。

版权所有©2017美国微生物学会。

PMID：
    28148795
DOI：
    10.1128 / JVI.01919-16