State Key Laboratory of Virology and College of Life Sciences, Wuhan Institutes of Biotechnology, Chinese-French Liver Disease Research Institute at Zhongnan Hospital, Wuhan University, Wuhan, China.
FASEB J. 2011 Dec;25(12):4511-21. doi: 10.1096/fj.11-187781. Epub 2011 Sep 8.
Regulated gene expression and progeny production are essential for persistent and chronic infection by human pathogens, such as hepatitis B virus (HBV), which affects >400 million people worldwide and is a major cause of liver disease. In this study, we provide the first direct evidence that a liver-specific microRNA, miR-122, binds to a highly conserved HBV pregenomic RNA sequence via base-pairing interactions and inhibits HBV gene expression and replication. The miR-122 target sequence is located at the coding region of the mRNA for the viral polymerase and the 3' untranslated region of the mRNA for the core protein. In cultured cells, HBV gene expression and replication reduces with increased expression of miR-122, and the expression of miR-122 decreases in the presence of HBV infection and replication. Furthermore, analyses of clinical samples demonstrated an inverse linear correlation in vivo between the miR-122 level and the viral loads in the peripheral blood mononuclear cells of HBV-positive patients. Our results suggest that miR-122 may down-regulate HBV replication by binding to the viral target sequence, contributing to the persistent/chronic infection of HBV, and that HBV-induced modulation of miR-122 expression may represent a mechanism to facilitate viral pathogenesis.
调控基因表达和后代产生对于乙型肝炎病毒（HBV）等人类病原体的持续和慢性感染至关重要，HBV 影响着全球超过 4 亿人，是肝脏疾病的主要病因。在本研究中，我们首次提供了直接证据，表明一种肝脏特异性 microRNA，miR-122，通过碱基配对相互作用与高度保守的 HBV 前基因组 RNA 序列结合，从而抑制 HBV 基因表达和复制。miR-122 的靶序列位于病毒聚合酶 mRNA 的编码区和核心蛋白 mRNA 的 3'非翻译区。在培养的细胞中，随着 miR-122 表达的增加，HBV 基因表达和复制减少，而在 HBV 感染和复制存在的情况下，miR-122 的表达降低。此外，对临床样本的分析表明，在 HBV 阳性患者的外周血单核细胞中，miR-122 水平与病毒载量之间存在体内呈负线性相关。我们的研究结果表明，miR-122 可能通过与病毒靶序列结合来下调 HBV 复制，从而导致 HBV 的持续/慢性感染，而 HBV 诱导的 miR-122 表达的调节可能代表了促进病毒发病机制的一种机制。
