Viral pathogenesis is a complex event and its regulation involve dynamic interactions with various host factors, of which microRNAs are the key players. In the current study, we have identified the functional importance of an interplay between hepatitis E virus (HEV) and miR-214. Computational analysis indicated that miR-214 binding site is significantly conserved among HEV and related RNA viruses. Intact miR-214 binding site is imperative for HEV replication. miR-214 is an essential host factor for HEV replication. Herein, we demonstrate that miR-214 interacts directly with HEV RNA to enhance HEV replication and HEV genome translation. Augmented translation results in increased levels of HEV ORF2, which is a factor responsible for upregulation of miR-214. HEV usurps host cellular machinery for improving viral fitness and elevates miR-214 expression for amplifying the expression of proviral host factor intracellular active thrombin. This is because miR-214 represses the expression of the negative regulator of thrombin, i.e., protein C. Another viral factor, HEV ORF3, also contributes to the enhancement of intracellular active thrombin. Furthermore, miR-214 directly targets antiviral host factor 2′–5′-oligoadenylate synthetase. Conclusively, we identified a novel mechanism of positive regulation of HEV replication. miR-214 interacts directly with HEV genome and fine-tunes host factors expression. This results in outweighing the proviral factors on the proviral–antiviral axis probably for generating virus supportive environment.

病毒发病机制是一个复杂的事件，其调控涉及与各种宿主因素的动态相互作用，其中微小RNA是关键因素。在当前的研究中，我们已经确定了戊型肝炎病毒（HEV）与miR-214之间相互作用的功能重要性。计算分析表明，miR-214结合位点在戊型肝炎病毒和相关RNA病毒之间是显着保守的。完整的miR-214结合位点对于HEV复制至关重要。miR-214是HEV复制的重要宿主因子。在本文中，我们证明了miR-214与HEV RNA直接相互作用以增强HEV复制和HEV基因组翻译。增强的翻译导致HEV ORF2水平升高，这是导致miR-214上调的因素。HEV篡改宿主细胞机制以改善病毒适应性，并升高miR-214表达以放大前病毒宿主因子细胞内活性凝血酶的表达。这是因为miR-214抑制凝血酶负调节剂（即蛋白C）的表达。另一种病毒因子HEV ORF3也有助于增强细胞内活性凝血酶。此外，miR-214直接靶向抗病毒宿主因子2'-5'-寡腺苷酸合成酶。最终，我们确定了HEV复制积极调控的新机制。miR-214与HEV基因组直接相互作用，并微调宿主因子的表达。这导致在前病毒-抗病毒轴上超过了前病毒因素，可能会产生病毒支持环境。