Powell Bonita H, Witwer Kenneth W, Meffert Mollie K
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Virol. 2025 Jul 22;99(7):e0091425. doi: 10.1128/jvi.00914-25. Epub 2025 Jun 18.
Altered gene regulation downstream of infection has been linked to devastating cancers and neurological diseases, highlighting the importance of understanding viral:host gene interactions. Historically, approaches based on bioinformatic binding prediction showed that host microRNAs (miRNAs) can target and regulate viral genes to impact viral replication and pathogenesis. More recently, Argonaute cross-linking and immunoprecipitation (AGO-CLIP) and advancements incorporating a miRNA:target RNA ligation step (AGO-CLIP + ligation) enable a global view of miRNA interactions with target cellular and viral transcripts. These genome-wide approaches paired with RNA sequencing reveal that miRNA binding to viral transcripts can not only act conventionally to regulate viral replication but can also act to reduce miRNA targeting of host genes with resulting de-repression of host target genes and downstream biological impacts. Viruses with accumulated evidence of miRNA sequestration are selected as examples for review and include hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and respiratory syncytial virus (RSV). The significant impact of target de-repression on host cellular biology warrants a broader investigation of this mechanism. In this mini-review, we examine examples of crosstalk between host miRNAs and viral transcripts and highlight the advance and potential of analyses from AGO-CLIP + ligation with RNA-seq for expanding the identification of global miRNA:viral target interactions and interrogating the biological impacts of host miRNA sequestering and target de-repression. Host target de-repression by miRNA:viral target interactions could shed light on antiviral therapeutic candidates to aid in mitigating consequences such as malignancies and neurodegeneration.
感染下游的基因调控改变与毁灭性癌症和神经疾病有关，凸显了理解病毒与宿主基因相互作用的重要性。从历史上看，基于生物信息学结合预测的方法表明，宿主微小RNA（miRNA）可以靶向并调控病毒基因，从而影响病毒复制和发病机制。最近，AGO交联免疫沉淀法（AGO-CLIP）以及纳入miRNA与靶RNA连接步骤的改进方法（AGO-CLIP +连接），使人们能够全面了解miRNA与靶细胞和病毒转录本的相互作用。这些全基因组方法与RNA测序相结合，揭示了miRNA与病毒转录本的结合不仅可以按照传统方式调控病毒复制，还可以减少miRNA对宿主基因的靶向作用，从而导致宿主靶基因的去抑制以及下游生物学影响产生。积累了miRNA隔离证据的病毒被选作综述示例，包括丙型肝炎病毒（HCV）、严重急性呼吸综合征冠状病毒2（SARS-CoV-2）和呼吸道合胞病毒（RSV）。靶标去抑制对宿主细胞生物学的重大影响值得对这一机制进行更广泛的研究。在本综述中，我们研究了宿主miRNA与病毒转录本之间相互作用的例子，并强调了AGO-CLIP +连接与RNA测序分析在扩大对全局miRNA与病毒靶标相互作用的识别以及探究宿主miRNA隔离和靶标去抑制的生物学影响方面的进展和潜力。miRNA与病毒靶标相互作用导致的宿主靶标去抑制可能有助于揭示抗病毒治疗候选药物，以减轻诸如恶性肿瘤和神经退行性变等后果。
