Publication date: Jun 18, 2025

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.

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