In the intricate battlefield of viral infections, microRNAs (miRNAs) have emerged as pivotal regulators orchestrating immune responses. A recent comprehensive review sheds light on the profound roles of miRNAs in modulating immunity across four major viral pathogens: SARS-CoV-2, Hepatitis B virus (HBV), Human Immunodeficiency Virus (HIV), and Herpes Simplex Virus (HSV). By synthesizing insights from over one hundred studies, researchers have outlined how these small RNAs intricately interface with key signalling pathways, modulating viral replication, immune activation, and infection persistence.
At the heart of miRNA-mediated immunoregulation lies a dynamic interplay with central immune signalling cascades, notably the NF-κB, MAPK, JAK-STAT, and TGF-β/Smad pathways. Viral proteins, alongside host-produced cytokines, trigger these pathways through pattern recognition receptors (PRRs) that form the frontline detection system against invading pathogens. These cascades transduce signals essential for immune cell activation and cytokine secretion, but miRNAs fine-tune these responses by differentially targeting nodes within these pathways, ensuring an immune balance that can either favor viral clearance or promote chronic infection.
The NF-κB pathway, activated by viral components like the SARS-CoV-2 spike protein, HIV Tat and Nef, HBV X protein, and HSV glycoprotein B, is subject to nuanced regulation by miRNAs. This pathway’s activation amplifies inflammatory signals upon recognition of pathogens via PRRs such as Toll-like receptor 4 (TLR4). Studies highlight miR-155 and miR-30e-5p as positive regulators enhancing NF-κB signalling, while miR-21, miR-146a, and its isoform miR-146a-5p serve as negative feedback modulators curbing excessive inflammation. Interestingly, HSV-specific host miRNAs exhibit context-dependent influences, demonstrating the complexity of miRNA function during infection.
Parallel to NF-κB control, the IL-1 receptor-mediated MAPK cascade undergoes regulation by diverse miRNAs targeting upstream kinases and adaptor proteins. miR-146a suppresses IRAK1 and TRAF6, thereby attenuating the IL-1R-MyD88-dependent MAP3K activation, which otherwise leads to the phosphorylation of p38 MAPK and the subsequent activation of the AP-1 transcription factor complex (Fos/Jun). Contrastingly, miR-16-2-3p and miR-618 bolster p38 phosphorylation, enhancing AP-1-driven pro-inflammatory gene expression, with miR-939 further promoting IL-8 transcription. Thus, miRNA networks modulate the fine balance between pro- and anti-inflammatory signals pivotal in viral pathogenesis.
The receptor tyrosine kinase (RTK)-MAPK pathway, which processes signals from growth factors and viral proteins such as HIV gp120 and HBV X protein, is tightly modulated by miRNAs influencing intracellular signal relay. miR-93 targets the adaptor protein GRB2, diminishing RTK-induced MAPK activation, whereas miR-1246 amplifies ERK signalling leading to increased cytokine production. Moreover, miR-212-3p directly represses MAPK1/ERK, attenuating HBV envelope antigen (HBeAg)-induced inflammatory cytokine secretion. These divergent miRNA effects highlight virus-specific exploitation of this pathway to modify host immune responses.
Central to regulating immune suppression, fibrosis, and cell cycle control is the TGF-β/SMAD pathway, modulated by both viral and host miRNAs. HSV-encoded miRNAs such as miR-H2, miR-H3, and miR-H4 target SMAD3/4 proteins, effectively disrupting the nuclear complex essential for downstream gene regulation. Host-derived miR-145 also negatively regulates SMAD3, reflecting a convergence of viral and host miRNAs in immune modulation. Additionally, miR-369-3p influences T-cell receptor (TCR), Notch, and IL-4 signalling during HSV infection, thus altering T-cell polarization and immune outcome.
The JAK-STAT pathway is a principal mediator of interferon and cytokine signalling, critical for antiviral defense. Its responsiveness is fine-tuned by a spectrum of miRNAs: inhibitory miR-150-5p tempers signalling amplitude, while activating miRNAs such as HBV-miR-3, miR-7, and miR-18a enhance pathway activity. Notably, SARS-CoV-2 encodes miRNAs capable of robustly suppressing the JAK-STAT axis, facilitating immune evasion and viral survival. This opposing regulation exemplifies the adaptive complexity of viral miRNA strategies versus host defenses.
Despite these distinct viruses differing in tropism and life cycles, a subset of miRNAs—miR-21, miR-146a, miR-150, and miR-155—consistently emerges as a conserved core in regulating immune responses. These miRNAs orchestrate cytokine production, immune cell differentiation, and antiviral mechanisms by targeting shared transcriptional regulators. Yet, the downstream cellular effects vary: HIV predominantly involves T-cell regulation, HBV modulates antigen processing and natural killer (NK) cell cytotoxicity, HSV impacts NK-cell activity and T-cell polarization, while SARS-CoV-2 primarily alters type I interferon responses. Such differential targeting underscores a shared molecular strategy employed by diverse viruses through distinct immunological routes.
The interface of viral-encoded and host-derived miRNAs reveals a sophisticated regulatory layer often underappreciated. Viral miRNAs can compete with host miRNAs for binding sites, act as competitive endogenous RNA (ceRNA) sponges, or co-target immune-related genes, subtly tuning infection progression. In HSV-1, latent-associated transcript (LAT)-encoded miRNAs like miR-H2 antagonize host miR-155, dampening inflammation and favoring viral latency. Similarly, HBV’s HBV-miR-3 modulates both viral replication and host pathways, sustaining chronic infection states. These interactions highlight viral evolution in exploiting miRNA biology to balance immune evasion and coexistence.
Crucially, miRNA-mediated regulation exhibits marked cell-type specificity and temporal dynamics. A single miRNA may impose divergent effects depending on the immune cell subset and infection phase. For example, miR-146a-5p attenuates NF-κB activation in macrophages, reducing inflammation, whereas miR-146a-3p promotes pro-inflammatory functions in other immune cells. Likewise, miR-150-5p typically undergoes early downregulation to enhance antiviral responses, followed by normalization facilitating inflammation resolution. These spatiotemporal differences reflect intricate control at transcriptional, cytokine feedback, and epigenetic levels, challenging therapeutic exploitation but offering nuanced intervention points.
The clinical potential of miRNAs extends beyond mechanistic insight; circulating miRNAs represent stable, accessible biomarkers reflecting immune activation status, viral load, and therapeutic responses. Such miRNAs hold promise in diagnostic and prognostic applications, facilitating personalized medicine approaches during viral infections. On the therapeutic front, strategies to inhibit pro-inflammatory miRNAs via antagomirs or enhance anti-inflammatory ones with mimics and extracellular vesicle (EV)-based delivery systems are gaining traction to restore immune homeostasis and limit pathology.
Further, viral miRNAs themselves constitute attractive therapeutic targets or vaccine adjuncts. Their roles in latency, immune modulation, and viral persistence underscore their significance. Targeting viral miRNAs could disrupt infection maintenance while boosting host immunity. Conversely, using viral miRNAs as adjuvants may refine vaccine efficacy by modulating host immune responses in beneficial ways.
Despite these advances, several challenges persist. The context-dependent nature of miRNA regulation demands precise characterization across immune cell types and infection stages. Additionally, interplay with other non-coding RNAs and cellular factors warrants deeper investigation. Comprehensive experimental approaches integrating transcriptomics, proteomics, and functional assays will be crucial to untangle these layers and guide translational applications.
Ultimately, the convergence of diverse viruses on a limited set of immune signalling nodes via miRNA-mediated mechanisms provides a unifying conceptual framework. This paradigm not only enhances our understanding of viral pathogenesis but also illuminates pathways ripe for targeted interventions. Efforts accelerating miRNA research promise to unlock novel diagnostics and therapeutics, transforming the clinical management of viral infections with global health implications.
Subject of Research: miRNA-mediated immunoregulation in viral infections, focusing on SARS-CoV-2, HBV, HIV, and HSV.
Article Title: Decoding miRNA-Mediated Immunoregulation in SARS-CoV-2, HBV, HIV, and HSV Infections.
Article References:
Arziman, S., Aydemir, S., & Bozok, V. Decoding miRNA-Mediated Immunoregulation in SARS-CoV-2, HBV, HIV, and HSV Infections. Genes Immun (2026). https://doi.org/10.1038/s41435-026-00376-4
Image Credits: AI Generated
DOI: 10.1038/s41435-026-00376-4
Keywords: microRNA, immunoregulation, SARS-CoV-2, HBV, HIV, HSV, NF-κB, MAPK, JAK-STAT, TGF-β/Smad, viral miRNAs, immune evasion, antiviral responses.
