Epigenetic regulation of varicella-zoster virus infection: a systematic synthesis of mechanisms

Background: Herpes zoster (HZ), resulting from varicella-zoster virus (VZV) reactivation, imposes a significant and growing public health burden, especially among aging populations. Viral epigenetics is crucial for understanding viral persistence and reactivation, yet its role in VZV pathogenesis, particularly its interplay with immunity, requires systematic synthesis. Methods: We conducted a comprehensive bibliometric analysis (n = 3,294 publications) to map the viral epigenetics research landscape. We then systematically characterized the dynamic immune-epigenetic interactions throughout the VZV lifecycle (primary infection, latency, reactivation), focusing on tissue-specific mechanisms (skin, neurons) and analyzing how VZV exploits host epigenetic machinery. Results: Bibliometric analysis revealed a critical gap: herpesviruses receive disproportionately low epigenetic research focus (0.3% of viral epigenetics publications), with only 1.46% of studies being clinical. Immune-related mechanisms dominate recent viral epigenetics research. Our analysis demonstrates that VZV hijacks host epigenetic processes (transcriptional modulation, DNA methylation, histone remodeling) to establish latency, reactivate, and evade immune detection. Crucially, we identify a bidirectional regulatory network: epigenetic modifications directly influence immune signaling pathways (e.g., IFN response, T-cell function), while immune mediators conversely shape the host epigenetic landscape, collectively determining viral pathogenesis and host defense outcomes. Conclusion: This review elucidates the intricate, reciprocal crosstalk between epigenetic regulation and immune responses in VZV infection. Our findings highlight the understudied nature of VZV epigenetics despite its clinical significance and reveal key nodes within the immune-epigenetic network as promising, clinically actionable therapeutic targets for improving HZ management. This synthesis provides a crucial translational framework for developing epigenetically informed interventions to control viral reactivation and mitigate disease burden.