From viral epigenetic reprogramming to neuroinflammation: Mechanisms driving neurodegeneration

: Viruses exploit host genetic machinery to establish chronic infections and contribute to chronic neurodegenerative and immune disorders. By manipulating DNA methylation, histone modifications, and non-coding RNA networks, viruses such as Epstein-Barr virus (EBV), Herpes Simplex virus (HSV), Zika virus (ZIKV), and Human immunodeficiency virus (HIV) induce epigenetic changes that silence or delay the host antiviral defenses and reprogram host gene expression. For instance, EBV recruits DNA methyltransferases (DNMTs) to hypermethylate genes such as SOCS1 while ZIKV disrupts neuronal DNA methylation via heterochromatinization. Concurrently, HIV-1 encoded Tat protein disrupts H3K27 acetylation in astrocytes that potently triggers glutamate excitotoxicity. Viruses also subvert the chromatin architecture to modulate 3D interactions and reader protein recruitment, thus rewiring transcriptional programs. Such epigenetic alterations correlate with neuropathologies wherein global hypomethylation and histone acetylation contribute to Alzheimer's or Parkinson's disease. Although several mechanisms are known, the field of viral control in neuroepigenetics is underexplored. Emerging therapies that target viral-host epigenetic crosstalk through DNMT or HDAC inhibitors are promising. This review highlights how neurotropic viruses co-opt epigenetic pathways to drive neurodegeneration. We also explore biomarker-driven strategies for personalized interventions in neurodegenerative disorders thus emphasizing potential epigenetic editing tools to restore neuronal homeostasis.