HSV-1 and VZV co-reactivation: implications for worsening neurological and neurodegenerative diseases

Herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) are neurotropic human alphaherpesviruses that establish lifelong latency in peripheral ganglia. While traditionally studied in isolation, increasing evidence indicates that co-reactivation of these viruses may be clinically significant, especially in the context of aging and immunosuppression, and underdiagnosed. Recent studies show that both viruses can reside in the same trigeminal ganglion (TG) and interact synergistically to potentiate and exacerbate neurological and neurodegenerative disease. This review summarizes emerging insights into the clinical, immunological, and neuropathological implications of HSV-1 and VZV co-reactivation, with a particular emphasis on VZV-derived extracellular vesicles (EVs) as mediators of immune suppression and enhancers of secondary HSV-1 infection.