Epstein–Barr Virus, Varicella-Zoster Virus, and Multiple Sclerosis: A Mechanistic Hypothesis

Abstract

Epstein–Barr virus (EBV), a major risk factor for multiple sclerosis (MS), cannot alone explain MS susceptibility or characteristic central nervous system (CNS) lesion patterns. Here, a two-hit mechanism is proposed whereby prior infection with a high-risk varicella-zoster virus (VZV) subgroup, potentially including clade 3, establishes susceptibility, with later primary EBV infection triggering MS. The model proposes an indirect VZV–EBV interaction within an oral–oropharyngeal epithelial/B-cell environment where epithelial cells and EBV-infected B cells lie near terminals of sensory neurons harboring latent VZV. There, EBV-induced changes in antiviral and inflammatory tone may generate signals that travel along sensory axons to their cell bodies, lowering the threshold for restricted or abortive VZV activity without shingles. A hypothetical heterogeneous extracellular output may include IE62-positive small extracellular vesicles, L-particles or other incomplete viral particles, DNA-containing material, late structural proteins, and infectious VZV, with relative abundance unknown. These outputs may enter cerebrospinal fluid (CSF), travel through CSF pathways to CNS-border compartments, and initiate inflammation in the brain and spinal cord. Rather than requiring widespread or sustained productive CNS infection, VZV-derived extracellular material and induced inflammatory signals may act beyond MRI-visible lesions and promote injury at perivenular or CNS-border sites supporting antigen capture and immune-cell recruitment. The model predicts relapse-associated enrichment of VZV-derived extracellular material, potentially marked by IE62, in saliva, CSF, cranial sensory pathways, and CSF-facing compartments. If validated, the model predicts that childhood varicella and EBV vaccination could prevent MS and identifies VZV latency and extracellular-output-mediated inflammation as potential therapeutic targets.