Viral associations in multiple sclerosis: pathogenetic mechanisms and therapeutic implications

Multiple sclerosis (MS) is a neurological inflammatory disease with a complex etiology involving the dysregulated immune system, chronic inflammation, and genetic susceptibility. Although the precise cause of MS is unknown, previous studies have found a strong link between MS and certain viral infections, leading researchers to speculate that viruses may play a role in MS pathogenesis by acting as environmental triggers. We present a comprehensive review of viral associations with MS, focusing on viruses with strong evidence for involvement in disease development, including members of the Herpesviridae family-such as Epstein-Barr virus, human herpesvirus 6, varicella-zoster virus, herpes simplex virus 1, cytomegalovirus, and SARS-CoV-2. Those viruses appear to modulate the neuro-immunological system in genetically susceptible individuals, leading to immune-mediated demyelination. Viral exposure is thought to represent an early initiating or permissive event that triggers downstream immune dysregulation, ultimately leading to MS onset in predisposed hosts. Additionally, they can cause latent infections with episodes of reactivation, which might be associated with relapsing presentation of MS. Several theories have been proposed to explain the viral etiology of MS, including molecular mimicry, virus-induced inflammatory response, autoreactive T- and B-cell activation, and increased susceptibility to antigenic exposure. Besides addressing the current knowledge gap, we also highlight future research directions for effective MS management, including developing experimental models and conducting clinical trials, identifying specific biomarkers, and investigating novel antiviral agents. An improved understanding of MS etiology and the role of viruses in its physiopathology may enable more targeted interventions and better treatment outcomes.