Herpesvirus infection and antiviral treatment: a Nationwide Study Exploring Epidemiological Links Between Viral Infections and Immune-Mediated Neurodegenerative Diseases

Background: Herpesvirus infections have been suggested as triggers for neurodegenerative and autoimmune diseases. We examined associations between herpesvirus infections, antiviral use, and HIV with subsequent risk of multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and systemic lupus erythematosus (SLE). Methods: Using Danish national health registry data from 1995–2018, we conducted a cohort study of 48,897 individuals with herpesvirus infections (Herpes Simplex Virus type 1 or 2, Epstein–Barr virus, Cytomegalovirus) or HIV, and 546,890 matched controls. Diagnoses of MS, ALS, or SLE ≥5 years after infection were primary outcomes. Risk estimates were calculated with absolute risk regression, adjusting for competing risks. Results: Prior herpesvirus infection was associated with increased 20-year cumulative incidence of MS (~0.5% vs ~0.2%), with the strongest effect for Epstein–Barr virus. Herpes simplex virus was linked to a modest rise in MS, while Cytomegalovirus showed no association. No link was found with ALS, and only a small increase was observed for SLE. Higher antiviral use correlated with increased MS and SLE risk, likely reflecting confounding by indication. HIV-positive individuals on long-term antiretroviral therapy had lower incidence of MS, ALS, and SLE compared with controls, suggesting that studies of a potential protective effect are warranted. Conclusion: This nationwide study supports Epstein–Barr virus as a major risk factor for MS, while ALS and SLE involve distinct mechanisms. Patterns of antiviral use indicate underlying immune dysfunction, and modulation of viral latency may represent a preventive or therapeutic avenue in MS.