Risk of a first clinical diagnosis of central nervous system demyelination in relation to human herpesviruses in the context of Epstein–Barr virus

Abstract

Background and purpose Epstein–Barr virus (EBV) is implicated in multiple sclerosis (MS) risk; evidence for other herpesviruses is inconsistent. Here, we test blood markers of infection with human herpesvirus 6 (HHV‐6), varicella zoster virus (VZV), and cytomegalovirus (CMV) as risk factors for a first clinical diagnosis of central nervous system demyelination (FCD) in the context of markers of EBV infection. Methods In the Ausimmune case–control study, cases had an FCD, and population controls were matched on age, sex, and study region. We quantified HHV‐6‐ and VZV‐DNA load in whole blood and HHV‐6, VZV, and CMV antibodies in serum. Conditional logistic regression tested associations with FCD risk, adjusting for Epstein–Barr nuclear antigen (EBNA) IgG, EBV‐DNA load, and other covariates. Results In 204 FCD cases and 215 matched controls, only HHV‐6‐DNA load (positive vs. negative) was associated with FCD risk (adjusted odds ratio = 2.20, 95% confidence interval = 1.08–4.46, p = 0.03). Only EBNA IgG and HHV‐6‐DNA positivity were retained in a predictive model of FCD risk; the combination had a stronger association than either alone. CMV‐specific IgG concentration modified the association between an MS risk‐related human leucocyte antigen gene and FCD risk. Six cases and one control had very high HHV‐6‐DNA load (>1.0 × 106 copies/mL). Conclusions HHV‐6‐DNA positivity and high load (possibly due to inherited HHV‐6 chromosomal integration) were associated with increased FCD risk, particularly in association with markers of EBV infection. With growing interest in prevention/management of MS through EBV‐related pathways, there should be additional consideration of the role of HHV‐6 infection.

Cytomegalovirus, Epstein-Barr Virus, Herpes Simplex Virus, and Varicella Zoster Virus Infection Dynamics in People with Multiple Sclerosis from Northern Italy

“…VZV infection may be associated with the development of MS particularly in non-European regions with different virus transmission characteristics [ 52 ]. There is strong evidence [ 7 , 53 ] that another human herpesvirus—HHV6A—is also associated with the development of MS. We plan to investigate this association in a separate study. The events that combine for MS to develop may occur many years before the appearance of disease.…”

Mendelian randomization analysis suggests no associations of human herpes viruses with amyotrophic lateral sclerosis

“…CMV can exhibit tropism for neural stem cells and cause multiple spinal cord radiculitis ( Kleinschmidt-DeMasters and Gilden, 2001 ; Kamte et al, 2021 ). The viral load of HHV-6 is associated with increased central nervous system demyelination ( Lucas et al, 2023 ). The damage to the CNS system by HHV-7 has also been reported ( Li et al, 2022 ).…”