Herpes viral infection and the multiple sclerosis prodrome: is HHV-6A infection a second hit? 2024

Establishing whether this two-step process occurs will require acquisition of serial serum samples from a large group of pre-symptomatic individuals. The Department of Defense Serum Repository, which was used to identify EBV as a risk factor, could also potentially be used to understand and confirm the role of HHV-6A. Using this repository, an auto-antibody motif common in human peptides that is also present in viral pathogens was recently identified from samples obtained during the multiple sclerosis prodrome and was also detected in a cohort of participants with relapsing multiple sclerosis within 90 days of symptom onset.10 That two EBV proteins—BRRF2 and envelope glycoprotein M—share homology with this motif suggests that reactivity against these viral epitopes could trigger autoreactivity against human peptides with similar sequences.

Identification of CSF antibodies that recognize HHV-6A peptides and cross react with human CNS peptides would add credence to a potential role for HHV-6A in molecular mimicry. PCR studies are needed to determine whether HHV-6A DNA can be detected in the saliva, peripheral blood mononuclear cells or CSF of newly diagnosed patients relative to well matched unaffected controls to provide evidence for a role of active HHV-6A infection in multiple sclerosis. At present, vaccinations against EBV and HHV-6A are not commercially available. However, should such vaccines become available, individuals who are at high risk for developing multiple sclerosis could become early beneficiaries of a primary prevention strategy.

https://academic.oup.com/brain/article/147/1/7/7477816

 

Commentary on —

Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis
Grut, Viktor; Biström, Martin; Salzer, Jonatan; Stridh, Pernilla; Jons, Daniel; Gustafsson, Rasmus; Fogdell-Hahn, Anna; Huang, Jesse; Butt, Julia; Lindam, Anna; Alonso-Magdalena, Lucia; Bergström, Tomas; Kockum, Ingrid; Waterboer, Tim; Olsson, Tomas; Zetterberg, Henrik; Blennow, Kaj; Andersen, Oluf; Nilsson, Staffan; Sundström, Peter

Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of NfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A.

A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and NfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and NfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included.

In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis).

In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.

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