Unveiling the Role of Human Endogenous Retroviruses in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) and a leading cause of neurological disability in young adults. The etiology of MS is complex, involving both genetic and environmental factors. Among these, viral infections, particularly those involving human endogenous retroviruses (HERVs), have been implicated in the pathogenesis of MS.

HERVs are ancient viral elements integrated into the human genome millions of years ago. They constitute about 8% of the human genome and are classified into multiple families, including HERV-W, HERV-H, and HERV-K. Although most HERVs are defective and cannot produce infectious particles, their reactivation has been associated with various diseases, including MS.

This study aim to evaluate the association between the expression of different HERV families and MS. Specifically, it focuses on the HERV-W family, known for its member MS-associated retrovirus (MSRV).

The review followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. A comprehensive search of Medline, Embase, and the Cochrane Library was conducted to identify studies examining the association between HERV expression and MS. The inclusion criteria were case-control studies reporting on the expression of HERV proteins or nucleic acids in any tissue from MS patients and controls.

A total of 43 studies were included in the review, with 25 focusing on HERV-W, 13 on HERV-H, 9 on HERV-K, and a few on other HERV families. Meta-analysis was performed for the HERV-W family, particularly examining MSRV/HERV-W expression in peripheral blood mononuclear cells (PBMCs), serum/plasma, and cerebrospinal fluid (CSF).

HERV-W in Peripheral Blood: Four studies examined MSRV/HERV-W env RNA in PBMCs. The meta-analysis revealed a strong association with an odds ratio (OR) of 22.66 (95% CI: 6.32–81.20), indicating significantly higher expression in MS patients compared to healthy controls.
HERV-W in Serum/Plasma: Six studies investigated MSRV/HERV-W pol RNA in serum/plasma, showing an OR of 44.11 (95% CI: 12.95–150.30), further supporting the association with MS.
HERV-W in CSF: Four studies analyzed MSRV/HERV-W pol RNA in CSF, resulting in an OR of 6.00 (95% CI: 3.35–10.74), indicating elevated expression in MS patients compared to controls with other neurological diseases.

The review underscores a strong association between HERV-W expression and MS. The mechanisms underlying this association are not fully understood, but it is hypothesized that MSRV/HERV-W env protein can activate the immune system through Toll-like receptor 4 (TLR4), leading to the production of pro-inflammatory cytokines and potentially contributing to MS pathogenesis. Additionally, MSRV/HERV-W may be reactivated by other viral infections, such as Epstein-Barr virus (EBV), which is a known risk factor for MS.

Conclusion
This study provide robust evidence for the association between HERV expression, particularly HERV-W, and MS. Further research is needed to elucidate the pathogenic mechanisms and potential therapeutic targets involving HERVs in MS.

References
Morandi, E., Tanasescu, R., Tarlinton, R. E., Constantinescu, C. S., Zhang, W., Tench, C., & Gran, B. (2017). The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis. PloS one, 12(2), e0172415.