Anna Sentmanat

Background: Multiple Sclerosis is a chronic demyelinating disease that affects over one million people in the United States.¹ It occurs through autoimmune mediated destruction of oligodendrocytes and myelin sheaths in the central nervous system.^1,2 The exact etiology of the disease is unknown, but research has implicated viral factors, such as herpesviruses, in its development.^2,3 Current treatment uses corticosteroids and monoclonal antibodies for broad based immune suppression, but further investigation into viral etiology could result in more specific therapeutic and preventative options.^1,4

Objective: In this narrative review, we explored the effect and mechanisms through which Human Herpesvirus 6 (HHV6) could contribute to MS development.

Search Methods: An online search in the PubMed database was conduction from 2018 to 2024 using the following keywords: “multiple sclerosis,” “human herpesvirus 6,” “mechanisms.”

Results: Studies indicate that the HHV6A serotype is associated with MS development in serum samples from individuals that went on to develop early onset relapsing-remitting MS.⁵ High levels of anti-HHV6A early protein IgG was found in serum as compared to controls.⁵ When studied in comparison to a known marker for axonal injury, sNfL, it was seen that anti-HHV6A IgG was increased along with sNfL in patients with early onset RR-MS.⁶ Timing of the increase predated the sNfL increase, indicating that HHV6A IgG can be used as a very early marker for the development of MS symptoms.⁶ The mechanism for HHV6A immune mediated destruction of CNS myelin sheaths was seen to involve the transactivation of human endogenous retroviruses (HERVs), which have been present in human genomes for centuries.⁷ Specific transactivation of multiple sclerosis associated retrovirus (MSRV) was seen to be increased in serum samples of MS patients with HHV6A antibodies.⁷ MSRV envelope proteins went on to initiate an inflammatory cascade using TLR4 pathways.⁸ Activation of SH2 and SH3 domains of the CD46 receptor due to HHV6A infection was seen to increase MSRV transactivation in susceptible cells, giving a potential mechanism and target for MS treatment specific to HHV6A.⁸

Conclusions: Studies have found that the presence of HHV6A IgG is associated with the development of RRMS. Further research into the mechanisms of HHV6A also implicates MSRV and CD46 in development of the chronic inflammation associated with MS pathology. Consideration of this pathway and the immune cells specific to it could lead to improved therapeutic and preventative measures, including virus specific antibodies and potential vaccines.

Works Cited:

1. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and Treatment of Multiple Sclerosis: A Review [published correction appears in JAMA. 2021 Jun 1;325(21):2211]. JAMA. 2021;325(8):765-779. doi:10.1001/jama.2020.26858
2. Tarlinton RE, Martynova E, Rizvanov AA, Khaiboullina S, Verma S. Role of Viruses in the Pathogenesis of Multiple Sclerosis. Viruses. 2020;12(6):643. Published 2020 Jun 13.
3. Meier UC, Cipian RC, Karimi A, Ramasamy R, Middeldorp JM. Cumulative Roles for Epstein-Barr Virus, Human Endogenous Retroviruses, and Human Herpes Virus-6 in Driving an Inflammatory Cascade Underlying MS Pathogenesis. Front Immunol. 2021;12:757302. Published 2021 Nov 1.
4. Pi KS, Sang Y, Straus SK. Viral Proteins with PxxP and PY Motifs May Play a Role in Multiple Sclerosis. Viruses. 2022;14(2):281. Published 2022 Jan 28.
5. Engdahl E, Gustafsson R, Huang J, et al. Increased Serological Response Against Human Herpesvirus 6A Is Associated with Risk for Multiple Sclerosis. Front Immunol. 2019;10:2715. Published 2019 Nov 26.
6. Grut V, Biström M, Salzer J, et al. Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis. Brain. 2024;147(1):177-185.
7. Pérez-Pérez S, Domínguez-Mozo MI, García-Martínez MÁ, et al. Anti-Human Herpesvirus 6 A/B Antibodies Titers Correlate With Multiple Sclerosis-Associated Retrovirus Envelope Expression. Front Immunol. 2021;12:798003. Published 2021 Nov 29.
8. Charvet B, Reynaud JM, Gourru-Lesimple G, Perron H, Marche PN, Horvat B. Induction of Proinflammatory Multiple Sclerosis-Associated Retrovirus Envelope Protein by Human Herpesvirus-6A and CD46 Receptor Engagement. Front Immunol. 2018;9:2803. Published 2018 Dec 6.