Human herpesvirus 6A and other risk factors for multiple sclerosis

   Based on a review of the literature, this article summarises the findings of original studies on the role of human herpesvirus 6A (HHV-6A) in the development of multiple sclerosis (MS). The review also presents the immunological and pathogenetic rationale for the role of other viruses – Epstein–Barr virus (EBV) and human endogenous retrovirus-W (HERV-W) – in the development of MS. Experimental and clinical data on risk factors for the development of MS are examined in the context of the established presence of the aforementioned viruses in patients.

   Particular attention is paid to the role of HHV-6A as a potential trigger of the inflammatory autoimmune cascade in MS.

   Information on the possible role of the combination of HHV-6A with other viruses (co-infection) in the pathogenesis of MS is summarized and presented. In addition to the viral nature of MS development, the article focuses on endogenous (genetically determined) and other external factors.

1. Vitturi BK, Cellerino M, Boccia D, et al. Environmental risk factors for multiple sclerosis : a comprehensive systematic review and meta-analysis. J Neurol. 2025 Jul;272(8):513. doi: 10.1007/s00415-025-13248-0

2. Clinical Guidelines of the Ministry of Health of Russia. Available at: https://cr.minzdrav.gov.ru/view-cr/739_2 (accessed 01. 02. 2026) (In Russ.).

3. Belbasis L, Bellou V, Evangelou E, Tzoulaki I. Environmental factors and risk of multiple sclerosis: Findings from meta-analyses and Mendelian randomization studies. Mult Scler. 2020 Apr;26(4):397-404. doi: 10.1177/1352458519872664

4. Dunn N, Kharlamova N, Fogdell-Hahn A. The role of herpesvirus 6A and 6B in multiple sclerosis and epilepsy. Scand J Immunol. 2020 Dec;92(6):e12984. doi: 10.1111/sji.12984

5. Pormohammad A, Azimi T, Falah F, Faghihloo E. Relationship of human herpes virus 6 and multiple sclerosis : A systematic review and meta-analysis. Cell Physiol. 2018 Apr;233(4):2850-62. doi: 10.1002/jcp.26000

6. Caserta MT. Human Herpesvirus 6 Infection of the Central Nervous System. Curr Infect Dis Rep. 2004 Aug;6(4):316-21. doi: 10.1007/s11908-004-0054-x

7. Kostare G, Kostares E, Kostares M, et al. Prevalence of HHV-6 Detection Among People Living with HIV : A Systematic Review and Meta-Analysis. Viruses. 2025 Apr;17(4):531. doi: 10.3390/v17040531

8. ICTV Global. ICTV Global Taxonomy. International Committee on Taxonomy of Viruses. 2024. Available at: https://ictv.global/taxonomy/

9. Bartolini L, Theodore WH, Jacobson S, Gaillard WD. Infection with HHV-6 and its role in epilepsy. Epilepsy Res. 2019 Jul;153:34-9. doi: 10.1016/j.eplepsyres.2019.03.016

10. Forni D, Cagliani R, Clerici M, et al. Evolutionary analysis of exogenous and integrated HHV-6A/HHV-6B populations. Virus Evol. 2020 Apr;6(1):veaa035. doi: 10.1093/ve/veaa035

11. Pellett PE, Ablashi DV, Ambros PF, et al. Chromosomally integrated human herpesvirus 6: questions and answers. Rev Med Virol. 2012 May;22(3):144-55. doi: 10.1002/rmv.715

12. Tarlinton RE, Martynova E, Rizvanov AA, et al. Role of Viruses in the Pathogenesis of Multiple Sclerosis. Viruses. 2020 Jun;12(6):643. doi: 10.3390/v12060643

13. Meier UC, Cipian RC, Karimi A, et al. 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 Nov;12:757302. doi: 10.3389/fimmu.2021.757302

14. Ballerini C, Amoriello R, Maghrebi O, et al. Exploring the role of EBV in multiple sclerosis pathogenesis through EBV interactome. Front Immunol. 2025 Apr;16:1557483. doi: 10.3389/fimmu.2025.1557483

15. Louveau A, Herz J, Alme MN, et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci. 2018 Oct;21(10):1380-91. doi: 10.1038/s41593-018-0227-9

16. Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunol. 2017 Jan;6(1):e126. doi: 10.1038/cti.2016.87

17. Van Langelaar J, Rijvers L, Smolders J, van Luijn MM. B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers. Front Immunol. 2020 May;11:760. doi: 10.3389/fimmu.2020.00760

18. Jog NR, McClain MT, Heinlen LD, et al. Epstein Barr virus nuclear antigen 1 (EBNA-1) peptides recognized by adult multiple sclerosis patient sera induce neurologic symptoms in a murine model. J Autoimmun. 2020 Jan;106:102332. doi: 10.1016/j.jaut.2019.102332

19. Liu R, Du S, Zhao L, et al. Autoreactive lymphocytes in multiple sclerosis: Pathogenesis and treatment target. Front Immunol. 2022 Sep;13:996469. doi: 10.3389/fimmu.2022.996469

20. Absinta M, Maric D, Gharagozloo M, et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature. 2021 Sep;597(7878):709-14. doi: 10.1038/s41586-021-03892-7

21. Ten Bosch GJA, Bolk J, 't Hart BA, Laman JD. Multiple sclerosis is linked to MAPKERK overactivity in microglia. Mol Med (Berl). 2021 Aug;99(8):1033-42. doi: 10.1007/s00109-021-02080-4

22. Kumar N, Sharma N, Mehan S. Connection between JAK/STAT and PPARγ Signaling During the Progression of Multiple Sclerosis: Insights into the Modulation of T-Cells and Immune Responses in the Brain. Curr Mol Pharmacol. 2021;14(5):823-37. doi: 10.2174/1874467214666210301121432

23. Massey J, Jackson K, Singh M, et al. Haematopoietic Stem Cell Transplantation Results in Extensive Remodelling of the Clonal T Cell Repertoire in Multiple Sclerosis. Front Immunol. 2022 Feb;13:798300. doi: 10.3389/fimmu.2022.798300

24. Reynaud JM, Jegou JF, Welsch JC, Horvat B. Human herpesvirus 6A infection in CD46 transgenic mice: viral persistence in the brain and increased production of proinflammatory chemokines via Toll-like receptor 9. J Virol. 2014 May;88(10):5421-36. doi: 10.1128/JVI.03763-13

25. Leibovitch E, Wohler JE, Cummings Macri SM, et al. Novel marmoset (Callithrix jacchus) model of human Herpesvirus 6A and 6B infections: immunologic, virologic and radiologic characterization. PLoS Pathog. 2013 Jan;9(1):e1003138. doi: 10.1371/journal.ppat.1003138

26. Challoner PB, Smith KT, Parker JD, et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A. 1995 Aug;92(16):7440-4. doi: 10.1073/pnas.92.16.7440

27. Chapenko S, Millers A, Nora Z, et al. Correlation between HHV-6 reactivation and multiple sclerosis disease activity. J Med Virol. 2003 Jan;69(1):111-7. doi: 10.1002/jmv.10258

28. Soldan SS, Fogdell-Hahn A, Brennan MB, et al. Elevated serum and cerebrospinal fluid levels of soluble human herpesvirus type 6 cellular receptor, membrane cofactor protein, in patients with multiple sclerosis. Ann Neurol. 2001 Oct;50(4):486-93. doi: 10.1002/ana.1135

29. Zheng W, Xu Q, Zhang Y, et al. Toll-like receptor-mediated innate immunity against herpesviridae infection: a current perspective on viral infection signaling pathways. J Virol. 2020 Dec;17(1):192. doi: 10.1186/s12985-020-01463-2

30. Mori Y, Yang X, Akkapaiboon P, et al. Human herpesvirus 6 variant A glycoprotein H-glycoprotein L-glycoprotein Q complex associates with human CD46. J Virol. 2003 Apr;77(8):4992-9. doi: 10.1128/jvi.77.8.4992-4999.2003

31. 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 Nov;10:2715. doi: 10.3389/fimmu.2019.02715

32. De Bolle L, Van Loon J, De Clercq E, Naesens L. Quantitative analysis of human herpesvirus 6 cell tropism. J Med Virol. 2005 Jan;75(1):76-85. doi: 10.1002/jmv.20240

33. Goodman AD, Mock DJ, Powers JM, et al. Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions. Infect Dis. 2003 May;187(9):1365-76. doi: 10.1086/368172

34. Ortega-Madueno I, Garcia-Montojo M, Dominguez-Mozo MI, et al. Anti-human herpesvirus 6A/B IgG correlates with relapses and progression in multiple sclerosis. PLoS One. 2014 Aug;9(8):e104836. doi: 10.1371/journal.pone.0104836

35. Amini R, Karampoor S, Zahednasab H, et al. Serum levels of matrix metalloproteinase-2, -9, and vitamin D in patients with multiple sclerosis with or without herpesvirus-6 seropositivity. Braz Infect Dis. 2020 Mar-Apr;;24(2):144-9. doi: 10.1016/j.bjid.2020.02.001

36. Tejada-Simon MV, Zang YC, Hong J, et al. Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann Neurol. 2003 Feb;53(2):189-97. doi: 10.1002/ana.10425

37. Pi KS, Bortolotti D, Sang Y, et al. Studying the Interactions of U24 from HHV-6 in Order to Further Elucidate Its Potential Role in MS. Viruses. 2022 Oct;14(11):2384. doi: 10.3390/v14112384

38. Biström M, Jons D, Engdahl E, et al. Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis. Eur Neurol. 2021 Feb;28(2):579-86. doi: 10.1111/ene.14597

39. Maple PAC, Tanasescu R, Gran B, Constantinescu CS. A different response to cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infection in UK people with multiple sclerosis (PwMS) compared to controls. J Infect. 2020 Mar;80(3):320-5. doi: 10.1016/j.jinf.2019.10.017

40. Langer-Gould A, Wu J, Lucas R, et al. Epstein–Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study. Neurology. 2017 Sep;89(13):1330-7. doi: 10.1212/WNL.0000000000004412

41. Grut V, Biström M, Salzer J, et al. Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis-a presymptomatic case-control study. Eur Neurol. 2021 Sep;28(9):3072-9. doi: 10.1111/ene.14961

42. Perez-Perez S, Dominguez-Mozo MI, Garcia-Martinez MA, et al. Anti-Human Herpesvirus 6 A/B Antibodies Titers Correlate With Multiple Sclerosis-Associated Retrovirus Envelope Expression. Front Immunol. 2021 Nov;12:798003. doi: 10.3389/fimmu.2021.798003

43. Schmidt H, Williamson D, Ashley-Koch A. HLA-DR15 haplotype and multiple sclerosis: a HuGE review. Am J Epidemiol. 2007 May;165(10):1097-109. doi: 10.1093/aje/kwk118

44. De Jager PL, Chibnik LB, Cui J, et al. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. Lancet Neurol. 2009 Dec;8(12):1111-9. doi: 10.1016/S1474-4422(09)70275-3

45. Ramroodi N, Sanadgol N, Ganjali Z, et al. Monitoring of active human herpes virus 6 infection in Iranian patients with different subtypes of multiple sclerosis. J Pathog. 2013 Jan;2013:194932. doi: 10.1155/2013/194932

46. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008 Sep;8(9):685-98. doi: 10.1038/nri2378

47. Simpson S Jr, Wang W, Otahal P, et al. Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis. Neurol Neurosurg Psychiatry. 2019 Nov;90(11):1193-200. doi: 10.1136/jnnp-2018-320189

48. Lau LW, Cua R, Keough MB, et al. Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat Rev Neurosci. 2013 Oct;14(10):722-9. doi: 10.1038/nrn3550

49. Leppert D, Ford J, Stabler G, et al. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain. 1998 Dec;121 (Pt 12):2327-34. doi: 10.1093/brain/121.12.2327

50. Bjornevik K, Munger KL, Cortese M, et al. Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis. JAMA Neurol. 2020 Jan;77(1):58-64. doi: 10.1001/jamaneurol.2019.3238

51. Gaetani L, Parnetti L, Calabresi P, Di Filippo M. Tracing Neurological Diseases in the Presymptomatic Phase: Insights From Neurofilament Light Chain. Front Neurosci. 2021 May;15:672954. doi: 10.3389/fnins.2021.672954

52. Kuhle J, Plavina T, Barro C, et al. Neurofilament light levels are associated with long-term outcomes in multiple sclerosis. Mult Scler. 2020 Nov;26(13):1691-9. doi: 10.1177/1352458519885613

53. Ziemssen T, Arnold DL, Alvarez E, et al. Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials. Front Immunol. 2022 Mar;13:852563. doi: 10.3389/fimmu.2022.852563

54. Grut V, Biström M, Salzer J, et al. Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis. Brain. 2024 Jan;147(1):177-85. doi: 10.1093/brain/awad374

55. Lünemann JD, Sao Aviles A, Tintore M, et al. Cytomegalovirus immune responses are associated with lower serum NfL and disability accumulation risk at multiple sclerosis onset. Mult Scler. 2024 Oct;30(11-12):1445-54. doi: 10.1177/13524585241274571