Top

Published in:

Open Access 01-12-2017 | Review

Multiple sclerosis: an example of pathogenic viral interaction?

Author: Walter Fierz

Published in: Virology Journal | Issue 1/2017

Abstract

A hypothesis is formulated on viral interaction between HHV-6A and EBV as a pathogenic mechanism in Multiple Sclerosis (MS). Evidence of molecular and genetic mechanisms suggests a link between HHV-6A infection and EBV activation in the brain of MS patients leading to intrathecal B-cell transformation. Consequent T-cell immune response against the EBV-infected cells is postulated as a pathogenic basis for inflammatory lesion formation in the brain of susceptible individuals. A further link between HHV-6A and EBV involves their induction of expression of the human endogenous retrovirus HERV-K18-encoded superantigen. Such virally induced T-cell responses might secondarily also lead to local autoimmune phenomena. Finally, research recommendations are formulated for substantiating the hypothesis on several levels: epidemiologically, genetically, and viral expression in the brain.

Winnock M, Salmon-Céron D, Dabis F, Chêne G. Interaction between HIV-1 and HCV infections: towards a new entity? J Antimicrob Chemother. 2004;53:936–46. doi:10.1093/jac/dkh200.CrossRefPubMed

Lin L, Verslype C, van Pelt JF, van Ranst M, Fevery J. Viral interaction and clinical implications of coinfection of hepatitis C virus with other hepatitis viruses. Eur J Gastroenterol Hepatol. 2006;18:1311–9. doi:10.1097/01.meg.0000243881.09820.09.CrossRefPubMed

Grivel JC, Ito Y, Fagà G, Santoro F, Shaheen F, Malnati MS, et al. Suppression of CCR5- but not CXCR4-tropic HIV-1 in lymphoid tissue by human herpesvirus 6. Nat Med. 2001;7:1232–5. doi:10.1038/nm1101-1232.CrossRefPubMed

Lisco A, Grivel J-C, Biancotto A, Vanpouille C, Origgi F, Malnati MS, et al. Viral interactions in human lymphoid tissue: Human herpesvirus 7 suppresses the replication of CCR5-tropic human immunodeficiency virus type 1 via CD4 modulation. J Virol. 2007;81:708–17. doi:10.1128/JVI.01367-06.CrossRefPubMed

Leibovitch EC, Jacobson S. Evidence linking HHV-6 with multiple sclerosis: an update. Curr Opin Virol. 2014;9:127–33. doi:10.1016/j.coviro.2014.09.016.CrossRefPubMed

Pender MP. The essential role of Epstein-Barr virus in the pathogenesis of multiple sclerosis. Neuroscientist. 2011;17:351–67. doi:10.1177/1073858410381531.CrossRefPubMedPubMedCentral

Owens GP, Bennett JL. Trigger, pathogen, or bystander: the complex nexus linking Epstein- Barr virus and multiple sclerosis. Mult Scler. 2012;18:1204–8. doi:10.1177/1352458512448109.CrossRefPubMedPubMedCentral

Fierz W. Virale Hypothese der Multiplen Sklerose. In: Kesselring J, editor. Multiple Sklerose. 4th ed. Stuttgart: Kohlhammer-Verlag; 2004.

Ablashi D, Agut H, Alvarez-Lafuente R, Clark DA, Dewhurst S, DiLuca D, et al. Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol. 2014;159:863–70. doi:10.1007/s00705-013-1902-5.CrossRefPubMed

10.

Donati D, Martinelli E, Cassiani-ingoni R, Ahlqvist J, Hou J, Major EO, et al. Variant-specific tropism of human herpesvirus 6 in human astrocytes. J Virol. 2005;79:9439–48. doi:10.1128/JVI.79.15.9439.CrossRefPubMedPubMedCentral

11.

Alvarez-Lafuente R, Martinez A, Garcia-Montojo M, Mas A, De Las Heras V, Dominguez-Mozo MI, et al. MHC2TA rs4774C and HHV-6A active replication in multiple sclerosis patients. Eur J Neurol. 2010;17:129–35. doi:10.1111/j.1468-1331.2009.02758.x.CrossRefPubMed

12.

Bronson PG, Caillier S, Ramsay PP, McCauley JL, Zuvich RL, De Jager PL, et al. CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis. Hum Mol Genet. 2010;19:2331–40. doi:10.1093/hmg/ddq101.CrossRefPubMedPubMedCentral

13.

Dong Y, Benveniste EN. Immune function of astrocytes. Glia. 2001;36:180–90. doi:10.1002/glia.1107.CrossRefPubMed

14.

Fierz W, Endler B, Reske K, Wekerle H, Fontana A. Astrocytes as antigen-presenting cells. I. Induction of Ia antigen expression on astrocytes by T cells via immune interferon and its effect on antigen presentation. J Immunol. 1985;134:3785–93.PubMed

15.

Barcia C, Mitxitorena I, Carrillo-de Sauvage MA, Gallego J-M, Pérez-Vallés A. Imaging the microanatomy of astrocyte-T-cell interactions in immune-mediated inflammation. Front Cell Neurosci. 2013;7:58. doi:10.3389/fncel.2013.00058.CrossRefPubMedPubMedCentral

16.

Meeuwsen S, Persoon-Deen C, Bsibsi M, Bajramovic JJ, Ravid R, De Bolle L, et al. Modulation of the cytokine network in human adult astrocytes by human herpesvirus-6A. J Neuroimmunol. 2005;164:37–47. doi:10.1016/j.jneuroim.2005.03.013.CrossRefPubMed

17.

De Jager PL, Jia X, Wang J, de Bakker PIW, Ottoboni L, Aggarwal NT, et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet. 2009;41:776–82. doi:10.1038/ng.401.CrossRefPubMedPubMedCentral

18.

Le Roy E, Mühlethaler-Mottet A, Davrinche C, Mach B, Davignon JL. Escape of human cytomegalovirus from HLA-DR-restricted CD4(+) T-cell response is mediated by repression of gamma interferon-induced class II transactivator expression. J Virol. 1999;73:6582–9.PubMedPubMedCentral

19.

Alenda R, Álvarez-Lafuente R, Costa-Frossard L, Arroyo R, Mirete S, Álvarez-Cermeño JC, et al. Identification of the major HHV-6 antigen recognized by cerebrospinal fluid IgG in multiple sclerosis. Eur J Neurol. 2014;21:1096–101. doi:10.1111/ene.12435.CrossRefPubMed

20.

Lossius A, Johansen JN, Vartdal F, Robins H, Benth JŠ, Holmøy T, et al. High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8(+) T cells. Eur J Immunol. 2014;44:3439–52. doi:10.1002/eji.201444662.CrossRefPubMed

21.

Van Nierop GP, et al. Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins. Multiple Sclerosis J. 2015. doi:10.1177/1352458515588581.

22.

Petzold A. Intrathecal oligoclonal IgG synthesis in multiple sclerosis. J Neuroimmunol. 2013;262:1–10. doi:10.1016/j.jneuroim.2013.06.014.CrossRefPubMed

23.

Yu X, Burgoon M, Green M, Barmina O, Dennison K, Pointon T, et al. Intrathecally synthesized IgG in multiple sclerosis cerebrospinal fluid recognizes identical epitopes over time. J Neuroimmunol. 2011;240–241:129–36.CrossRefPubMedPubMedCentral

24.

Willis SN, Stathopoulos P, Chastre A, Compton SD, Hafler DA, O’Connor KC. Investigating the antigen specificity of multiple sclerosis central nervous system-derived immunoglobulins. Front Immunol. 2015;6:600.CrossRefPubMedPubMedCentral

25.

Tosato G, Blaese RM, Yarchoan R. Relationship between immunoglobulin production and immortalization by Epstein Barr virus. J Immunol. 1985;135:959–64.PubMed

26.

Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007;204:2899–912. doi:10.1084/jem.20071030.CrossRefPubMedPubMedCentral

27.

Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue--report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain. 2011;134:2772–86. doi:10.1093/brain/awr197.CrossRefPubMedPubMedCentral

28.

Cepok S, Zhou D, Srivastava R, Nessler S, Stei S, Büssow K, et al. Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest. 2005;115:1352–60. doi:10.1172/JCI200523661.1352.CrossRefPubMedPubMedCentral

29.

Pfuhl C, Oechtering J, Rasche L, Gieß RM, Behrens JR, Wakonig K, et al. Association of serum Epstein–Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis. J Neuroimmunol. 2015;285:156–60. doi:10.1016/j.jneuroim.2015.06.012.CrossRefPubMed

30.

Flamand L, Stefanescu I, Ablashi DV, Menezes J. Activation of the Epstein-Barr virus replicative cycle by human herpesvirus 6. J Virol. 1993;67:6768–77.PubMedPubMedCentral

31.

Cuomo L, Angeloni A, Zompetta C, Cirone M, Calogero A, Frati L, et al. Human herpesvirus 6 variant A, but not variant B, infects EBV-positive B lymphoid cells, activating the latent EBV genome through a BZLF-1-dependent mechanism. AIDS Res Hum Retroviruses. 1995;11:1241–5. doi:10.1089/aid.1995.11.1241.CrossRefPubMed

32.

Cuomo L, Trivedi P, De Grazia U, Calogero A, D’Onofrio M, Yang W, et al. Upregulation of Epstein-Barr virus-encoded latent membrane protein by human herpesvirus 6 superinfection of EBV-carrying Burkitt lymphoma cells. J Med Virol. 1998;55:219–26. doi:10.1002/(SICI)1096-9071(199807)55:3<219::AID-JMV7>3.0.CO;2-4.CrossRefPubMed

33.

Mechelli R, Manzari C, Policano C, Annese A, Picardi E, Umeton R, et al. Epstein-Barr virus genetic variants are associated with multiple sclerosis. Neurology. 2015;84(13):1362–8. doi:10.1212/WNL.0000000000001420.CrossRefPubMedPubMedCentral

34.

Juryńczyk M, Selmaj K. Notch: a new player in MS mechanisms. J Neuroimmunol. 2010;218:3–11. doi:10.1016/j.jneuroim.2009.08.010.CrossRefPubMed

35.

Henkel T, Ling PD, Hayward SD, Peterson MG. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science. 1994;265:92–5. doi:10.1126/science.8016657.CrossRefPubMed

36.

Zhao B, Zou J, Wang H, Johannsen E, Peng C-W, Quackenbush J, et al. Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. Proc Natl Acad Sci U S A. 2011;108:14902–7. doi:10.1073/pnas.1108892108.CrossRefPubMedPubMedCentral

37.

Querol L, Clark PL, Bailey MA, Cotsapas C, Cross AH, Hafler DA, et al. Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology. 2013;81:956–63. doi:10.1212/WNL.0b013e3182a43b48.CrossRefPubMedPubMedCentral

38.

Liu H, Zheng H, Li M, Hu D, Tang M, Cao Y. Upregulated expression of kappa light chain by Epstein-Barr virus encoded latent membrane protein 1 in nasopharyngeal carcinoma cells via NF-kappaB and AP-1 pathways. Cell Signal. 2007;19:419–27. doi:10.1016/j.cellsig.2006.07.012.CrossRefPubMed

39.

Rinker JR, Trinkaus K, Cross AH. Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis. Neurology. 2006;67:1288–90. doi:10.1212/01.wnl.0000238107.31364.21.CrossRefPubMed

40.

Presslauer S, Milosavljevic D, Huebl W, Aboulenein-Djamshidian F, Krugluger W, Deisenhammer F, et al. Validation of kappa free light chains as a diagnostic biomarker in multiple sclerosis and clinically isolated syndrome: a multicenter study. Mult Scler J. 2015;online before print:1–9. doi:10.1177/1352458515594044.

41.

Mameli G, Poddighe L, Mei A, Uleri E, Sotgiu S, Serra C, et al. Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis. PLoS One. 2012;7, e44991. doi:10.1371/journal.pone.0044991.CrossRefPubMedPubMedCentral

42.

Antony JM, Deslauriers AM, Bhat RK, Ellestad KK, Power C. Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants? Biochim Biophys Acta. 1812;2011:162–76. doi:10.1016/j.bbadis.2010.07.016.

43.

Sutkowski N, Conrad B, Thorley-Lawson DA, Huber BT. Epstein-Barr virus transactivates the human endogenous retrovirus HERV- K18 that encodes a superantigen. Immunity. 2001;15:579–89.CrossRefPubMed

44.

Tai AK, Luka J, Ablashi D, Huber BT. HHV-6A infection induces expression of HERV-K18-encoded superantigen. J Clin Virol. 2009;46(1):47–8. doi:10.1016/j.jcv.2009.05.019.CrossRefPubMed

45.

Tai AK, O’Reilly EJ, Alroy KA, Simon KC, Munger KL, Huber BT, et al. Human endogenous retrovirus-K18 Env as a risk factor in multiple sclerosis. Mult Scler. 2008;14:1175–80. doi:10.1177/1352458508094641.CrossRefPubMedPubMedCentral

46.

Sutkowski N, Palkama T, Ciurli C, Sekaly RP, Thorley-Lawson DA, Huber BT. An Epstein-Barr virus-associated superantigen. J Exp Med. 1996;184:971–80.CrossRefPubMed

47.

Hong J, et al. A Common TCR V-D-J Sequence in Vβ13.1 T Cells Recognizing an Immunodominant Peptide of Myelin Basic Protein in Multiple Sclerosis. J Immunol. 1999;163:3530.PubMed

48.

Lycke J, Svennerholm B, Hjelmquist E, et al. Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. J Neurol. 1996;243:214–24.CrossRefPubMed

49.

Annibali V, Mechelli R, Romano S, et al. IFN-β and multiple sclerosis: From etiology to therapy and back. Cytokine Growth Factor Rev. 2015;26:221–8.CrossRefPubMed

50.

Garcia-Montojo M, De Las Heras V, Dominguez-Mozo M, et al. Human herpesvirus 6 and effectiveness of interferon beta 1b in multiple sclerosis patients. Eur J Neurol. 2011;18:1027–35. doi:10.1111/j.1468-1331.2011.03410.x.CrossRefPubMed

51.

Ganne V, Siddiqi N, Kamaplath B, et al. Humanized anti-CD20 monoclonal antibody (Rituximab) treatment for post-transplant lymphoproliferative disorder. Clin Transplant. 2003;17:417–22.CrossRefPubMed

52.

Hauser SL, Waubant E, Arnold DL, et al. B-Cell Depletion with Rituximab in Relapsing–Remitting Multiple Sclerosis. N Engl J Med. 2008;358:676–88. doi:10.1056/NEJMoa0706383.CrossRefPubMed

53.

Montalban X, Hemmer B, Rammohan K, et al. Efficacy and Safety of Ocrelizumab in Primary Progressive Multiple Sclerosis: Results of the Phase III Double-Blind, Placebo-Controlled ORATORIO Study (S49.001). Neurology. 2016;86:S49.001.

54.

Warnke C, Menge T, Hartung H-P, Racke MK, Cravens PD, Bennett JL, et al. Natalizumab and progressive multifocal leukoencephalopathy. Arch Neurol. 2010;67:923–30.CrossRefPubMedPubMedCentral

55.

Yao K, Gagnon S, Akhyani N, Williams E, Fotheringham J, Frohman E, et al. Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS One. 2008;3, e2028.CrossRefPubMedPubMedCentral

56.

Sfriso P, Ghirardello A, Botsios C, Tonon M, Zen M, Bassi N, et al. Infections and autoimmunity: the multifaceted relationship. J Leukoc Biol. 2010;87:385–95.CrossRefPubMed

57.

Sjöholm MIL, Dillner J, Carlson J. Multiplex detection of human herpesviruses from archival specimens by using matrix-assisted laser desorption ionization-time of flight mass spectrometry. J Clin Microbiol. 2008;46:540–5. doi:10.1128/JCM.01565-07.CrossRefPubMed

58.

Yamamoto T, Nakamura Y. A single tube PCR assay for simultaneous amplification of HSV-1/-2, VZV, CMV, HHV-6A/-6B, and EBV DNAs in cerebrospinal fluid from patients with virus-related neurological diseases. J Neurovirol. 2000;6:410–7. doi:10.3109/13550280009018305.CrossRefPubMed

Title: Multiple sclerosis: an example of pathogenic viral interaction?
Author: Walter Fierz
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Virology Journal / Issue 1/2017
Electronic ISSN: 1743-422X
DOI: https://doi.org/10.1186/s12985-017-0719-3

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Multiple sclerosis: an example of pathogenic viral interaction?

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2017

Molecular evolution of two asymptomatic echovirus 6 strains that constitute a novel branch of recently epidemic echovirus 6 in China

Detection of a genetic footprint of the sofosbuvir resistance-associated substitution S282T after HCV treatment failure

Clade homogeneity and low rate of delta virus despite hyperendemicity of hepatitis B virus in Ethiopia

Unexpected complexity in the interference activity of a cloned influenza defective interfering RNA

Correlation of cytokine level with the severity of severe fever with thrombocytopenia syndrome

Genetic characterization of 11 porcine reproductive and respiratory syndrome virus isolates in South China from 2014 to 2015

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page