Skip to main content
NCBI home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;16(1):20–27. doi: 10.1111/j.1750-3639.2006.tb00558.x

Human Herpesvirus 6 and Multiple Sclerosis: A One‐Year Follow‐up Study

Roberto Álvarez‐Lafuente 1,✉, Virginia DeLas Heras 1, Manuel Bartolomé 1, Marta García‐Montojo 1, Rafael Arroyo 1
PMCID: PMC8095909  PMID: 16612979

Abstract

Background. This study was undertaken in order to investigate the possible relation of HHV‐6 and EBV in relapsing‐remitting MS (RRMS).

Materials and methods. A one‐year follow up study was performed analysing peripheral blood mononuclear cells and serum samples of 57 patients with RRMS and 57 healthy blood donors (HBD) by a quantitative real time PCR, to detect HHV‐6 and EBV. Clinical data (starting age and EDSS increase) were collected.

Results. We did not find any statistically significant difference for EBV between RRMS patients and HBD. Regarding HHV‐6: i) There was a higher prevalence of HHV‐6 in RRMS patients than in controls: 80.7% versus 29.8% respectively. ii) HHV‐6 active replication seems to be related to exacerbations. iii) Only variant A was detected among RRMS patients with HHV‐6 active replication. iv) Although some difference was found when we compared clinical data in RRMS patients with and without HHV‐6 active replication, the results did not reach statistical significance.

Conclusions. A higher HHV‐6A frequency of active infection (reactivation or new infection) would lead to a more frequent exposure of HHV‐6A antigens to the immune system of RRMS patients; this active replication of HHV‐6A seems to be specifically related with the exacerbations in a subset of RRMS patients.

References

  • 1. Ablashi DV, Lapps W, Kaplan M, Whitman JE, Richert JR, Pearson GR (1998) Human Herpes‐virus‐6 (HHV‐6) infection in multiple sclerosis: a preliminary report. Mult Scler 4:490–496. [DOI] [PubMed] [Google Scholar]
  • 2. Akhyani N, Berti R, Brennan MB, Soldan SS, Eaton JM, McFarland HF, Jacobson S (2000) Tissue distribution and variant characterization of human herpesvirus (HHV)‐6: increased prevalence of HHV‐6A in patients with multiple sclerosis. J Infect Dis 182:1321–1325. [DOI] [PubMed] [Google Scholar]
  • 3. Alvarez‐Lafuente R, Martin‐Estefania, C . de las Heras, V , Castrillo C, Cour I, Picazo JJ, Varela De Seijas, E . Arroyo, R (2002) Prevalence of herpesvirus DNA in MS patients and healthy blood donors. Acta Neurol Scand 105:95–99. [DOI] [PubMed] [Google Scholar]
  • 4. Álvarez‐Lafuente, R , Martín‐Estefanía, C . de las Heras, V , Castrillo C, Picazo, JJ . Varela de Seijas, E , Gonzalez RA (2002) Active human herpesvirus 6 infection in patients with multiple sclerosis. Arch Neurol 59:929–933. [DOI] [PubMed] [Google Scholar]
  • 5. Álvarez‐Lafuente, R . De las Heras, V , Bartolomé M, Picazo JJ, Arroyo R (2004) Relapsing‐remitting multiple sclerosis and HHV‐6 active infection. Arch Neurol 61:1523–1527. [DOI] [PubMed] [Google Scholar]
  • 6. Ascherio A, Munger KL, Lennette ET, Spiegel‐man D, Hernan MA, Olek MJ, Hankinson SE, Hunter DJ (2001) Epstein‐Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286:3083–3088. [DOI] [PubMed] [Google Scholar]
  • 7. Berneman ZN, Ablashi DV, Li G, Eger‐Fletcher M, Reitz MS Jr, Hung CL, Brus I, Komaroff AL, Gallo RC (1992) Human herpesvirus 7 is a T‐lymphotropic virus and is related to but significantly different from human herpesvirus 6 and human cytomeg‐alovirus. Proc Natl Acad Sci USA 89:10552–10556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Blumberg BM, Mock DJ, Powers JM, Ito M, Assouline JG, Baker JV, Chen B, Goodman AD (2000) The HHV‐6 paradox: ubiquitous commensal or insidious pathogen? A two‐step in situ PCR approach. J Clin Virol 16:159–178. [DOI] [PubMed] [Google Scholar]
  • 9. Braun DK, Domínguez G, Pellet PE (1997) Human herpesvirus 6. Clin Micr Rev 10:521–567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Campadelli‐Fiume G, Mirandola P, Menotti L (1999) Human herpesvirus 6: an emerging pathogen. Emerg Infect Dis 5:353–366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Carrigan DR, Harrington D, Knox KK (1996) Subacute leukoencephalitis caused by CNS infection with human herpesvirus‐6 manifesting as acute multiple sclerosis. Neurology 47:145–148. [DOI] [PubMed] [Google Scholar]
  • 12. Cepok S, Zhou D, Srivastava R, Nessler S, Stei S, Bussow K, Sommer N, Hemmer B. (2005) Identification of Epstein‐Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 115:1352–1360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Challoner PB, Smith KT, Parker JD, MacLeod DL, Coulter SN, Rose TM, Schultz ER, Bennett JL, Garber RL, Chang M, Schad PA, Stewart PM, Nowinski RC, Brown PB, Burmer GC (1995) Plaque‐associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci USA 92:7440–7444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Chapenko S, Millers A, Nora Z, Logina I, Ku‐kaine R, Murovska M (2003) Correlation between HHV‐6 reactivation and multiple sclerosis disease activity. J Med Virol 69:111–117. [DOI] [PubMed] [Google Scholar]
  • 15. Cirone M, Cuomo L, Zompetta C, Ruggieri S, Frati L, Faggioni A, Ragona G (2002) Human herpesvirus 6 and multiple sclerosis: a study of T cell cross‐reactivity to viral and myelin basic protein antigens. J Med Virol 68:268–272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Cole PD, Stiles J, Boulad F, Small TN, O'Reilly RJ, George D, Szabolcs P, Kiehn TE, Kernan NA (1998) Successful treatment of human herpesvirus‐6 encephalitis in a bone marrow transplant recipient. Clin Infect Dis 27:653–654. [DOI] [PubMed] [Google Scholar]
  • 17. Derfuss, T . Hohlfeld, R , Meinl E (2005) Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20% of multiple sclerosis patients and might be linked to a polyspecific B‐cell response. J Neurol 252:968–971. [DOI] [PubMed] [Google Scholar]
  • 18. Flebbe‐Rehwaldt LM, Wood C, Chandran B (2000) Characterization of transcripts expressed from Human Herpesvirus 6A strain GS Immediate‐Early Region B U16‐U17 Open Reading Frames. J Virol 74:11040–11054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Fogdell‐Hahn A, Soldan SS, Shue S, Akhyani N, Refai H, Ahlqvist J, Jacobson S (2005) Co‐purification of soluble membrane cofactor protein (CD46) and human herpesvirus 6 variant A genome in serum from multiple sclerosis patients. Virus Res 110:57–63. [DOI] [PubMed] [Google Scholar]
  • 20. Friedman JE, Zabriskie JB, Plank C, Ablashi D, Whitman J, Shahan B, Edgell R, Shieh M, Rapalino O, Zimmerman R, Sheng D (2005) A randomized clinical trial of valacyclovir in multiple sclerosis. Mult Scler 11:286–295. [DOI] [PubMed] [Google Scholar]
  • 21. Hong, J . Tejada‐Simon, MV , Rivera VM, Zang YC, Zhang JZ (2002) Anti‐viral properties of interferon β treatment in patients with multiple sclerosis. Mult Scler 8:237–242. [DOI] [PubMed] [Google Scholar]
  • 22. Josephs SF, Salahuddin SZ, Ablashi DV, Schachter F, Wong‐Staal F, Gallo RC (1986) Genomic analysis of the human B‐lymphotropic virus (HBLV). Science 234:601–603. [DOI] [PubMed] [Google Scholar]
  • 23. Kirby H, Rickinson A, Bell A (2000) The activity of the Epstein‐Barr virus BamHIW promoter in B cells is dependent on the binding of CREB/ATF factors. J Gen Virol 81:1057–1066. [DOI] [PubMed] [Google Scholar]
  • 24. Knox KK, Carrigan DR (1995) Active human herpesvirus (HHV‐6) infection of the central nervous system in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 9:69–73. [PubMed] [Google Scholar]
  • 25. Kondo S, Horikawa T, Takeshita H, Kanegane C, Kasahara Y, Sheen TS, Sato H, Furukawa M, Yoshizaki T (2004) Diagnostic value of serum EBV‐DNA quantification and antibody to viral capsid antigen in nasopharyngeal carcinoma patients. Cancer Sci 95:508–513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Kurtzke JF (1995) MS epidemiology world wide. One view of current status. Acta Neurol Scand Suppl 161:23–33. [DOI] [PubMed] [Google Scholar]
  • 27. Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A (2003) Multiple sclerosis and Epstein‐Barr virus. JAMA 289:1533–1536. [DOI] [PubMed] [Google Scholar]
  • 28. Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A (2005). Temporal relationship between elevation of ep‐stein‐barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293:2496–2500. [DOI] [PubMed] [Google Scholar]
  • 29. Locatelli G, Santoro F, Veglia F, Gobbi A, Lusso P, Malnati MS (2000) Real‐time quantitative PCR for human herpesvirus 6 DNA. J Clin Microbiol 38:4042–4048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Mackenzie IR, Carrigan DR, Wiley CA (1995) Chronic myelopathy associated with human herpesvirus‐6. Neurology 45:2015–2017. [DOI] [PubMed] [Google Scholar]
  • 31. Merelli E, Bedin R, Sola P, Barozzi P, Mancardi GL, Ficarra G, Franchini G (1997) Human herpes virus 6 and Human herpes virus 8 DNA sequences in brains of multiple sclerosis patients normal adults and childrens. J Neurol 244:450–454. [DOI] [PubMed] [Google Scholar]
  • 32. Mirandola P, Menegazzi P, Merighi S, Ravaioli T, Cassai E, Di Luca, D (1998) Temporal Mapping of Transcripts in Herpesvirus 6 Variants. J Virol 72:3837–3844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Nitsche A, Müller CW, Radonic A, Landt O, Ellerbrok H, Pauli G, Siegert W (2001) Human Herpesvirus 6A DNA is detected frequently in plasma but rarely in peripheral blood leukocytes of patients after bone marrow transplantation. J Infect Dis 183:130–133. [DOI] [PubMed] [Google Scholar]
  • 34. Paterson DL, Singh N, Gayowski T, Cardigan DR, Marino IR (1999) Encephalopathy associated with human herpesvirus 6 in a liver transplant recipient. Liver TransplSurg 5:454–455. [DOI] [PubMed] [Google Scholar]
  • 35. Portolani M, Cermelli C, Moroni A, Bertolani MF, Di Luca, D , Cassai E, Sabbatini AM. (1993) Human herpesvirus‐6 infections in infants admitted to hospital. J Med Virol 39:146–151. [DOI] [PubMed] [Google Scholar]
  • 36. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231. [DOI] [PubMed] [Google Scholar]
  • 37. Rotola A, Cassai E, Tola MR, Granieri E, Di Luca, D (1999) Human herpesvirus 6 is latent in peripheral blood of patients with relapsing‐remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 67:529–531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Rotola A, Merlotti I, Caniatti L, Caselli E, Granieri E, Tola MR, Di Luca, D , Cassai E (2004) Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease. Mult Scler 10:348–354. [DOI] [PubMed] [Google Scholar]
  • 39. Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, Halligan G, Biberfeld P, Wong‐Staal F, Kramarsky B (1986) Isolation of a new virus HBLV in patients with lymphoproliferative disorders. Science 234:596–601. [DOI] [PubMed] [Google Scholar]
  • 40. Scarisbrick IA, Rodriguez M (2003) Hit‐Hit and hit‐Run: viruses in the playing field of multiple sclerosis. Curr Neurol Neurosci Rep 3:265–271. [DOI] [PubMed] [Google Scholar]
  • 41. Sola P, Merelli E, Marasca R, Poggi M, Luppi M, Montorsi M, Torelli G (1993) Human herpesvirus 6 and multiple sclerosis survey of anti‐HHV‐6 antibodies by immunofluorescence analysis and of viral sequences by polymerase chain reaction. J Neurol Neurosurg Psychiatry 56:917–919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Soldan SS, Berti R, Salem N, Secchiero P, Flamand L, Calabresi PA, Brennan MB, Maloni HW, McFarland HF, Lin HC, Patnaik M, Jacobson S (1997) Association of human herpes virus 6 (HHV‐6) with multiple sclerosis: increased IgM response to HHV‐6 early antigen and detection of serum HHV‐6 DNA. Nat Med 3:1394–1397. [DOI] [PubMed] [Google Scholar]
  • 43. Sundstrom P, Juto P, Wadell G, Hallmans G, Svenningsson A, Nystrom L, Dillner J, Forsgren L (2004) An altered immune response to Epstein‐Barr virus in multiple sclerosis: a prospective study. Neurology 62:2277–2282. [DOI] [PubMed] [Google Scholar]
  • 44. Tejada‐Simon MV, Zang YCQ, Hong J, Rivera VM, Zhang JZ (2003) Cross‐reactivity with myelin basic protein and human‐herpesvirus‐6 in multiple sclerosis. Ann Neurol 53:189–197. [DOI] [PubMed] [Google Scholar]
  • 45. Van den Bosch, G , Locatelli G, Geerts L, Faga G, Ieven M, Goossens H, Bottiger D, Oberg B, Lusso P, Berneman ZN (2001) Development of Reverse Transcriptase PCR assays for detection of active Human Herpesvirus 6 infection. J Clin Microbiol 39:2308–2310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Virtanen JO, Zabriskie JB, Siren V, Friedman JE, Lyons MJ, Edgar M, Vaheri A, Koskiniemi M (2005) Co‐localization of human herpes virus 6 and tissue plasminogen activator in multiple sclerosis brain tissue. Med Sci Monit 11 :BR84–87. [PubMed] [Google Scholar]
  • 47. Wagner HJ, Hennig H, Jabs WJ, Siekhaus A, Wessel K, Wandinger KP (2000) Altered prevalence and reactivity of anti‐Epstein‐Barr virus antibodies in patients with multiple sclerosis. Viral Immunol 13:497–502. [DOI] [PubMed] [Google Scholar]
  • 48. Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, Bucsky P (2001) Patients and risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein‐Barr viral load by using real‐time poly‐merase chain reaction. Transplantation 72:1012–1019. [DOI] [PubMed] [Google Scholar]
  • 49. Wagner HJ, Munger KL, Ascherio A (2004) Plasma viral load of Epstein‐Barr virus and risk of multiple sclerosis. Eur J Neurol 11:833–834. [DOI] [PubMed] [Google Scholar]
  • 50. Wekerle H, Hohlfeld R (2003) Molecular mimicry in multiple sclerosis. N Engl J Med 349:185–186. [DOI] [PubMed] [Google Scholar]
  • 51. Wolfson C (2001) Multiple sclerosis and antecedent infections. Epidemiology 12:298–299. [DOI] [PubMed] [Google Scholar]
  • 52. Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, Kurata T (1988) Identification of human herpesvirus‐6 as a causal agent for exanthem subitum. Lancet 1:1065–1067. [DOI] [PubMed] [Google Scholar]
  • 1. Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte‐endothelial interactions at the blood‐brain barrier. Nat Rev Neurosci 7:41–53. [DOI] [PubMed] [Google Scholar]
  • 2. Ghiso J, Rostagno A, Tomidokoro Y, Lashley T, Bojsen‐Møller M, Braend‐gaard H, Plant G, Holton J, Lal R, Revesz, T . Frangione, B (2006) Genetic alterations of the BRI2 gene: familial British and Danish dementias. Brain Pathol 16:71–79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Herzig MC, van Nostrand WE, Jucker M (2006) Mechanism of cerebral β‐amyloid angiopathy formation: murine and ceullar models. Brain Pathol 16:40–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Levy E, Jaskolski M, Grubb A (2006) The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models. Brain Pathol 16:60–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494. [DOI] [PubMed] [Google Scholar]
  • 6. Palsdottir A, Snorradottir AO, Thorensteinsson L (2006) Hereditary cystatin C amyloid angiopathy: genetic, clinical, and pathological aspects. Brain Pathol 16:55–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Pickford F, Coomaraswamy J, Jucker M, McGowan E (2006) Modeling familial British dementia in transgenic mice. Brain Pathol 16:80–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18:311–324. [DOI] [PubMed] [Google Scholar]
  • 9. Wright CF, Teichmann SA, Clarke J, Dobson CM (2005) The importance of sequence diversity in the aggregation and evolution of proteins. Nature 438: 878–881. [DOI] [PubMed] [Google Scholar]
  • 10. Zhang‐Nunes SX, Maat‐Schieman MLC, van Duinen SG, Roos RAC, Frosch MP, Greenberg SM (2006) The cerebral β‐amyloid angiopathies: hereditary and sporadic. Brain Pathol 16:30–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Zlokovic BV (2005) Neurovascular mechanism of Alzheimer's neurodegeneration. Trends Neurosci 28:202–208. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES