Epstein-Barr Virus Stimulates Torque Teno Virus Replication: A Possible Relationship to Multiple Sclerosis

Borkosky, Silvia S.; Whitley, Corinna; Kopp-Schneider, Annette; zur Hausen, Harald; deVilliers, Ethel-Michele

Several viruses have been considered to be involved [3, 4] . Morbilli-and coronaviruses [15, 16] which, similar to Theiler's murine encephalomyelitis virus (TMEV) in mice [3, 17] , induce demyelinating disease in their natural hosts. JC polyomavirus was also proposed, but is presently considered to be a bystander in MS [18, 19] . A number of herpesviruses have been investigated as etiological factors for MS. Activation of varicella zoster virus (VZV) was demonstrated during exacerbations [20, 21] . An upregulation of the endogenous retroviruses HERV-H and HERV-W transcription was mediated by herpesviruses Herpes simplex-1 (HSV-1), human herpesvirus-6 (HHV-6) and VZV [22, 23] . A more direct role for HHV-6 in MS was suspected [24, 25] , but was subsequently questioned because no difference was observed in the HHV-6 prevalence between cases and controls [26, 27] , although its possible role prior to onset of disease was not excluded [28] . HHV-6 glycoprotein expressed on the surface of infected T lymphocytes allows for its fusion to oligodendrocytes and astrocytes expressing the CD46 receptor which is necessary for viral entry [29] . Cross-reaction of HHV-6 and myelin has also been reported [30] . Individuals with a history of EBV-induced infectious mononucleosis are at 2-to 3-fold increased risk of developing MS [31, 32] in contrast to the risk being extremely low in EBVnegative individuals [33] . Elevated EBV antibody titres have been associated with the onset of MS [4, 9, 10, 12, [34] [35] [36] , but not during the course of disease [37] and whether active EBV infection actually plays a role in ongoing MS disease is controversial [38] [39] [40] . Mechanistic aspects through which EBV infections may participate in the pathogenesis of MS also remain elusive, despite the compelling epidemiological data available [32, 33] .