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

Presently, studies on an association between both TTV and EBV infection in lymphocytes of B-cell lymphoma and Hodgkin's lymphoma have been inconclusive [92, 93] . An increased permissiveness for infection with herpes simplex virus during the first 48 hours of infection has been demonstrated in EBV-converted, previously negative Burkitt's lymphoma derived cell lines [74] . Therefore the presence of both TTV and EBV in the same B cell is feasible. Naive and memory B cells are equally susceptible to EBV infection [94] . EBV infection may lead to EBV persistence in B cells providing ground for differentiation into EBV-latently infected circulating memory B cells [95] . Ectopic follicle-like structures harbouring B cells, similar to those found in other organ-specific immune disease, have also been described in the cerebral meninges of some MS patients [96] . The persistence of EBV infection, as measured by elevated EBNA-1 antibodies, could provide a fertile field for the induction of molecular mimicry. It has been proposed that autoreactive T cells induced by molecular mimicry may need such a fertile field of persistent viral infection to become autoaggressive [97] . In vivo clonally expanded CD4 + T cells isolated from cerebrospinal fluid of an MS patient, responded to a poly-arginine motif present in TT viruses [43] . The TTV-HD14 isolates used in the present study were isolated from MS brain tissue. Putative proteins from genes and their transcripts of TTV-HD14 and its mTTV share similar but sufficiently modified signature motifs to cellular genes including myelin basic protein (MBP) (unpublished results). A number of studies have indicated an elevated myelin specific T cell population in MS patients [36, 47] . We propose the following model for a role of both EBV and TTV infections as etiological agents in MS: Simultaneous infection by either TTV or mTTV in EBV-infected memory B cells leads to persistence of the TTV supported by EBNA-1 expression. Spontaneous activation of the EBV lytic cycle in such cells could result in a burst of TTV or mTTV expression and production and infection of neighbouring cells. TTV autoimmune-reactive epitopes in turn induce autoreactive T cells [97] reacting against specific proteins of the TTV-infected cells. This model could explain the local autoimmune response, the focal nature of MS lesions and the re-emergence of new foci. We have demonstrated EBV-helper dependent activation of TTV-HD14 isolated from MS brain tissue. Ongoing studies are investigating the crossreactivity of TTV-HD14 expressed proteins to myelin immune response.