Expression and Activation by Epstein Barr Virus of Human Endogenous Retroviruses-W in Blood Cells and Astrocytes: Inference for Multiple Sclerosis

Abstract

BackgroundProposed co-factors triggering the pathogenesis of multiple sclerosis (MS) are the Epstein Barr virus (EBV), and the potentially neuropathogenic MSRV (MS-associated retrovirus) and syncytin-1, of the W family of human endogenous retroviruses.Methodology/Principal FindingsIn search of links, the expression of HERV-W/MSRV/syncytin-1, with/without exposure to EBV or to EBV glycoprotein350 (EBVgp350), was studied on peripheral blood mononuclear cells (PBMC) from healthy volunteers and MS patients, and on astrocytes, by discriminatory env-specific RT-PCR assays, and by flow cytometry. Basal expression of HERV-W/MSRV/syncytin-1 occurs in astrocytes and in monocytes, NK, and B, but not in T cells. This uneven expression is amplified in untreated MS patients, and dramatically reduced during therapy. In astrocytes, EBVgp350 stimulates the expression of HERV-W/MSRV/syncytin-1, with requirement of the NF-κB pathway. In EBVgp350-treated PBMC, MSRVenv and syncytin-1 transcription is activated in B cells and monocytes, but not in T cells, nor in the highly expressing NK cells. The latter cells, but not the T cells, are activated by proinflammatory cytokines.Conclusions/Significance In vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1, in cells deriving from blood and brain. In vivo, pathogenic outcomes would depend on abnormal situations, as in late EBV primary infection, that is often symptomatic, or/and in the presence of particular host genetic backgrounds. In the blood, HERV-Wenv activation might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, toxic mechanisms against oligodendrocytes could be established, inducing inflammation, demyelination and axonal damage. Local stimulation by proinflammatory cytokines and other factors might activate further HERV-Ws, contributing to the neuropathogenity. In MS pathogenesis, a possible model could include EBV as initial trigger of future MS, years later, and HERV-W/MSRV/syncytin-1 as actual contributor to MS pathogenicity, in striking parallelism with disease behaviour.

Human endogenous retroviruses in the aetiology of MS

“…7,8 HERV-HF and HERV-W/MSRV are activated in MS, and levels of HERV RNA and HERV antigens are increased, both in the brain (autopsied MS brain material) [9][10][11][12] and in the periphery (mononuclear cells, PBMCs). 13,14 Concerning the consequences of HERV expression in MS brain cells, in vitro analyses of HERV-W encoded Env (syncytin-1) have demonstrated induction of a reduced capacity of oligodendroglial differentiation, 15 and further, that expression in astrocytes of the syncytin-1 can induce oligodendrocyte cell death. 16 Notably, in PBMCs, HERV antigens are predominantly expressed on monocytes and B cells, and the expression is linked to disease activity, with increased levels in active disease and decreased levels in inactive disease and following efficacious therapy.…”

“…16 Notably, in PBMCs, HERV antigens are predominantly expressed on monocytes and B cells, and the expression is linked to disease activity, with increased levels in active disease and decreased levels in inactive disease and following efficacious therapy. 13,14,17 It is also known that cell-mediated as well as humoral immune responses to HERV-H/F and HERV-W/MSRV are augmented in MS, particularly in active MS, 18,19 and-when studying antibody reactivity in MS families-this increased reactivity was found in MS-affected family members but not in their unaffected relatives. 20 Accordingly, anti-HERV-antibody levels have been suggested as a candidate biomarker for MS disease activity.…”

Des séquences rétrovirales endogènes dans le génome humain peuvent jouer un rôle physiologique ou pathologique

“…En effet, HCMV peut induire une hypométhylation de la chromatine en rétro-transloquant les ADN-méthyltransférases 1 et 3 (DNMT-1, -3) nucléaires dans le cytoplasme permettant l'activation des séquences HERV-K (ou HML-2 [human mouse mammary tumor virus like-2]) [9]. [5][6][7]. En effet, la glycoprotéine d'enveloppe d'EBV (la gp350) active la transcription de la famille HERV-W dans les cellules astrocytaires et lymphoïdes [5], montrant ainsi les spécificités multiples, virales, cellulaires et de famille (voire d'éléments) HERV, requises pour que ces transactivations soient effectives.…”

“…[5][6][7]. En effet, la glycoprotéine d'enveloppe d'EBV (la gp350) active la transcription de la famille HERV-W dans les cellules astrocytaires et lymphoïdes [5], montrant ainsi les spécificités multiples, virales, cellulaires et de famille (voire d'éléments) HERV, requises pour que ces transactivations soient effectives. Les récepteurs des fragments du complément L'engagement des récepteurs membranaires des fragments du complément, notamment le C3b, semble aussi jouer un rôle important dans la transactivation d'HERV.…”

The aliens inside human DNA: HERV-W/MSRV/syncytin-1 endogenous retroviruses and neurodegeneration

“…In human DNA, there are multiple copies of HERV-W elements; numbers can vary [19][20], but there are about 70 gag, 100 pro, and 30 env HERV-Wrelated regions [21][22]; the family is retrotransposably active [12] and generates new recombinant copies in cancer cells [23]. Full-length HERV-Wenv DNA sequences are present on ten human chromosomes (X, 3, 4, 5, 7, 12, 14, 15, 17, and 18), and three additional chromosomes have HERV-W elements containing incomplete HERV-Wenvs spanning ≥ 80% of the gene [24]. As for their transcription, only the ERVW-1 locus on chromosome 7 is transcribed in a full-length env mRNA that can be translated in a complete protein, syncytin-1; all the other HERV-Wenv genes present in the current version of the human genome either are not transcribed, or originate HERV-Wenv fragments with stop codons and other gene alterations [24].…”