Brains and peripheral blood mononuclear cells of multiple sclerosis (MS) patients hyperexpress MS-associated retrovirus/HERV-W endogenous retrovirus, but not Human herpesvirus 6

Abstract

Multiple sclerosis (MS)-associated retrovirus (MSRV)/HERV-W (human endogenous retrovirus W)and Human herpesvirus 6 (HHV-6) are the two most studied (and discussed) viruses as environmental co-factors that trigger MS immunopathological phenomena. Autopsied brain tissues from MS patients and controls and peripheral blood mononuclear cells (PBMCs) were analysed. Quantitative RT-PCR and PCR with primers specific for MSRV/HERV-W env and pol and HHV-6 U94/rep and DNA-pol were used to determine virus copy numbers. Brain sections were immunostained with HERV-W env-specific monoclonal antibody to detect the viral protein. All brains expressed MSRV/HERV-W env and pol genes. Phylogenetic analysis indicated that cerebral MSRV/HERV-W-related env sequences, plasmatic MSRV, HERV-W and ERVWE1 (syncytin) are related closely. Accumulation of MSRV/HERV-W-specific RNAs was significantly greater in MS brains than in controls (P=0.014 vs healthy controls; P=0.006 vs pathological controls). By immunohistochemistry, no HERV-W env protein was detected in control brains, whereas it was upregulated within MS plaques and correlated with the extent of active demyelination and inflammation. No HHV-6-specific RNAs were detected in brains of MS patients; one healthy control had latent HHV-6 and one pathological control had replicating HHV-6. At the PBMC level, all MS patients expressed MSRV/HERV-W env at higher copy numbers than did controls (P=0.00003). Similar HHV-6 presence was found in MS patients and healthy individuals; only one MS patient had replicating HHV-6. This report, the first to study both MSRV/HERV-W and HHV-6, indicates that MSRV/HERV-W is expressed actively in human brain and activated strongly in MS patients, whilst there are no significant differences between these MS patients and controls for HHV-6 presence/replication at the brain or PBMC level. INTRODUCTIONThe aetiopathogenesis of multiple sclerosis (MS) disease is complex and debated. Immunopathogenic phenomena are thought to be triggered by environmental (viral?) factors operating on a predisposing genetic background (Noseworthy et al., 2000). Among the viruses suggested as MS co-factors are ubiquitous members of the family Herpesviridae, Human herpesvirus 6 (HHV-6) (AlvarezLafuente et al., 2004;Moore & Wolfson, 2002) and Epstein-Barr virus (EBV) (Christensen, 2006), and a human endogenous retrovirus (HERV), the MS-associated retrovirus (MSRV) (Dolei, 2005;Perron et al., 1989), a member of the HERV-W multicopy family; links between HERVs and some human diseases have been observed increasingly (Dolei, 2006). HHV-6 can be neurotropic, can become latent and be reactivated, and has potential immunopathogenic properties. Meta-analyses indicate that the available reports provide some support for a link between HHV-6 and MS, but none shows causative relationships (Clark, 2004;Moore & Wolfson, 2002 Firouzi et al., 2003). Activities strikingly concordant with findings on MSRV and MS (Dolei et al., 2002;Firouzi et al., 2003;Lafon et al., 2002;Perron et al., 2005; Sotgiu et al., ...

A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients — A twelve month follow-up

“…Several studies have demonstrated links between the expression of MSRV-Env and multiple sclerosis (MS); in particular immunohistochemical analyses of post-mortem brain tissue from MS patients localize the MSRV-Env protein to MS plaques with a higher level of protein expression in active plaques compared to inactive plaques (Mameli et al, 2007;Perron et al, 2012).…”

Silver nanoparticles exhibit size-dependent differential toxicity and induce expression of syncytin-1 in FA-AML1 and MOLT-4 leukaemia cell lines

“…Most significantly expression of syncytin-1 has also been shown to suppress staurosporin-induced apoptosis in Chinese hamster ovary (CHO) cells (45) Although there is significant evidence for syncytin-1 conferring a growth/survival advantage in malignant cells, there is also evidence that its expression induces demyelination and cell death in oligodendrocytes which is consistent with the protein playing a causative role in neurodegenerative disease (48). Indeed, as previously mentioned, syncytin-1 is thought to play an instrumental role in MS (30,32,49). Thus it is significant that AgNPs are also known to cause neuronal damage (50,51) and we speculate this could be augmented by induction of syncytin-1.…”

“…The reason for this is that syncytin-1 is known to be up-regulated in multiple sclerosis (30)(31)(32) and a variety of cancers (33,34), including lymphoma and leukaemia (35). It is also known to promote the fusion of malignant cells, both to themselves and normal endothelial cells which contributes to enhanced genetic instability (15,16,34) and recent work has shown that mutations in the HERV-W genomic 3'-long terminal repeat induce up-regulation of syncytin-1 expression in urothelial cell carcinoma (36).…”

Human Herpesvirus 6 Infection as a Trigger of Multiple Sclerosis

“…Of these, 4 were classified as A-quality studies. 32,58,76,78 Blumberg et al 78 presented the results as high and low values of HHV-6 DNA.…”

“…Another 2 studies were classified as A quality without reaching statistical significance. 39,58 Of the studies classified as B quality, 1 study reached statistical significance, 44 whereas 8 studies did not. 23,47,[59][60][61][62]67,68 In most B-quality studies, a greater proportion of MS patients had detectable HHV-6 DNA in their PBMCs than controls; however, the results were not statistically signifi-For personal use.…”