Activation of MSRV-Type Endogenous Retroviruses during Infectious Mononucleosis and Epstein-Barr Virus Latency: The Missing Link with Multiple Sclerosis?

Abstract

The etiology of multiple sclerosis (MS) is still unclear. The immuno-pathogenic phenomena leading to neurodegeneration are thought to be triggered by environmental (viral?) factors operating on predisposing genetic backgrounds. Among the proposed co-factors are the Epstein Barr virus (EBV), and the potentially neuropathogenic HERV-W/MSRV/Syncytin-1 endogenous retroviruses. The ascertained links between EBV and MS are history of late primary infection, possibly leading to infectious mononucleosis (IM), and high titers of pre-onset IgG against EBV nuclear antigens (anti-EBNA IgG). During MS, there is no evidence of MS-specific EBV expression, while a continuous expression of HERV-Ws occurs, paralleling disease behaviour. We found repeatedly extracellular HERV-W/MSRV and MSRV-specific mRNA sequences in MS patients (in blood, spinal fluid, and brain samples), and MRSV presence/load strikingly paralleled MS stages and active/remission phases. Aim of the study was to verify whether HERV-W might be activated in vivo, in hospitalized young adults with IM symptoms, that were analyzed with respect to expression of HERV-W/MSRV transcripts and proteins. Healthy controls were either EBV-negative or latently EBV-infected with/without high titers of anti-EBNA-1 IgG. The results show that activation of HERV-W/MSRV occurs in blood mononuclear cells of IM patients (2Log10 increase of MSRV-type env mRNA accumulation with respect to EBV-negative controls). When healthy controls are stratified for previous EBV infection (high and low, or no anti-EBNA-1 IgG titers), a direct correlation occurs with MSRV mRNA accumulation. Flow cytometry data show increased percentages of cells exposing surface HERV-Wenv protein, that occur differently in specific cell subsets, and in acute disease and past infection. Thus, the data indicate that the two main links between EBV and MS (IM and high anti-EBNA-1-IgG titers) are paralleled by activation of the potentially neuropathogenic HERV-W/MSRV. These novel findings suggest HERV-W/MSRV activation as the missing link between EBV and MS, and may open new avenues of intervention.

The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis

“…2,3 In search of links between EBV and HERV-W/MSRV/ Syncytin-1, the expression of HERV-W/MSRV/ Syncytin-1 was studied in vitro, with/without exposure to EBVgp350 (the major protein of EBV envelope), on PBMC from healthy donors and MS patients, and on astrocytes, 5 and, in another study, in hospitalized young adults with infectious mononucleosis, and healthy controls, who were either EBV-negative or latently EBVinfected, with/without high titers of anti-EBNA-1 IgG. 16 The results showed that in vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/Syncytin-1, in cells deriving from blood and brain. In vivo HERV-W/MSRV activation was higher in blood cells of patients with infectious mononucleosis, and in healthy controls with high anti-EBNA-1 IgG titers.…”

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

“…Thus, the data indicate that the two main links between EBV and MS (IM and high anti-EBNA-1-IgG titers) are paralleled by activation of the potentially neuropathogenic HERV-W/MSRV. Considering our data and those of the literature on MS pathogenesis, we postulate the possibility that EBV is an initial trigger of future MS, years later, and that MSRV has a direct role as effector of neuropathogenesis before and during MS [24,36].…”

“…We verified whether HERV-W might be activated also in vivo, in hospitalized young adults with IM symptoms, and in healthy controls that were either EBV negative or latently EBV infected with or without high titers of anti-EBNA-1 IgG [24,36]. Briefly, the results showed that in vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1 in cells deriving from the blood and brain.…”

“…However, due to the sequence similarities, effective distinction between the two elements by discriminatory quantitative real-time reverse transcription (RT)-PCR assays was carried out only by our group [24,[28][29]36] and later on, with the same assay, by Perron et al [37]. With the aid of these realtime PCR assays, which can amplify selectively either MSRVenv or syncytin-1 [29], we found that the DNA of MS patients had increased MSRVenv copies (sixfold mean increase, p = 0.02), while the syncytin-1-specific assay gave almost identical mean values for both patients and controls [29].…”

“…The MS-EBV link remains unclear and seems to be indirect, since no studies have found evidence of EBV expression specific to MS, and currently there is no consensus in establishing whether there is a presence of EBV-infected cells in the central nervous system (CNS) of MS patients [57]. Therefore, it remains to be determined whether EBV continues to play a role after disease initiation [24,36].…”