HERVs and EBV the link with MS

Finding the link between EBV and HERVs. #MSBlog #MSResearch

"For those of you who follow the MS viral hypothesis will know that EBV and human endogenous retroviruses (HERVs) are the currently the leading contenders for being involved in the causal pathway that leads to the development of MS. This study on subjects without MS demonstrates that EBV is a powerful trigger of HERVs and transactivate their expression. This is not a new finding; it is well known that herpes viruses (EBV is a herpes virus) are capable of activating HERVs. What is important about this study is that EBV transactivates HERV-W the HERV virus that is most closely associated with MS. This study supports the rationale for targeting these viruses in MS as a therapeutic strategy. This is what we are trying to do with raltegravir as part of the Charcot Project."

Mameli et al. Activation of MSRV-Type Endogenous Retroviruses during Infectious Mononucleosis and Epstein-Barr Virus Latency: The Missing Link with Multiple Sclerosis? PLoS One. 2013 Nov 13;8(11):e78474.

Background: The aetiology 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 titres 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. 

Objective: 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. 

Methods: Healthy controls were either EBV-negative or latently EBV-infected with/without high titers of anti-EBNA-1 IgG. 

Results: 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. 

Conclusion: Thus, the data indicate that the two main links between EBV and MS (IM and high anti-EBNA-1-IgG titres) 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.

Expression and Activation by Epstein Barr Virus of Human Endogenous Retroviruses-W in Blood Cells and Astrocytes: Inference for Multiple Sclerosis Giuseppe Mameli, Luciana Poddighe, Alessandra Mei, Elena Uleri, Stefano Sotgiu, Caterina Serra, Roberto Manetti, Antonina DoleiResearch Article | published 27 Sep 2012 | PLOS ONE10.1371/journal.pone.0044991

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