EBV and HERV: the dual viral hyppothesis

"This paper is quite complicated for the uninitiated reader; don't despair the following summary should suffice. It is simply saying the when EBV infects cells it activates a dormant retrovirus that resides in our genome. This retrovirus, called MS-associated retrovirus, which when activated produces a protein called syncytin-1. Syncytin-1 could potentially damage, or augment damage, within the brain and spinal cord in MS and also stimulate the immune system further by activating T-cells as a superantigen. Whether this occurs in the human body is controversial as syncitin-1 has been shown to play a role in normal human physiology in relation to the formation of the human placenta. Unfortunately, this and other papers in the field on the topic of MS-associated retrovirus are very controversial; retrovirologists in general have yet to accept the virus as a definitive entity. This is causing problems for the field; for example funding agencies are unlikely to fund research in the field due to controversy that manifests itself as poor reviews. In my opinion the peer-review system acts as a hurdle for controversial topics. At the end of the day the only way to overcome this impasse is by doing further work in the field and getting experts from outside of MS involved. We are therefore planning to convene a meeting next year, of experts in field, under the umbrella of the Charcot Project to review the data and define a path forward. This is such an important issue that we are planning clinical trials in MS that target both EBV and human retroviruses. At the moment we are targeting them separately, but if this research is accurate we may need a dual therapy."

"Finally, the link between EBV, and other herpes viruses, and retroviruses is not new. This is what underpins the dual virus hypothesis of MS pathogenesis."

Epub: Mameli et al. Expression and Activation by Epstein Barr Virus of Human Endogenous Retroviruses-W in Blood Cells and Astrocytes: Inference for Multiple Sclerosis. PLoS One. 2012;7(9):e44991. Epub 2012 Sep 27

BACKGROUND: Proposed co-factors triggering the pathogenesis of 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 FINDINGS: In 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 MSers, 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 MSers, 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.

Extra reading: HERVs

Additional post on this blog about HERVs:

25 May 2012
Effects of interferon-beta therapy on elements in the antiviral immune response towards the human herpesviruses EBV, HSV, and VZV, and to the human endogenous retroviruses HERV-H and HERV-W in multiple sclerosis.
21 Sep 2012
Recently, our group provided genetic evidence for association between the endogenous retrovirus HERV-Fc1 and MS, suggesting that HERV-Fc1 plays a role in this multifactorial disease. We have found increased expression ...
30 Jan 2012
The HERV-Fc1, which belongs to the HERV-H/F family, has received our attention largely because of the genetic association with MS. The expression of a capsid (Gag) coat protein of HERV-H/F origin by flow cytometry in ...
04 Dec 2011
There is growing evidence that the envelope (env) genes of two or more human endogenous retroviruses (HERVs)* of the W family are contributing to the inflammatory processes, and thus to the pathogenesis, of MS.

31 Mar 2012
Background: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family 'W' (HERV-W), induces dysimmunity and inflammation. Objective: ...
31 Mar 2012
The locus on chromosome 7 maps to HERV...."evidence for the Charcot Project?" They point to genes involved in neurodegeneration, is this because they think that progression links to neurodegeneration. Until more ...
01 Feb 2012
The link between the various risk factors is the discovery of a Human Endogenous Retrovirus (HERV) that is significantly present in patients with MS and not in patients with other neurological conditions or in healthy controls.
10 Mar 2012
Prof G has been building the idea of a dual viral hit hypothesis, where EBV may trigger the activation of another virus such as endogenous retrovirus (HERV) that could be involved in a trigger of MS. This study shows that EBV ...

04 Apr 2012
"If we all carry HERV's in our brain cells that are part of our DNA and thus wouldn't be attacked by CD8 could EBV be mimicking them?" An interesting idea; this would need some work in silico and in the lab! Friday, April 06 ...
13 Feb 2012
18 comments: Anonymous said... No mention of EBV & HERV? I thought that's a big part of your research. Also, are causation and prevention two different questions? Prevention will come with or after an answer to causation.

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