Friday, 12 July 2013

Inhibiting Endogenous retrovirus may allow remyelination

Epub: Kremer et al. HERV-W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann Neurol. 2013 Jul 8.

Objective: Differentiation of oligodendroglial precursor cells is crucial for central nervous system remyelination and is influenced by both extrinsic and intrinsic factors. Recent studies showed that a human endogenous retrovirus type W (HERV-W) contributes significantly to brain damage. In particular, its envelope protein ENV can mediate injury to specific cell types of the brain and immune system. Here, we investigated whether ENV protein affects oligodendroglial differentiation.

Methods: Immunostaining and gene expression analyses were performed to establish the expression and regulation of the known ENV receptor, Toll-like receptor 4 (TLR4), on oligodendroglial precursor cells in human brain tissue and in culture. Cultured primary oligodendroglial precursor cells were stimulated with ENV protein to determine the effects of this ligand/receptor interaction.

Results: We demonstrated that the ENV protein is present in close proximity to TLR4-expressing oligodendroglial precursor cells adjacent to multiple sclerosis lesions. Human and rat oligodendroglial precursor cells expressed TLR4, and the ENV-mediated activation of TLR4 led to the induction of proinflammatory cytokines and inducible nitric oxide synthase as well as the formation of nitrotyrosine groups and a subsequent reduction in myelin protein expression.

Interpretation: Our findings suggest that ENV-mediated induction of nitrosative stress via activation of TLR4 results in an overall reduction of the oligodendroglial differentiation capacity, thereby contributing to remyelination failure. Therefore, pharmacological or antibody-mediated inhibition of ENV may prevent the blockade of myelin repair in the diseased or injured central nervous system.


The INSPIRE Trial, part of the Charcot Project, is on ongoing and recruiting study subjects. It is targeting HERVs. Maybe you are eligible and interested for this study? 


15 Jan 2013
The INSPIRE Trial: the Charcot Project launches its first trial. #MSBlog: At last its official our first anti-viral trial in MS! Although I have been arguing that the anti-CD20 therapies are working as anti-EBV agents. A Phase II ...

4 comments:

  1. I am on this trial and am very excited and hopeful that it will be the breakthrough we all want and need!

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  2. Interesting.....might both EBV and HERVs act synergistically? Just as HIV-1 tat protein may contribute to BBB disruption followed by JC virus activation (http://www.pnas.org/content/87/9/3479.short) leading to PML.

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  3. Puzzled: In another comment today Prof G said that there is no remyelination failure in MS

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    1. After reading the literature remyelination seems to occur spontaneously albeit less than normal thickness but as years pass the effects of low level or "smoldering" inflammation cause axon damage and irreversible deficit. The key is to hit hard and early to reduce inflammation. Sometimes it seems if remyelination is just a smoke screen. Until the microenvironment around the damaged area can be restored remyelination will be ineffective.

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