Oh dear this is a mess: ERVs and Multiple Sclerosis #5

Okay, I have written a LOT about the connection between wayward ERV activity and Multiple Sclerosis. This is something scientists have been investigating for a long time... but we still do not know exactly what is going on.

It seems the running hypothesis is that 'something'/'somethings' alter the epigenetic profile of individuals DNA, allowing for expression of an endogenous retroviral Envelope protein, especially in the brains of (future) MS patients. These proteins are pro-inflammatory, start causing all sorts of trouble, like MS.

Its gotten to the point where other scientists are trying anti-ERV-Env therapies to fight MS.

But, we still dont *know* this chain of events is what is leading to MS, or that targeting Env expressing cells would stop MS.

Comprehensive Analysis of Human Endogenous Retrovirus Group HERV-W Locus Transcription in Multiple Sclerosis Brain Lesions by High-Throughput Amplicon Sequencing

A lot of the ERV-->MS papers are looking at ERV expression in the blood cells of MS patients. That has *really* bothered me. Why would someones CD8+ T-cells tell you anything about what is going on in their brains?

But, I fully understand that brains are not as easy to study as blood.

In this paper, however, they looked at the brains of MS patients and controls.

There was no difference in ERV expression between MS patients and controls.


The data was all over. Some MS patients had some ERV expression up, and other ERVs were down. And some ERV expression was up compared to some controls, but equal to other controls. They called it "interindividual variation regarding overall and locus-specific HERV-W transcript levels".

It still might have nothing to do with the ERV Env proteins. The presence of the proteins might be an artifact of the ERV LTR (promoter) activity. Because this paper did note that the LTRs associated with the ERVs associated with MS retain promoter activity in both directions (think of it as a book you can read forwards and backwards), even if they arent perfect LTRs (mutations).

Maybe its not the ERVs in the genome, but the stuff around the ERVs that are being expressed inappropriately that are causing trouble?


What a mess.

Though we have learned a *lot* about ERVs-->MS, we are still where we were at when I wrote about this in 2009:

Active ERV proteins could be a cause of MS, an effect of the cause of MS, or an effect of a cause that ends up perpetuating MS.




Bonus for those of you familiar with the XMRV fiasco-- In 1997, a paper in PNAS reported they found a novel retrovirus in Multiple Sclerosis patients, MSRV. This current paper says those 'novel retroviral sequences' were really just recombination in sequencing of ERVs. Totally an artifact, not 'real'. Yup...

More like this

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I wasnt super thrilled about the last ERV-->MS paper I wrote about, but I really like this new one:Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Those of you who have been following the XMRV fiasco will find…
ERVs and Multiple Sclerosis ERVs and Multiple Sclerosis, #2 Hmmm... This new paper on the association between 'active' ERVs and Multiple Sclerosis is a step back, and a step forward, at the same time:Expression of HERV-Fc1, a human endogenous retrovirus, is increased in patients with active…
Amyotrophic Lateral Sclerosis, aka Lou Gherigs disease. Pretty much sounds like hell, to me. Your mind is fine, while your body is collapsing around you-- slowly but surely paralyzing you, taking away your ability to eat and breathe, while your mind is fine and dandy so you are acutely aware of…

Not to be snarky, but...

Why would someones CD8+ T-cells tell you anything about what is going on in their brains?

CD8+ T cells are the major pathological cell in MS. It is these cells that enter the CNS and kill oligiodendrocytes. And since these cells continually re-circulate, looking at them tells you a hell of a lot of what is going on at the site of immune activity. We (grand 'we', not me specifically) have been IDing active, MS-antigen specific T and B cells in the peripheral blood of MS patients for a good 20 years.

This results is pretty much what any immunologist would have expected. Many immune cells - T cells among them - produce HERVs when activated. As far as I can recall, the first images of HERV VLP's exiting cells were observed in activated T cells.

I suspect that the variability they observed could have been due to sampling errors - if they took pieces of inflammed brain from some patient, but uninflammed regions from others, you would expect to see this sort of heterogenety. This is quite common with immune responses in the brain - they tend to be highly localized (to the point that immune cells for tertiary lymphoid structures - transient "lymph nodes" in the brain). Finding consistent results requires either analysis of large brain volumes, or careful microdissection to include/exclude things like the tertiary lymphoid structures.

"This results is pretty much what any immunologist would have expected. Many immune cells – T cells among them – produce HERVs when activated...."

Indeed, so HERV expression is associated with inflammation. MS is an inflammatory disease. Correlation not causation.

"I suspect that the variability they observed could have been due to sampling errors"

Indeed..or..not errors. Just the inflammatory state of the T-cells in the sample.

One other question, from an interested outsider. HERV-W gag and env are expressed normally in healthy brain tissue, though the levels may or may not be higher in MS related inflammation. Functional necessity had been suggested by the same group for at least the gag in CNS, as with env / syncitin in the placenta? That wouldn't necessarily make anti-ERV Rx dangerous even in the long term - but it would add to the caution about targetting env.

By charles soper (not verified) on 03 May 2014 #permalink

HERV-W gag CNS expression is particularly high in various CNS sites with high and consistently specific levels of local variability. The middle temporal gyrus, not an area renowned for redundancy, for example showing esp. high expression. The authors conclude, 'Our current findings that human tissues harbor patterned and extensive expression of genomic loci containing HERV-W elements, suggests that functionality for such transcripts cannot be ruled out.

By charles soper (not verified) on 03 May 2014 #permalink