Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How?, 2019, Morris et al

Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How?
Morris G, Maes M, Murdjeva M, Puri BK

The gammaretroviral human endogenous retrovirus (HERV) families MRSV/HERV-W and HERV-H (including the closely related HERV-Fc1) are associated with an increased risk of multiple sclerosis (MS). Complete HERV sequences betray their endogenous retroviral origin, with open reading frames in gag, pro, pol and env being flanked by two long terminal repeats containing promoter and enhancer sequences with the capacity to regulate HERV transactivation and the activity of host genes in spite of endogenous epigenetic repression mechanisms.

HERV virions, RNA, cDNA, Gag and Env, and antibodies to HERV transcriptional products, have variously been found in the blood and/or brain and/or cerebrospinal fluid of MS patients, with the HERV expression level being associated with disease status. Furthermore, some HERV-associated single nucleotide polymorphisms (SNPs), such as rs662139 T/C in a 3-kb region of Xq22.3 containing a HERV-W env locus, and rs391745, upstream of the HERV-Fc1 locus on the X chromosome, are associated with MS susceptibility, while a negative association has been reported with SNPs in the tripartite motif-containing (TRIM) protein-encoding genes TRIM5 and TRIM22.

Factors affecting HERV transcription include immune activation and inflammation, since HERV promoter regions possess binding sites for related transcription factors; oxidative stress, with oxidation of guanine to 8-oxoguanine and conversion of cytosine to 5-hydroxymethylcytosine preventing binding of methyl groups transferred by DNA methyltransferases; oxidative stress also inhibits the activity of deacetylases, thereby favouring the acetylation of histone lysine residues favouring gene expression; interferon beta; natalizumab treatment; impaired epigenetic regulation; and the sex of patients.

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For those reading, this paper uses the abbreviations "MSRV" and "MRSV", seemingly interchangeably. This isn't clear in context and I read that as a typo - one that is repeated in two other similar papers. In the more recent literature the comment has been made that "MSRV" was unsatisfactory and caused confusion. Nomenclature has been updated and "pHERV-W" ('p' for pathological) is preferred.

 

Selected quotes from introduction (my bold highlights for summary or emphasis) —

 

And lastly some more passages that stood out to me —

 

This all looks like complete nonsense.
In line with previous papers from these authors.
Is it of any interest to an ME forum? I cannot quite see why.

 

Yea, when I noticed the headline "---Endogenous Retroviruses---" I thought of the recent study which showed a link between the EBV/Mono --- the though occurred how could "---Endogenous Retroviruses---" be relevant?

 

I added it as it was referenced in papers noted here which included some recent literature I thought might be interesting to the group, given some publications and anti-HERV-W MAb trials in LC. This has no direct link to ME but I thought it was potentially peripherally related and probably worth recording for look-back when studies report their findings.

 

Very interesting, the literature coming out on neuroinflammation.

 

Thanks for posting, @SNT Gatchaman

Related - In this Jan 30 Washington Post article, NIH's Avi Nath discusses his interest in the role of endogenous retroviruses in triggering illnesses such as ALS, MS, and Alzheimer.

His interest arose after seeing ALS disappear in a patient who had taken antiretroviral drugs. He's now going to conduct a placebo-controlled clinical trial for drugs that can suppress an embedded virus called HERV-K.

While the 2009 report of retrovirus in ME by Mikovitz was discredited, there had been an 1991 report by Paul Cheney, David Bell, and Elaine DeFreitas. I don't know why it was not followed up.

Can't tell what relevance this research will have to ME but it will be interesting to see where this research leads.

 

Thanks @Hutan and @Medfeb for more background - I had previously noted Nath's comments on this as well. Even if no ultimate relevance to ME/LC I think it's still interesting to take note of what is hypothesised/found/discounted in our second cousin-twice-removed diseases. I would be surprised if there is no mechanistic overlap at all between them (eg even confined to BBB dysfunction), even though we don't show the same neuro-degeneration for example in our neuro issues.

In terms of any potential role of retroviruses in ME, I personally wasn't turned off the idea due to the XMRV history, though I was only thinking about that as "poorly done" investigations for that particular virus and as it was such an unfortunate bust I had only had a cursory look at the history rather than background knowledge.

I did have the first post on hold a bit before hitting go with this particular review paper, as I had recognised the names from prior threads. Still, I thought it was a reasonable enough walk-through though I appreciate I don't have any depth of understanding here to judge it beyond that. I did find some of the other papers I'd read so far got quite complex quite quickly. Given history, in hindsight this probably wasn't the best choice of paper as noted above and up-thread.

Of course my better judgement was taking note of Betteridge's law, so perhaps my gut-brain axis should have been prioritised more to gut with this one!

Probably no need to go digging too much more into the area of HERVs, unless or until there are more relevant reports in LC, so will park for now. (Mods might consider nuking this thread if it's more noise than signal - it can always be replaced with a better overview in due course, if desired.)