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

[SNT Gatchaman]

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.

Link | PDF

 

[SNT Gatchaman]

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.

 

[SNT Gatchaman]

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

HERV classification has been a subject of considerable controversy but the most recent analysis of HERV elements in the human genome indicates that HERVs consist of the following three main classes [...]

Each class encompasses a variable number of groups. At the time of writing, bioinformatics-based approaches have identified 103 HERV families, although only 40 HERV families have been characterised in laboratory studies.

Complete HERV sequences betray their endogenous retroviral origin, with open reading frames (ORFs) in gag (the group-specific antigen gene), pro (the protease gene), pol (the polymerase gene) and env (the envelope gene) being flanked by two long terminal repeats (LTRs) containing promoter and enhancer sequences with the capacity to regulate HERV transactivation and the activity of host genes.

However, over millions of years, integrated HERV sequences have accumulated mutations in their ORFs leaving them replication defective and for the most part unable to move within the genome.

In addition, the original proviruses have undergone extreme recombination events often leaving the original virus represented by a solo LTR. Solo LTRs appear to have been selected for because of their positive role in the regulation of host genes.

[...] while the retention of HERV sequences in the human genome is likely because the beneficial effects on the species outweigh any detrimental effects in individuals, the danger of inappropriate HERV expression to individuals may be considerable.

HERV expression can initiate and increase the activation of immune and inflammatory pathways and dysregulate gene pathways by affecting the levels of DNA transcription factors such as cAMP (cyclic adenosine monophosphate) response element-binding protein (CREB) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Abnormal HERV expression can also potentially compromise neurotransmission and brain chemistry.

HERVs continue to be expressed in the periphery and in the brain. Moreover, HERVs are transcribed at high levels in rheumatoid arthritis, Sjögren’s disease, systemic lupus erythematosus (SLE), schizophrenia and multiple sclerosis (MS), and are proposed to play a major role in the pathogenesis of these illnesses.

 

[SNT Gatchaman]

And lastly some more passages that stood out to me —

The MSRV virion was the first member of the HERV-W family associated with MS and indeed the first member of the HERV-W family described.

known HERV-W env loci or recombinations among them most likely involving the HERV-W env locus are located on chromosome Xq22.3 [...]
recently challenged by [...] evidence suggesting that MRSV env could originate from as many as six different loci.

the potential for mobilising HERV-W elements in the genome leading to phenomena akin to insertional mutagenesis, or at least temporally variable patterns of gene regulation, would appear to be significant and a source of potential pathology which appears to be under-researched.

reported a positive association between the presence of the single nucleotide polymorphism (SNP) rs662139 T/C in a 3-kb region of Xq22.3 containing a HERV-W env locus and increased susceptibility to MS in females.

The presence of this polymorphism in females was also associated with increased levels of MSRV and disease severity.

When considered as a whole, this evidence is suggestive of HERV involvement in the pathogenesis of MS but is far from conclusive.

Oxidative stress exerts a range of effects on chromatin and DNA methylation levels which broadly favour HERV expression.

Chronic systemic inflammation invariably co-occurs with chronic oxidative stress and this state can also influence the transactivation of HERVs

chronic neuro-inflammation is also characterised by chronically upregulated transcription and activation of NF-κB, which is known to transactivate HERVs

While activated glial cells are responsible for maintaining the chronic neuroinflammation seen in MS, the contribution of recently discovered follicle-like regions, containing follicular helper T cells, B cells and follicular dendritic cells, seen in the brains of some people with the illness, to this inflammatory state is being increasingly recognised

The pattern and levels of gene expression in resting immune cells are also strikingly different. In particular, genes such as TNFRSF17, pivotally involved in the activation of NF-κB and Jak-STAT (Janus kinases/signal transducer and activator of transcription protein) signalling pathways, are significantly upregulated following stimulation in B cells extracted from females, which is a pattern not seen in B cells extracted from males and likely related to oestrogen levels. Males have almost four times the number of circulating Foxp3 regulatory T cells than females and higher numbers of regulatory T cells per se.

Moreover, there is now evidence that Epstein-Barr virus (EBV) is reactivated in B cells of female RRMS patients during relapse but this phenomenon is not seen in the B lymphocytes of male patients.

This observation is important as EBV-encoded glycoprotein 350 (EBV-gp350) induces the expression of HERV-W/MSRV/syncytin-1 in astrocytes, apparently secondary to the upregulation of the NF-κB pathway.

Levels of HERV-W/MRSV transcription are almost two orders of magnitude higher in patients with infectious mononucleosis compared with healthy controls, which provides further evidence of the capacity of EBV to activate these HERVs.

Several herpesviruses have the capacity to stimulate the transactivation of HERV-W. It appears that even inactivated herpesviruses have the ability to transactivate the expression of HERV virions in B cells and monocytes from MS patients, albeit in vitro.

 

[Jonathan Edwards]

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.

 

[FMMM1]

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?

 

[SNT Gatchaman]

Is it of any interest to an ME forum? I cannot quite see why.

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.

 

[hibiscuswahine]

Very interesting, the literature coming out on neuroinflammation.

 

[Medfeb]

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.

 

[Hutan]

In line with previous papers from these authors.

For newer members, Maes and Morris have a bit of a track record of producing vague ME/CFS papers with a lot of suggestions of 'neuroinflammation' and 'immune activation' and 'oxidative stress', often a few diagrams of something, but nothing much that is solid, no new data for example, that might take us forward. I am interested to learn more about HERVs, but I was disappointed to see who the authors are.

I find the idea of alleles of HERV genes on the X chromosome causing problems under certain conditions interesting as a possible explanation of gender skews.

 

[SNT Gatchaman]

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.)

 

[Trish]

We have lots of threads about papers speculating about all sorts of diseases and possible causes. I think better to post any that raise our interest and discuss them, even if they don't appear to have much if any sound science. I find I learn intersting things from critiques of dodgy research as well as from good research.