Virus, virus where art thou hiding?

V

Barts-MS rose-tinted-odometer: ★★★★★★★★★★

Would you volunteer to participate in a clinical trial of an antiviral drug cocktail to suppress MS disease activity, in particular smouldering MS?

There is reasonable evidence in the literature that HERVs (human endogenous retroviruses) may play a role in autoimmunity, in particular MS. HERVs are viruses (genetic code) that have been incorporated into the human genome over deep time. Some HERV genetic elements have taken on important functional roles, for example, they are involved in the development of the mammalian placenta and hence are part of our human biology. 

When HERVs elements are transcribed they may be capable of forming replication-competent viruses, which can reinfect cells and integrate back into the genome. These reintegration sites may be important in themselves and may drive the selection of cells with enhanced functions and may also result in cancer. Other HERV elements are replication-incompetent and although they can produce functional transcripts can’t form an infectious virus. 

Some HERV proteins act as danger signals activating so-called toll-like receptors and other danger-signalling pathways. These pathways then upregulate innate immunity and provide the immunological nudge that drives autoimmunity. This is why there have been some attempts to try and suppress HERV activation with antiviral drugs or to neutralise some of the HERV proteins that may activate the immune system, or are directly toxic to myelin-producing cells and/or neurones, as a treatment for MS. 

These HERV-related hypotheses are supported by several studies showing upregulation of HERVs transcripts and HERV proteins in the brains of people with MS. The study below uses a new technology called next-generation RNA sequencing to show that some HERV-W (a specific type of HERV) transcripts are exclusively present in MS brains and as they are located on chromosome 7 close to one of the MS genetic risk loci may be relevant to MS. Could this finding be part of the proof we need to show that HERV-W may be in the causal pathway that leads to the development of MS? Importantly, HERV transcripts (RNA message) close to the MS risk locus on chromosome 7 were overrepresented in MS brains. 

Although some would interpret these findings as being potentially causal, i.e. HERV transactivation and expression is driving the pathology that is MS, another interpretation is that whatever causes MS transactivates HERVs, which is then simply a bystander phenomenon. The only way to separate ‘causation’ from ‘association’ is to do an experiment to suppress HERV transactivation to see if it improves MS outcomes. This is a conclusion that Prof. Julian Gold and I came to several years ago and is why we have been trying to get funding to do a CNS penetrant combination antiretroviral trial in MS.

Some of the cynics will ask ‘well what about your EBV hypothesis’? Interestingly, EBV and some of the other herpes viruses are potent transactivators of HERVs, i.e. infection with EBV wakes-up HERVs in our genome and results in their transcription. Therefore, increased HERVs may be a marker of EBV infection. This may be important, but recent data indicates that some HAART (highly active antiretroviral therapies) components are also effective against EBV. Therefore, clinical trials of HAART may actually target both EBV and HERVs. This is why I am so excited about the news that a small HAART trial in MS will be starting soon in the US.  However, Prof. Julian Gold and I, as part of our Charcot Project, will still continue to prod and encourage big Pharma companies (ViiV-GSK, Gilead, Merck, etc.) with a footprint in the antiretroviral space, to come to the table with their products (HAART) and money to fund a large adequately powered study to test the hypothesis in a definitive MS study. 

It would be a travesty if in 20 years time the next generation of MS researchers discover that HAART is a very effective treatment for MS when we have the tools to answer this question now, i.e. in the next 4 to 5 years? In fact, we have a clue that this may be the case already. Having HIV infection protects one from getting MS. This may be due to the therapy (HAART) that is used to treat HIV and not due to the HIV virus itself. 

As you know outside-the-box ideas or paradigm shifts often take generations to occur. So you shouldn’t be surprised if the MS community continues to reject these hypotheses and nothing happens for decades.   

Maria L Elkjaer et  al. Unbiased examination of genome-wide human endogenous retrovirus transcripts in MS brain lesions. Mult Scler. 2021 Jan 19;1352458520987269. doi: 10.1177/1352458520987269. 

Background: Human endogenous retrovirus (HERV) expression in multiple sclerosis (MS) brain lesions may contribute to chronic inflammation, but the expression of genome-wide HERVs in different MS lesions is unknown.

Objective: We examined the HERV expression landscape in different MS lesions compared to control brains.

Methods: Transcripts from 71 MS brain samples and 25 control WM were obtained by C and mapped against HERV transcripts across the human genome. Differential expression of mapped HERV-W and HERV-H reads between MS lesion types and controls was analysed.

Results: Out of 6.38 billion high-quality paired-end reads, 174 million reads (2.73%) mapped to HERV transcripts. There was no difference in HERVs expression level between MS and control brains, but HERV-W transcripts were significantly reduced in chronic active lesions. Of the four HERV-W transcripts exclusively present in MS, ERV3633503 located on chromosome 7q21.13 close to the MS genetic risk locus had the highest number of reads. In the HERV-H family, 75% of transcripts located to nearby 7q21-22 were overrepresented in MS, and ERV3643914 was expressed more than 16 times in MS compared to control brains. 

Conclusion: Novel HERV-W and HERV-H transcripts located at chromosome 7 regions were uniquely expressed in MS lesions, indicating their potential role in brain lesion evolution.

CoI: multiple

Twitter: @gavinGiovannoni                                    Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

44 comments

  • Interesting findings.

    Meanwhile an mRNA based application to suppress disease in EAE and to conceptualize a vaccine for MS may be on the horizon. As published in Science, Jan 2021, I believe and it is big.

    • Look at the data it isnt good enough, but they willl have the money to do it. There is no excuse for it not to work if they have their mechanism right so lets hope they dont mess up.

  • “As you know outside-the-box ideas or paradigm shifts often take generations to occur. So you shouldn’t be surprised if the MS community continues to reject these hypotheses and nothing happens for decades.”

    What a defeatist attitude! Why bother getting out of bed each morning?

    As Gandhi said “Be the change that you wish to see in the world.”

    You’ve hidden behind the “science is slow” excuse for years. Your recent accident should have convinced you that time is precious. Rather than coming up with excuses why things don’t happen, make them happen. Perhaps the G in Prof G stands for gutless?

    My late uncle used to say “there are talkers and doers”. I fear you fall into the latter. Enough readers of this blog would be happy to get involved in a HAART trial (and pay there own way rather than see you hobbling through a London park to raise a few quid). Your defeatist attitude and churning out the same excuses for failing to get things moving is not what one would expect from a South African. I know the readers of the blog will rally to your defence, but some honesty is needed. I attended the research days with Prof Gold and got sucked into the hope of an anti-viral trial. It’s time to deliver some positive results.

    • Three grant rejections later and numerous meetings later with Gilead, ViiV and Merck our energy levels flagged. Maybe time to go back to them with the new data. To be fair to Merck they did fund our raltegravir trial.

      • You’re free to say whatever you want Mr Sid
        So am I, so here’s some feedback: Your posts are useless
        (This is a politer version of what I originally wrote)

        Take your own advice and “Be the change that you wish to see in the world.”
        Set up the trials, do the tests, find out the cause of MS, find a cure

        Not possible? Too much to ask? Why?
        You’re demanding a miracle. Why not perform the miracle yourself?

        • Sadly, trials cost many millions and we just don’t have the funds. Simple, but true, even if participants offer to pay their own costs, which they are not allowed to do.

    • Julian (Prof Gold), how are your energy levels? Looking forward to seeing you back in London. Time for some grant writing and Big Pharma meetings again?

  • I’m ready for this! Also always looking for wisdom in my old school copaxone. Is this protein soup I inject fooling my immune system?

  • New data X Improvements in vaccination technology X The ball rolling on vaccinations and knowledge right now
    May= A better time then ever to look at this.

    Hope you get somewhere Prof G 👍

  • Thank you Prof G and yes, I would be happy to sign up too!

    I do believe my MS is smouldering away and I say – ‘Inflammation, inflammation inflammation!’

    By the way – have you had any luck patenting your amazing glasses for reading lying down! Reason why I’m asking – I have had a few requests for folk with various health problems to enable them to use their laptop or read whilst lying down! Although, I think they should be sleeping or resting 🙂

    Take care,

    Jane

  • ‘the viral hypothesis of MS will continue to be rejected by the wider MS community’…..an “outside the box idea’

    The viral hypothesis is far from an ‘outside the box’ hypothesis. The viral hypothesis has been the subject of thousands of serious, published extensive investigations for many decades, and is still being investigated using probes for viral ‘imprints’ with remarkable power.

    The problem that you have is that the results of these investigations in MS have largely been negative. There are very good reasons to doubt the involvement of hidden virus in MS.

    It would be illuminating an appropriate to present the potent reasons behind the ‘rejection’ of your proposals rather than imply that the ‘rejection’ (to the detriment of PwMS) is unjustified and a potential ‘travesty’.

    • Frederick. The response to our proposals seem a little like the response to Biden’s recent victory in the US. Some people just don’t want to believe it, despite irrefutable evidence to the contrary. The reviewers (only one or two) stated that they just don’t believe a virus could be involved in the pathogenesis of MS, despite a huge amount of laboratory evidence (see attached study). The reviewers just don’t want to consider doing a trial, even a well designed pilot study of combination antiviral therapy. However, in defense of reviewers, most agreed that a trial is indicated and essential. Sadly, some still insist on ‘alternate facts’ to make their judgement. Gavin needs to keep fighting so the goodies will win.

  • Wait before meeting with big pharma again, 2 key studies are about to come out that will help you peak their interest. Wait another 1-2 month before applying. Another gammaherpes virus 68 study is about to come out well actually 2-3 but only one of them will be of interest. As well as another study on haart that will surely help you out.

      • On february 1 2021 I will post a link here ( on the respective page that it will be posted on ) of the first gammaherpes virus 68 study I am referencing if it is not on pubmed by then. This will be the first one of an interesting series of gammaherpes virus 68 study.

  • This is very exciting. It is rare that I read anything about MS these days that really sparks my interest.

    The involvement of innate immunity upregulation by HERVs would ring true with my experience. I have early onset PPMS. My innate immunity must be pretty hyperactive, because I can’t remember having a full blown cold for about 20+ years. At most, I get a brief sore throat.

    I wonder if MS can shift gears through one’s life, depending on viral (EBV / herpes) infections.

    Because of where I live, it’s unlikely I could participate in a study, but thank you for pushing the boat out, for going the extra mile. Please don’t give up on those of us who are smouldering away.

  • 100% yes. As a person who has never had a relapse, I dont see MS for myself as anything but smoldering. I found out that my wierd progressive symptoms were ms the same year I found out my daughter has EBV. Everyone gets EBV, sure. But with my MS history, I want her to have a treatment even though she doesn’t have MS yet.

  • You should also consider EBNA1 inhibitors that block EBV latent replication. The drug has a good safety profile–owing to the fact that EBNA1 doesn’t share structural homology with any known cellular protein. We may also be observing effects on EBV biomarkers in patients with advanced EBV-positive nasopharyngeal carcinoma. But it is still early and not yet published.

  • I have MS and had a relapse 3 days after a flu injection. I am now nervous of having the Oxford/Astrazeneca covid vaccine. Am I right to be and if so can I ask for the Pfizer vaccine instead?

  • I’d sign up but I’m NEDA and >70. Few studies are available to my age group. Silly really, as people still present the same way. It’s just that I don’t, but then there must be something at molecular level. Maybe.

  • Sid. Aren’t you being a bitter old git? It’s fair enough, as you may be really very ill, but look out for the old enemy – self pity.

  • Thanks for this, Prof G. I’m not in the UK, but if you could get Germany involved, I’d definitely sign up.

    PS – You have the patience of a saint.
    PPS – Sid, I’ve weirdly kind of missed you.

  • If HAART gets rid of EBV infection, reinfection would still be a high possibility unless we have a vaccine by then? or we are talking about a maintaining-DMT-like approach?

  • I looked up Prof Gold and found an interesting video. Do you know if the Lighthouse phase 3 Truimeq trial has/will begin?

    If I was eligible I would join an ms trial.

  • Gavin, my energy levels have never been higher. The Australian Government is keeping us all locked Down Under; for our own protection; so coming back to London isn’t in my control, although I would come tomorrow if I could. The study you summarize is another brick in the wall of proof that a trial absolutely needs to be done of combination antiretroviral therapy. We have safe, effective drugs which must be tested. Sadly, they are quite expensive and we need Pharma involvement. I am optimistic we can achieve this in the not-too-distant future. I am committed to be involved and to see our Charcot project come to fruition.nStay well Gavin and keep fighting for this. You are a beacon.

  • Fantastic post Gavin. Ive has mild MS most of my life and been lucky and aggressive with my lifestyle, but the HERV hypothesis is incredibly interesting and might point us in the right therapeutic direction. Frank Ryan and his books “Virolution” and Virusphere” changed he way I looked at MS, evolution and biology. It brings life science up to date and Im sure will lead to a new ageo of therapeutics. An mRNA vaccine for HERV W?

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