Wednesday, 6 January 2016

ClinicSpeak & CrowdSpeak: why is EBV so important in MS?

More about our crowdfunding initiative. #ClinicSpeak #CrowdFunding #MSBlog #MSResearch

"Did you know that if you develop infectious mononucleosis (IM) due to Epstein-Barr virus (EBV) infection you are more than twice as likely to develop MS than if you acquire EBV without any symptoms (asymptomatic EBV infection)? Even more impressive is that people who don't get infected with EBV are protected from getting MS. In addition, if you have been tested and shown to be EBV negative and then go onto develop MS you alway get infected with EBV prior to developing MS. These epidemiological insights are the main pillars supporting EBV as the likely cause of MS. What we don't know is how EBV causes MS at a molecular level. Does EBV simply trigger the disease and then have nothing to do with ongoing MS disease activity (the hit and run theory)? Is ongoing EBV infection central to driving MS disease activity (the direct viral hypothesis)? Does EBV trigger another virus to act, for example HERVs (human endogenous retroviruses) (the dual-viral hypothesis)? Does EBV simply act as an essential cofactor in driving autoimmunity (the danger or co-stimulatory signal autoimmune hypothesis)? Does EBV immortalise autoimmune B-cells that drive MS disease activity (B cell hypothesis)?"

"The only way to test these different hypotheses is to do experiments. As there is no good animal model of EBV and MS we need to do these experiments in pwMS. One could argue that the effectiveness of anti-CD20 therapy in MS would suggest that the B-cell is where the money is. However, this may not necessarily be the case. Anti-CD20 therapy depletes B-cells and hence we can't be confident that it is working via an anti-EBV mechanism. This is why we want to test drug(s) that specifically target EBV. If we are able to inhibit EBV replication in the body of pwMS and show it shuts down MS disease activity then this would go a long way to support the direct viral and/or dual viral hypotheses. Sadly, we still don't have a small molecule anti-viral drug that has been licensed to treat EBV infection. Reasons for this are complex and relate to how Pharm works. We are trying to convince Pharma that IM is a worthwhile disease to treat and if they develop anti-EBV drugs there will be a market for them. Despite this we have circumstantial evidence that an old anti-herpes drug is capable of suppressing EBV infection. We now want to test this in pwMS. Before doing this we need show that it is capable of inhibiting EBV pwMS and to find out what dose is required to do this. Once we have answered these two questions we will be able to design a study to test this drug in pwMS."

"We know that people infected with EBV intermittently shed EBV in their saliva. This shedding is due to active EBV infection in the salivary glands. We can use this shedding to test whether or not this anti-viral drug works against EBV. Before doing the trial we need to know how many pwMS shed virus on their saliva and how long they shed virus for in serial samples collected over months. Evidence exist from studies in healthy people that EBV shedding is intermittent and seasonal (see abstract below and figures). What we need is this information from pwMS."

EBV shedding in saliva of normal people. Figure from Ling et al. J Infect Dis. 2003 May 15;187(10):1571-80. 

"The good news is that we can answer this question quickly from a saliva samples collected as part of an another study that was measuring stress hormones. We now want to process these samples ASAP so that we can use the data for power calculations for our proposed dose-finding studies of our anti-viral drug. This is why we are asking you to help us raise the money to do the lab work for this study ASAP. I sincerely hope you can help. If everyone who visited this site donated £1 each time they visited we would raise the money we need in 1 or 2 days. I would like to thank all our supporters who have already donated so kindly; things are going well. Thank you."

Click here to find out more!

"If this work inspires you in any way please send the link to anyone you know who has a personal link with MS. I can't tell you how important it is for us not give up on the viral hypothesis of MS."



Humans are infected with viruses that establish long-term persistent infections. To address whether immunocompetent individuals control virus reactivation globally or independently and to identify patterns of sporadic reactivation, we monitored herpesviruses and polyomaviruses in 30 adults, over 14 months. Epstein-Barr virus (EBV) DNA was quantitated in saliva and peripheral blood mononuclear cells (PBMCs), cytomegalovirus (CMV) was assayed in urine, and JC virus (JCV) and BK virus (BKV) DNAs were assayed in urine and PBMCs. All individuals shed EBV in saliva, whereas 67% had >or=1 blood sample positive for EBV. Levels of EBV varied widely. CMV shedding occurred infrequently but occurred more commonly in younger individuals (P<.03). JCV and BKV virurias were 46.7% and 0%, respectively. JCV shedding was age dependent and occurred commonly in individuals >or=40 years old (P<.03). Seasonal variation was observed in shedding of EBV and JCV, but there was no correlation among shedding of EBV, CMV, and JCV (P>.50). Thus, adults independently control persistent viruses, which display discordant, sporadic reactivations.

46 comments:

  1. So is there a connection, related mechanism, between MS and the chronic fatigue that often follows Epstein Barr infection? Those with chronic fatigue tend not to show high levels of virus. After a very bad second attack of EB, I had a seasonal version that arrived every winter and went away sometime in the summer. It arrived and went away overnight and when it went away (the same night) I always developed a new enlarged lymph node in my neck that stayed. This when on for 6 years.

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  2. And what role does IL-6 play in all of this?

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  3. I felt really excited when I read this and donating feels incredibly empowering. I know it's just one little piece of research in the huge MS puzzle but it could bring finding the elusive holy grail one step closer.

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    1. Thank you, it is much appreciated.

      This is a real community project, which I am very proud of. The ARTEMIS trial was designed by you the community and this project is to enable the ARTEMIS trial. When we were designing the ARTEMIS study someone suggested we use CrowdFunding. I was a bit reticent, but we decided to give it a go. So this is a bit of an experiment. I am not very excited about seeing it through.

      As it is a community research project we will keep you updated on its progress at every stage. Doing research this way will demonstrate in real time how long it takes to do research; i.e. from the idea to getting the result.

      http://multiple-sclerosis-research.blogspot.com/2015/09/crowdspeak-we-will-be-launching-our.html

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  4. I'm not donating a penny. I've raised and contributed to MS causes for years and seen so little materialise for our efforts. Scientists badly design medical trials and everything eventually falls to pieces. We still don't know why MS happens, yet the disease was discovered and titled in the Victorian era.

    I'm boycotting MS.

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    1. Humbug, is that you Ebenezer?

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    2. That's your prerogative but I strongly disagree that we have seen little progress, particularly over recent years.

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    3. You might as well contribute to CCSVI research. It is about as valid as MS being directly caused by EBV. If Team G was in charge of the Chorcote 1 trial and it failed why should they be given a second chance?

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    4. "Ever tried, ever failed? No matter.
      Try again, fail again, fail better" Kinda thing.

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    5. Re: "If Team G was in charge of the Charcot 1 trial and it failed why should they be given a second chance?"

      This attitude explains why so many European entrepreneurs have to leave the EU to go to America to start their companies. If your start-up goes bankrupt in Europe you are blacklisted from getting more money for several years. In the US if your first start-up fails you are more likely to get funding second and third time round. Failure is worn as a badge of honor. Failure shows you can do things, your are prepared to take risks and more importantly you are prepared learn from your mistakes. We doing just that; we are picking ourselves up from the floor, dusting ourselves off and starting again. This time we are starting at base 1; we need to find out if our antiviral works first. We then need to find the correct dose and finally after these two steps we will do a study in pwMS. I am not ashamed of the INSPIRE being negative; it is our badge of honor. At least we are prepared to do something about a possible viral cause of MS. Like us or not, we are not going away.

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    6. Have you heard of the tall poppy syndrome?

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    7. Perfect time for an Edison quote:

      I have not failed. I've just found 10,000 ways that won't work.

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    8. The tall poppy syndrome is a pejorative term primarily used in the United Kingdom, Australia, New Zealand, and other Anglosphere nations to describe a social phenomenon in which people of genuine merit are resented, attacked, cut down, or criticised because their talents or achievements elevate them above or distinguish them from their peers. This is similar to begrudgery, the resentment or envy of the success of a peer.

      A similar saying occurs in Chinese and Japanese culture that translates to "The Nail that stands out gets hammered down"

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    9. Aidan - that quote is the best comment posted in the last 2 weeks!!!

      Team G - you go for it - even if your theories are wrong, at least a cause will have been "ruled out", and that is worth something in itself.

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  5. Good luck with this Prof G. If you can get this off the ground and show that EBV is inextricably linked with MS (regardless of what or how) and then show that dealing with EBV prevents or shuts down MS, then it will be as important as development of the cervical cancer vaccine.

    I had a full-blown case of EBV when I was 16yo - smack bang in the middle of exams. Also had a couple of suspected later infections of it some years later - although the blood tests came back negative on the later occasions, the Dr advised me that there were various forms of EBV viruses which did not (in those days) show up in blood tests. Then 30 years later, and now in my mid-50s, I'm told I have MS.

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  6. But pofy g if ebb shedding is so variable how can this be a substrate for a clinical trial?

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    1. Re: "But Prof G if EBVshedding is so variable how can this be a substrate for a clinical trial?"

      You would like to see close to zero shedding in the treatment arm (EBV suppression) compared to x% shedding in the non-treated arm (not suppressed). We need to do this study to show that our drug suppresses lytic viral infection in pwMS. The real question we have to be able to answer by this enabling study is how many pwMS do we need in each group to be confident that the result is real. The latter is called powering the study. I will do a post on this tomorrow to explain it in more detail.

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    2. But pof g are you going to run a trial in the same time of the year? How will you recruit? Have you really thought this through?

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    3. Re: "But pof g are you going to run a trial in the same time of the year?"

      I am not sure what you mean the same time of the year? It takes x months or years to recruit for trials. Randomisation is how you deal with variables such as season and you can always include that variable as a baseline covariate for which you need to adjust for when you pre-specify your statistical analysis plan.

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    4. if season can reduce ebb what's the point of famv?

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    5. So why do this study? Just save the money and factor it in the analysis. You can power the study based on this results presented here.

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    6. Re: "if season can reduce ebb what's the point of famv?"

      Seasonal effects refer to salivary shedding and viral load. It does not necessarily affect the virus in the other compartments of the body. Saliva is simply the portal for transmitting the virus. This data is from healthy controls; we don't know what happens in pwMS. For all we know there is no seasonal variation. Or the seasonal variation could be linked to season variation in vD levels. The latter is another reason for us to do the study.

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    7. MouseDoctor calls people who find reasons for not doing studies based on theoretical grounds armchair scientists. If we don't know the answer we can theorise until the cows come home and we still won't know the answer. The only way to answer the questions we have posed is to do the studies.

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    8. Re: "So why do this study? Just save the money and factor it in the analysis. You can power the study based on this results presented here."

      If only all peer-reviewer of grants were like you and would accept this. A large number of pwMS on DMTs. What if DMTs reduced viral shedding. If we used these numbers we would under power the study. We discussed this issue at some length and realised we need data from pwMS.

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    9. Pof g the Carter study where these samples are from are part of a trial. Will you be using the placebo arm?

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    10. Pof g how many of these patients are on dmts

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  7. I'm very happy to read of this crucial work. This seems such an important project, thank you for undertaking it. I wish you all the very best with this.

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  8. Good luck Prof G, the mouse doctor and the rest of the team!!! I feel a little bit confident every day I read your posts cause I know that there are people who are actively in this for the long haul. This gives me confidence. This gives me hope.

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  9. Upon doing a literature search briefly on PubMed, I could find only two randomized controlled trials using Valacyclovir. They showed a positive response in highly active MS patients on MRI in one trial and a non-statistically significant clinical improvement in another trial. Why have trials with Famcyclovir and Gancyclovir not have been completed-money? We use these existing drugs daily for many different forms of the herpes virus family. I am afraid your team will all be retired and all MSers will be worse off by the time a new treatment for EBV is from bench to humans. I would expect that if patients in a trial were given one year or lifelong suppressive therapy of the anti-virals after an EBV infection (pre-MS) that it would stop progression/conversion to MS for all the above theories.

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  10. Great news!!! Already will click the link to see how to donate. It is important, through this research many answers can be found to some questions that are already made for some time. And it is the attempts that are the answers. Sir Anthony Epstein and Dr. Yvonne Barr worked hard to prove that EBV, the same virus that they had discovered and which infects 95% of the population in certain people depending on the circumstances and causes various diseases that apparently are not related. The study can look up whether there is a relationship between VD and EBV. Go ahead Docs, do not despair, courage is not for everyone, surely something will come out as a result of this initiative. o//

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  11. EBV is responsible of the "kissing disease". This could maybe explain why immunosuppresion/immunomodulation therapies fail to work sometimes. Most people have partners that they kiss regularly. Maybe the immunosuppresion efficiently get rid of the infected cells and the partner re-infect the MSers regularly... Should our partner be tested for EBV?

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    1. Most partners will be positive if not all, because the partner with MS will be positive and they would infect the partner and over 90% of people without MS are positive anyway. But if you did rid someone of EBV they may get infected quickly again if treatment was not maintained

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    2. How difficult/expensive is it to be tested for the EBV? Would it be possible to ask your GP to be tested for EBV? So if you were to treat MSers with Famciclovir you might want to do the same thing to their partner(s). Maybe it was the reason why charcot 1 failed?

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    3. I dont know the cost sorry. However first thing is does famciclovir does the job

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    4. Famvir? Aciclovir? Another one? Which antiviral would they like to test?

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  12. "viruses outside a cell are as dead as a cow in space". This is a beautiful quote from "Ni dieu, ni genes" a book co-written by the guy who first sequenced the HIV (An estimated virologist as you may have guessed). Quite a change from the textbook view.

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    1. This may be true for HIV as you leave it on a bench for a few minutes and it is dead as a dodo however not so for others like flu and chickpox, flu can survive on banknotes for days-weeks

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    2. My point was that virus are alive contrary to what most people believe, i.e. "Viruses are not alive, so they can’t be ‘killed’." (quote from a great MS researcher). This point immediately raises a question: "How does EBV multiply in an organism?"

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    3. I think most experts would consider viruses as not a living organisms.

      http://www.scientificamerican.com/article/are-viruses-alive-2004/

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    4. To Anon :
      Not only experts say that. This was the topic of my first Biology class after high school: "How do you define life?" and I was told that viruses are by definition not "alive". Biology is full of dogma like that. Now as a researcher in Biology I have a few examples of that: great discoveries often question dogma.

      "Ni Dieu, ni genes" is where this idea comes from, a shame it is not yet translated in English. You have love to read that a "Un virus en dehors d'une cellule est aussi mort qu'une vache dans l'espace".

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  13. An article that might interest you on the link between EBV, MS. They even say that they successfully treated someone with secondary MS.

    Michael P Pender and Scott R Burrow "Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy" Clinical & Translational Immunology (2014) 3, e27; doi:10.1038/cti.2014.25

    And it is open access, no need for sci-hub:
    http://www.nature.com/cti/journal/v3/n10/full/cti201425a.html

    Let's call it a (good) day!

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  14. This has made me think about my fatigue with glandular fever at 19 (awake 6 hours a day, able to function for about 45 minutes in total during that day), and wonder whether my MS fatigue is to do with EBV again. I hadn't realised that EBV stayed in the system. Don't know whether it's a coincidence that after 6 months on tecfidera I had my first autumn since being diagnosed (5 years ago) without major fatigue issues. Good luck.

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  15. Good luck with the crowdsourcing and the project

    I really, really hope the EBV hypothesis turns out to be correct.

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