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Epstein-Barr Virus May Be Turning On Pathogenic Genes in ME/CFS

If there was ever a “prodigal virus” in ME/CFS it would surely be the Epstein-barr virus (EBV). Since the first EBV ME/CFS study 1984 no less than 51 ME/CFS or post-infectious viral studies have featured either Epstein-Barr virus or infectious mononucleosis in their titles. (That leaves out a considerable number of viral and immunological studies which didn’t put EBV in their titles.) While hypotheses of chronic viral reactivation in ME/CFS have lost favor the virus is too complex, too fascinating, and simply too problematic for it not to continue to be studied.

EBV budding out of B-cell

A B-cell with EBV budding out of it

A PubMed search brings up over 500 EBV citations associated with multiple sclerosis and over 30,000 citations associated with the virus.  To get an indication of how broad EBV research continues to be – one of the latest  EBV studies determined if the stress of space flights results in increased levels of EBV reactivation in astronauts. (It did and they advised astronauts to stay away from immunocompromised individuals upon return home…)

The research community clearly continues to find EBV – one of the few viruses our bodies are unable to kick out – a fascinating and important topic. Check out the first in  a series of two blogs on EBV’s possible contributions to ME/CFS.

The Review

In his EBV and ME/CFS review longtime ME/CFS researcher Jonathan Kerr digs down into some past ME/CFS EBV findings which recent understanding of EBV is shedding some new light.

Kerr notes that psychological stress is associated with EBV reactivation and maintaining that state of psychological stress can result in prolonged states of EBV reactivation and diseases such as ME/CFS, nasopharyngeal cancer and post-transplant lymphoproliferative disorder (PTLD).

Many studies have found that stress triggers the release of glucocorticoids which tell the pathogen that the coast is clear and it’s time to start growing the family and producing more virions.

Whether or not the original ME/CFS trigger is associated with increased levels of  psychological stress, the dysfunctions found in both stress response axes (HPA axis, autonomic nervous system) post-ME/CFS suggests that psychological stress could  possibly give a bug like EBV a leg up in diseases like ME/CFS. Plus, other studies have found evidence of an immune hole which could give EBV an extra foothold in ME/CFS.

In the U.S., Ariza and Williams have shown that attempts at EBV replication in ME/CFS can trigger the production of an enzyme called EBV dUTPase which, among other things, results in the production of pro-inflammatory cytokines which may produce fatigue, pain, flu-like symptoms, etc.

Kerr’s group in the U.K., though, has taken a different tack.

The 2008 Study

Assessing the expression of 88 genes Kerr suspected were playing a role in ME/CFS, his group was able to separate healthy controls from ME/CFS patients, and then break those ME/CFS patients into 7 subsets in 2008. No less than 12 of the genes his group assessed were known to be associated with EBV.

Finding such a huge split in gene expression between ME/CFS patients and healthy controls, and then being able to split up the ME/CFS group into gene expression subsets with unique symptom profiles, was striking.

One of the genes which stuck out back then is called Epstein-Barr Virus (EBV) induced gene 2 (EBI2). While EBI2 sounds like it comes from EBV, it’s a human gene. As EBV begins to reactivate it induces the expression of this gene, which regulates B-cell functioning, T-cell mediated antibody responses, and inflammation.

Kerr’s 2008 study suggested the gene was working overtime in 55% of ME/CFS patients. In another analysis, EBI2 was upregulated in 38% of 31 patients vs zero of 40 healthy controls.

The 2010 Study

A larger (n=117 ME/CFS patients) 2010 study analyzed antibodies associated with EBV in eight gene expression subsets. As before, twelve of these genes were known to be associated with Epstein-barr virus (EBV)

EBV Gene 2 expression

Greatly increased expression of the EBV Induced Gene 2 was found in the ME/CFS group

One subset – subset D – stood out in its severity. This group of patients, all females, demonstrated a consistency of the worst kind, posting the lowest functional scores  in no less than five of SF-36 functional domains (physical role, vitality, general health, bodily pain, and total score) and experiencing high rates of muscle pain and sleep issues.

They also led the pack in the expression of  EBV associated genes. Their EB12 genes were turned on and pumping away at higher levels of activity than in any of the other groups. So were all the other 11 associated EBV genes.

In other words, this appeared to be a highly afflicted EBV ME/CFS subset.  EBV may be involved in other subsets, but it appeared to be wreaking special havoc in this one.

Interestingly, the abnormal antibody (EBNA IgG) result found indicated the antibody was not elevated but was reduced. Since antibodies play a key role in immune clearance, the low levels suggested an immune deficit could be present.  For one, they suggested EBV was probably more often found in its latent state in this group.

EBV is found in two forms: its lytic form occurs mostly in epithelial cells, and its latent form in B-cells.  The low levels of EBNA IgG appear to suggest, if I have it right, that EBV is able to survive in B-cells longer, giving it more time, one would think, to possibly tweak those B-cells more. That’s an interesting finding given the role B-cells play in autoimmunity.

Nine Years Later – Science Marches On

Nine years ago, not much was known about EB12 but science has been moving on. EB12 is now recognized as a “critical regulator of the immune response”. It ordinarily plays a valuable role in the interaction between B and T-cell and the antibody response.

Gene expression

Jonathan Kerr believes EBV may be causing a gene to over express itself in ME/CFS

As one might suspect, though, EBV activation of this gene is not associated with good outcomes.  Increased EBI2 expression appears to dysregulate the delicate immune response – increasing B-cell activity (and therefore the risk of autoimmunity)  – while inhibiting T-cell activity – and potentially suppressing the immune system’s ability to deter pathogens and knock out cancerous cells. Kerr pointed out that EBI2 could also be contributing to the reduced cerebral perfusion, gray matter reduction and white matter hyper intensities found in both multiple sclerosis and ME/CFS.

Given the findings of the past 11 years, Kerr suggested that the EB12 gene deserves a deeper look in this disease.  The possibility that a severely ill EBV subset – characterized by a hyperactivation of the EBI2 gene – is present, is, of course enticing. Given that ME/CFS often has an infectious trigger, a special EBV subset makes perfect sense, and if it is present, it may offer some unforseen opportunities.

One of the advantages of having an upregulated gene that’s been implicated in a bunch of nasty diseases is possible increased interest from big pharma. If the EBI2 gene is wreaking havoc in some of the more severely ill ME/CFS patients, help may be at hand in the future.  Kerr pointed to two EBI2 modulators  (GSK682753A, NIBR189) currently under development.

Kerr acknowledged several caveats to his hypothesis. His findings need to be validated by other laboratories using other sets of ME/CFS patients. He noted that finding EBV antibodies in ME/CFS does not in any way indicate that the bug is causing ME/CFS – that is still in doubt. His hypothesis – that EBI2 upregulation is playing an important role in a subset of ME/CFS patients –  is unproven at this point.

It’s a hypothesis though, which is consistent with the data presented thus far and could account for “many of the immune and neurological abnormalities” found in a group of patients.

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40 Comments

  • Brenda

    June 29, 2019 at 5:50 pm - Reply

    I have severe FMS. I have lab test showing a “high” level of EBV antibodies (according to Dr. Dantini’s protocol). I took antivirals and celebrex for 6 months with no improvement before finding out the antivirals don’t work for EBV due to it not having the enzyme for reproduction that antivirals target. (Grrrr!) I even figured out later, after talking to my sister, that I was exposed to my her when she left college to recover post mononucleosis…and 1 month later, the pain started and full blown Fibromyalgia entered my life. Coincidence? Nope! I doubt it!
    18 years later, I am still very ill, unable to even shower or wash my hair on a daily basis. I’ve tried almost every path to wellness others have experienced remission with.
    *I just wish most studies on CFS/ME, especially with larger #’s of subjects, would also have a sub of FMS patients. They’re so similar and I like many suspect many of these autoimmune type illnesses are the same, presenting differently according to individual gene expressions and bio-physiology.
    This info is like an elbow nudge; I hope some researchers are piqued. Thank you for sharing this!
    Thanks Cort for keeping us up on cutting edge research most don’t even know or hear about! You are a lifeline to me! I’m certain your efforts will bring together and result in the research and results we all hope for! I just know it!

  • Guido den Broeder

    June 29, 2019 at 7:24 pm - Reply

    There exists no disease named ‘ME/CFS’, it is a fairytale for propaganda purposes.

    The disease ME is a polio variant, going back to at least 1894. Latent EBV can derail the immune system, making people more susceptible to ME and other neuroimmune diseases, but it doesn’t trigger ME.

    • Cort Johnson

      June 29, 2019 at 9:08 pm - Reply

      If only we had the research to back that up. Then the entire field could focus on the polio variant and we could cure this thing instead of wasting our time on these side issues.

      My guess is that if the polio variant hypothesis really made sense then a) the bug would show up in the pathogen studies that are using the latest technologies and b) someone would try to find it. This old hypothesis hasn’t gotten traction for decades, though. There must be a reason for that.

  • Kristi

    June 29, 2019 at 9:43 pm - Reply

    This really makes sense to me. I was infected w/EPV in 1978 and got ME/CFS in 1994, after prolonged stress at work. I hope this research continues to help people like me and others who are very ill.

  • Rita

    June 30, 2019 at 2:09 am - Reply

    I had severe mono at 13, fever 105, enlarged spleen, enlarged liver, swollen leg?
    I’m now 56 My Dr tested me for EBV and my VCA- IGG & EBNA- IGG both very high positive, my Dr. Asked me ‘ what is this? I still don’t know what it means for sure, also lyme test , Elisa very high positive 1.43 I think, in 3 different tests, yet Western negative.
    Dr’s told me I was negative for Lyme, now I look back in my records it says positive for previous Lyme testing?
    So I don’t know? and I’m not so confident that a large percentage of our Dr’s even know for sure.
    Yet for 11 years since becoming I’ll, I’ve had severe symptoms of both diseases, including shingles rash.
    Liver abnormalities, nerve damage, arthritis reactive, swollen lymph nodes, sore throat, severe fatigue, etc..
    Problem is as time goes by we get worse and develope other health issues, that could all be from initial infections, but are treated as all seperate illnesses?
    I don’t know what’s heads or tales anymore? Losing faith that we will ever know in my life time anyway.

  • Libby Boone

    June 30, 2019 at 6:41 am - Reply

    Brenda –

    I think some of the studies are including FM people. I could be wrong, because the parameters keep shifting. But I guess the only thing you can do is see if you fit any or all of the M.E./CFS/FM diagnostic criteria and check which groups are using which case definitions in their research.

    At any rate, using more narrow criteria is a good thing too, because it could turn out that people currently diagnosed with FM will learn something from that research – the same way as people who fit the various diagnostic criteria for M.E. or CFS. And apparently various immune signatures alter over time within one patient over the course of the illness.

  • Tony

    June 30, 2019 at 7:57 am - Reply

    Hi Brenda, Dr Martin learner said EBV is controlled by Valacyclovir http://www.treatmentcenterforcfs.com/documents/MECFSTreatmentResourceGuideforPractitioners.pdf Where was your info on EBV not being controlled by anti virals? Thanks

  • Lori

    June 30, 2019 at 8:06 am - Reply

    “The Mono Project” has been underway for quite some time at the University of Minnesota. In partnership with “industry,” recognizing how serious a health threat this virus is and its strong association with several cancers, MS, and other potentially fatal medical conditions, the U of M is trying to develop a vaccine for EBV. This vaccine has the “potential” to decrease the number of NEW cases of ME CFS that would have otherwise been “triggered” by the EBV virus. It seems to me we need to somehow bring this research effort into the ME CFS “fold.” There may be some unexpected benefits.

  • Tony

    June 30, 2019 at 8:24 am - Reply

    Additionally, this research (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025560/) say’s anti virals work clinically but not as well in practise. However, the testing was only carried out for 21 days, leading experts say this is the problem, anti virals have to be taken for years, Dr Jose Montoya said 5 years. Professor Ron Davies also said long term anti virals work on EBV.

  • Carolyn Richards

    June 30, 2019 at 3:59 pm - Reply

    This sounds quite logical in my particular case. Back in 1989 I was diagnosed with EBV then CEBV as I continued to have a fever. o was 46 at the time, cannot remember if I had mono when teenager. My father became ill and was terminal and then my son was killed with heavy equipment. Stress is putting it mildly. I have gone over different scenarios many times and remembered reading an article where rats were stressed by long term swimming then injected with dye and the dye seeped into the brain. Thus assuming the blood brain barrier may be compromised during stress. As time went on I moved and was diagnosed with Lyme, treated IV Rocephin plus other orals. Then diagnosed in Miami (Klimas) with CFIDS, and also in Miami with MS by Sheramata. Did do some oral antibiotics locally with infectious disease doctor and was diagnosed with Mycoplasma pneumonia (PCR) from Irvine CA. Doxy seemed to work on (something) had difficulty completing a sentence but improved with antibiotics. Klimas was then taking people who had high levels of EBV, I remember also having high titers I believe would have to check in EA & Nuclear. This was almost 10 years later. Then got diagnosed with RA, then they found a spot on a lung, had lobectomy from cancer. Now diagnosed with Mantel Cell lymphoma of course I was also an avid user of Roundup. However it sounds like I may fall into this category. Back in 1997 Klimas said that I fell into one of the CFIDS categories. EBV has long been associated with cancer.

  • Amy

    June 30, 2019 at 5:02 pm - Reply

    Carolyn Richards, do you still see Dr. Klimas? we have an appointment tomorrow at her clinic in Ft. Lauderdale. My son has been diagnosed with ME/CFS hoping we will get some answers

  • Annette

    June 30, 2019 at 5:15 pm - Reply

    I’ve only recently found out I have EBV after being ill 2 decades

    • Cort Johnson

      June 30, 2019 at 5:32 pm - Reply

      Well, your doctors have not been very quick off the mark have they? I take it your tests show signs of viral reactivation.

  • Annette

    June 30, 2019 at 5:19 pm - Reply

    And I had cancer as well 6 years ago always something I have a array of health problems that impact my life considerably managed to raise 2 kids alone and I’m’ comfortable ‘ bring lonliness I live as peaceful as I can now after recievi g no help wherever M. E comes from… At least we can talk online now back in first years of illness I was totally isolated

  • Cort Johnson

    June 30, 2019 at 5:23 pm - Reply

    To Brenda: It’s really a shame that ME/CFS and FM aren’t studied together more. I think, in many cases, whether you’re diagnosed with one or the other simply depends on which doctor you see first.

  • Cort Johnson

    June 30, 2019 at 5:26 pm - Reply

    Thanks for the reminder regarding The Mono Project! It’s encouraging that EBV research continues and I agree we need to get ME/CFS in there more. Given it’s background I’m surprised that it’s not.

  • Cort Johnson

    June 30, 2019 at 5:29 pm - Reply

    Yes, I believe Dr. Lerner had his patients on antivirals for at least a year. Montoya’s second antiviral study was starting to show results at the end of it but it may have ended too quickly for the real benefits to show up.

    A subset of patients respond very well to antivirals.

  • Terry Kay

    June 30, 2019 at 5:29 pm - Reply

    This rings true for me. I also began my CFS/ME journey with a lengthy (3 months) & extreme viral-like illness (had a poor doc, never tested me for anything), that occurred after a few years of extreme stress. Thirty years later I’m calmer but certainly have the underlying ruminating stress of being chronically ill. Maybe this is why the Gupta program works for some, if stress really offers viral overload a leg up. Time to start meditating.

    • Cort Johnson

      June 30, 2019 at 5:31 pm - Reply

      My thoughts exactly. Some other findings also suggest a hyper-sensitive immune system – put on alert by stress perhaps- may be present in ME/CFS.

  • David

    June 30, 2019 at 5:31 pm - Reply

    I don’t have the energy to read and understand this article. just too tired. at age 62, i feel i have little time left. doctors dont care as i’ve had CFS most my life and when i mention it they just roll their eyes at me then try to trow antidepressants at me over and over again.

    government docent care as they make it impossible to get on ss disability even though iv always paid my way and earned help. im the best saddle maker in my state and iv worked all my life up until last month as i was becoming unsafe to drive.

    iv read where CFS/EBV gets worse with trauma. and iv had more than my fare share. now living on $1200 a month SS. every day feels traumatic as i have bad anxiety from my child molesting father. i fear most every thing. which make the it worse.

    any way dont know why i even posted this. just need to tell someone about me i guess.

    • Cort Johnson

      June 30, 2019 at 5:41 pm - Reply

      Thanks for communicating David. If you can’t communicate something like that here – where can you? I’m sorry about your difficult situation and acknowledge there’s lot’s to worry about.

      In my experience, though, you are correct – fear makes everything worse – which is one reason I suspect EBV plays a role. The stress connection is just too obvious, at least for me.

      Being afraid of the fear of course only exacerbates it – so it might be useful to let it be there – let it bubble up a bit – observe it, let it be – and see if it lessens and leaves you and your body feeling a bit better.

      Please don’t give up hope. Health Rising has several recovery stories coming of people who were truly in difficult situations and managed to find their way out of it. The fact that we have so many interesting hypotheses now is encouraging as well. You never know what might show up and, sorry about the pun – get you back in the saddle again. Keep up the hope!

  • Sarah R.

    June 30, 2019 at 6:24 pm - Reply

    I had mono as a teenager, and I was diagnosed in 2004 with fibromyalgia and with ME/CFS in 2006. I’ve been on 3 grams of valacyclovir/day for probably 12 years now. I believe it’s keeping me somewhat functional (can go grocery shopping if I have to), and I know I’m more comfortable without constant swollen glands, sore throat, etc. A couple of years ago I went downhill in a hurry–had increased mono-like symptoms–and I decided there was little, if any of the active ingredient in valacyclovir I was taking. This seemed to be borne out by FDA reports on the company. I switched pharmacies and told the pharmacist my problem with that company’s product. He delivered valacyclovir from a different maker, and my symptoms receded again. I believe I would be much more ill and miserable if I didn’t have access to antivirals.

  • Tony

    June 30, 2019 at 8:16 pm - Reply

    I’m in the UK, 53 and have been ill for 26 years, the last 20 months unable to work, but for years dragged myself to work and home to collapse on the sofa every night / weekend. It started with an EBV diagnoses and whilst I made limited recoveries never a total one in that time. I now have a ME / CFS diagnosis. I searched my medical records and realised that two illnesses I had during my childhood would now be classified as ME / CFS, I did however recover both times after a few years. My childhood illnesses started with chicken pox and the next shingles. I have fallen ill with shingles numerous times since 1993 and one time was admitted to hospital with viral meningitis. I commenced valacyclovir four months ago and as the experts inform, have noticed slight improvements. I aim to continue taking them and hope a new healthier chapter is awaiting me. Good luck to us all.

  • Rivka

    June 30, 2019 at 9:44 pm - Reply

    Thanks for the article. Interestingly, i just today stumbled across this website: https://ebvhelp.com
    She is not an MD, but maybe a nutritionist, I’m not sure yet…? I see she wrote a book and offers an online class. i have no affiliation to the provider, but it looks interesting to me.

    • Cort Johnson

      July 1, 2019 at 4:37 pm - Reply

      It looks interesting to me too.

  • Carolyn

    June 30, 2019 at 11:15 pm - Reply

    Amy,

    I haven’t seen Klimas for about 20 years but research has come a long way since then. The best piece of advice I could give anyone is don’t overdo. Pushing ones self is self destructive. Plus the young have a much better chance of kicking this disease.

  • Aidan

    July 1, 2019 at 12:46 am - Reply

    They keep saying reactivation, it is onlyAntibodies, I was followed byone of the top HIV/Aids Doctors on theentire Globe he said stop reading about Antibodies you will bring Antibodies to your Grave you do not have any current infection you had Mono at some time in your life the Antibodies go up & down they are part of life…Someone must be pushing false hopes or dreaming or have Patents on useless Drugs stop believeing this garbage

  • Aidan

    July 1, 2019 at 12:49 am - Reply

    She Sellls Books, Run far far away…Too many Quacks & Liars now selling or Snake Oils

  • Aidan

    July 1, 2019 at 1:09 am - Reply

    I read a great article about a Family History they all were diagnosed with CFS Fibro EDS 3 over the years they all also had Genetic tests done they had 2 Types GSD Glycogen Storage Disease VIII & IX the number VIII GSD is now classed as a type of IX I think 3 kinds of IX…I think

    the term Chronic Fatigue Syndrome or call it ME is a Hoax stupid label name that has gone down the wrong side of the rode & has been plagued by useless stupid ideology treatments, we need some new Life in Doctors looking at all other possibilities of what it really is this illness

    I recall they used to call this Chronic EBV another silly Name…Antivirals also cause Lung Cancer they are horrendous toxic drugs…They can have their antivirals I will not touch them…Where is all the hoax gone on the Herpes Virus 1 big talk, absolutely Nothing…Coriell Institute for Medical Research is gifted in GSD types

    • Cort Johnson

      July 1, 2019 at 4:36 pm - Reply

      Very interesting Aidan!You wouldn’t happen to have a link to that family story do you? Glycogen Storage disease has shown up in two studies – both unpublished thus far – that I know. It looks like its going to be a part of the story for some of us.

  • Aidan

    July 1, 2019 at 1:21 am - Reply

    & there is a Doctor now in Japan making a Vaccine saying the Cause is Mycoplasma pneoumonia funded by the Japanes Government, another Dreamer

  • sophie

    July 1, 2019 at 9:37 am - Reply

    *orders some B-cell eliminating Rituximab from my online drugstore* ;p an think EBV is suppósed to activate to finish us off when we’re under some other fatal attack anyway but in us it gets confused and comes into action too soon ;(

  • Suki

    July 1, 2019 at 9:53 am - Reply

    I have gotten a lot of improvement from my CFS and FM by following the anti-viral diet in Anthony William’s first book, along with his detox smoothie. Cutting out dairy, gluten, and eggs helped with the FM pain and prickly headaches. They are gone now. Taking the adenosylcobalamin form of B-12 also helped the nerves.

    • Cort Johnson

      July 1, 2019 at 4:34 pm - Reply

      Isn’t that something Suki! It’s amazing the effect some foods can have. Thanks so much for passing that on. 🙂
      He is an interesting guy!

  • Griffin

    July 2, 2019 at 12:27 am - Reply

    Tony –

    Similar history with EBV. I saw Dr Bansal at Sutton & Cheam hospital (before he retired) about Lerner’s research as I also have tachycardia. He put me on Acyclovir. It didn’t work. But it was a much lower dose than they used in the trial. He said the dose they used would be dangerous outside trial conditions. Since I never recovered from EBV and my symptoms date from them I have always assumed my CFS comes from this. Convinced there’s a link.

  • Fabio

    July 2, 2019 at 12:42 pm - Reply

    My story is the same of many others. Got mono at age of 24. My lymphnodes were as big as tennis balls. Doctors at first thought I had AIDS (while I never had HIV). I never recovered from mono, but about 10 years later in a period of big stres at work I developed ME/CFS in a worse form (now I have the mild form with Idiopathic Hypersomnia) . Unfortunately here in Italy there are no doctors who will prescribe valacylovir (valgancyclovir cannot be prescribed at all) even if I have very high antibodies of past infections, while IVIG , Immunovir (Viruxan in Italy) didn’t work at all.

  • Tony

    July 4, 2019 at 6:44 pm - Reply

    Hi Griffin, and Fabio, the below could be of use for you too?

    I have been given aciclovir just recently as a preventative to shingles by my GP. Dr Learner also released the following for practitioners who were willing to prescribe anti virals for ME/CFS, http://www.treatmentcenterforcfs.com/documents/MECFSTreatmentResourceGuideforPractitioners.pdf . It’s considered that anti virals are a relatively safe drug, or at least when I’ve discussed it with relevant medics they agree so. Following Learners protocol wold be strongly advised. I have also been taking valacyclovir at 1g x 3 and acyclovir 2 x 400mg a day for about 4 months and I have experienced a slight improvement in my symptoms as Learner and Montoya said would happen. I found a private practitioner who was willing to help me with this.

  • Britt

    August 29, 2019 at 8:23 am - Reply

    Hi Cort, i always wonder why it is “maybe” EBV causes M E. From the day i got EBV, at 17 years d, i never got my energy back. Lateron my trouble with energy is diagnosed as M E, but it is defenitely related to EBV, i remember exactly the moment i got ill, at the day i got EBV, Pfeiffer.

    • Cort Johnson

      August 29, 2019 at 7:46 pm - Reply

      A) if you first get exposed to EBV during adolescence or later the body often really has a hard time fighting it off – you’re behind the 8-ball at bit simply by encountering at 17
      B) Plus some evidence suggests that people who get ME/CFS from have some immune holes which make it even harder to fight that virus off.

      I imagine we will find out more as time goes on. It should be noted that EBV is a very powerful virus that also increases the risk of multiple sclerosis.