You are here: Simmaron ResearchPathogensCould Crippled Herpesviruses Be Contributing to Chronic Fatigue Syndrome (ME/CFS) and Other Diseases?

Could Crippled Herpesviruses Be Contributing to Chronic Fatigue Syndrome (ME/CFS) and Other Diseases?

We provide evidence…. that herpesviruses dUTPases…(have) unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer. Williams et. al.

Most people are exposed to herpesviruses such as Epstein-Barr virus (EBV) early in their lives and carry the viruses in latent form in their B cells. Sometimes – particularly when the body is under stress – the immune system slips a bit and the viruses reactivate, causing anything from no symptoms at all to – more rarely – being associated with such devastating disorders as autoimmune diseases and cancer.  One study suggests that glucocorticoids released during stress tell EBV to come out of hibernation.

EBV virions leukemia

EBV infected (green) leukemia cells

Herpesviruses have a long enough history in ME/CFS for the disease to have been referred to as chronic Epstein-Barr virus syndrome by some in the 1980’s. However, over thirty years later, the role herpesviruses play in ME/CFS is unclear. Are they simply a common trigger of ME/CFS or do they play a more fundamental role? Several studies have found no evidence of herpesvirus reactivation while others suggest immune problems exist that could allow the virus to wreak havoc in some patients.

The Ohio State University team lead by Maria Ariza and Marshall Williams believes researchers have missed an obvious possibility. They don’t believe the virus per se is the problem. (If they’re right, you can basically throw out all the viral load studies.)

It’s not that the virus is reactivating; in fact, they believe the virus may be most dangerous in ME/CFS when it fails to reactivate properly and produces kind of a very low-level, smoldering infection. Even as the immune system in people with ME/CFS is mostly smothering EBV, the virus is producing a protein that’s causing harm.

“Surprisingly, none of these studies have approached the possibility that virus encoded proteins, rather than the viruses themselves, may act as drivers of/contribute to the pathophysiological alterations observed in a subset of patients with ME/CFS.” Authors

It turns out that in herpesviruses a failure to replicate produces something called “abortive lytic replication”.  As it does that, it produces proteins that get ejected into the blood stream or get inserted in vesicles called exosomes, which then travel through the blood. These exosomes are now believed to play important roles in cell to cell communication.  (Maureen Hanson is now studying exosomes in ME/CFS).



The protein released during abortive lytic replication is an enzyme called deoxyuridine triphosphate nucleotidohydrolase or EBV-dUTPase. The unusual herpesvirus dUTPase saga at Ohio State University began way back in 1985 with a Williams/Glaser study. It gathered force in the mid-2000’s with a series of papers suggesting the protein might be a good target for chemotherapy, produced “sickness behavior” in mice, and triggered pro-inflammatory cytokine production.

In 2010 Ronald Glaser won an NIH grant to study the protein titled Stress Effects on Virus Protein induced inflammation and sickness behavior and the hunt was on to determine dUTPase’s effects in ME/CFS.  (This long standing grant continues today under Ariza and Williams’ name.)

A 2013 paper suggested dUTPase might provide a way to reconcile the studies which had not found herpesvirus reactivation in ME/CFS with others suggesting that the virus could be having profound effects. It found that even under conditions of low viral load, herpesvirus dUTPases were able to trigger a pro-inflammatory response strong enough to promote atherosclerosis and perhaps even precipitate a heart attack.

In 2012, Williams, Ariza , Glaser and Martin Lerner and Lenny Jason produced the first direct evidence that dUTPases may be producing problems in ME/CFS. The small study found a prolonged antibody response to the protein in a large subset of ME/CFS patients.

A 2014 study indicated that during EBV’s last gasp while undergoing lytic replication, the virus was pouring enough dUTPase into exosomes to produce major immune effects that supported or promoted the establishment/maintenance of further EBV infections.

The 2017 ME/CFS Study

J Med Virol. 2017 Mar 17. doi: 10.1002/jmv.24810. [Epub ahead of print] Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Gulf War Illness patients exhibit increased humoral responses to the Herpesviruses-encoded dUTPase: Implications in disease pathophysiologyHalpin P1, Williams MV1,2, Klimas NG3,4, Fletcher MA3,4, Barnes Z3,5, Ariza ME1,2.

Then, in an expanded version of the 2012 study, the group in 2017 (which also included Nancy Klimas and Mary Fletcher) presented stronger evidence that herpesvirus produced dUTPases were present and could be causing harm in a subset of ME/CFS patients. The study looked for evidence that herpesvirus produced dUTPases were tweaking the immune systems of 74 ME/CFS patients – and found it.

The fact that antibodies to dUTPases produced by both EBV and HHV-6 were found in almost fifty percent of the ME/CFS patients in the study suggested that the two herpesviruses may be reactivating each other in ME/CFS – a feature also found in immune suppressed states such as organ transplant patients and drug induced hypersensitivity syndrome (DRSS).

Plus, for the first time, autoantibodies to the human dUTPases (humans produce a dUTPase as well) were found in ME/CFS – at much higher levels than in healthy controls (39% vs. 5%).

The authors suggested the Loebel’s 2014 study, which uncovered problems that ME/CFS patients’ T cell’s were having in suppressing EBV, could account for the evidence of multiple herpesvirus reactivations.

EBV I: A Deficient Immune Response, Increased Levels of Epstein-Barr Virus Opens Up EBV Question in Chronic Fatigue Syndrome Again

The immune system does ultimately jump in and suppress the virus in most people with ME/CFS, but it takes its time to do that. That delay appears to give herpesviruses the time they need to spill immune altering dUTPases into the bloodstream and slip them into exosomes to travel through the body.

EBV smoldering infection

EBV is halted from fully reactivating but the authors believe the smoldering infection present in ME/CFS could have significant consequences for some.

Besides the immune alterations possibly caused by herpesvirus produced dUTPases, they may be contributing to numerous symptoms including flu-like symptoms, fatigue, cognitive problems, anxiety, etc. in ME/CFS.

Plus, because failed herpesvirus reactivations commonly occur alongside actual herpesvirus reactivations, herpesvirus encoded dUTPases could end up being an excellent biomarker for herpesvirus reactivations.

This strange model of partial viral reactivation could end up playing a role in ME/CFS, Gulf War Syndrome and other diseases in several ways. It could be actually driving ME/CFS in a subset of patients, or it could, along with other possibly related immune issues, be exacerbating it.

Next Steps

However it all works out, it’s clear that the Ohio State University team’s long embrace of this novel protein is paying off. The more work they do with herpesvirus-encoded dUTPases, the more evidence they’re uncovering that it may play role in ME/CFS and other diseases. They have an 8-year continuing NIH grant under their belts – a grant that looks like it and the herpesvirus-dUTPase-ME/CFS saga will likely continue in the foreseeable future.

If the findings hold up, it may even provide a treatment option – the authors have published a paper alerting drug-makers to the potential this escaped protein may hold in treating herpesvirus infections.

Dr. Williams reported that the group has “some exciting data” concerning the potential role dUTPase plays in autoantibody production and the neurological effects the protein may be having in people with ME/CFS. The manuscripts are being written up now and will be submitted shortly.


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  • Sarah R.

    November 17, 2018 at 9:23 pm - Reply

    Another cause for hope. Thanks for covering this, Cort. I will follow along as more studies come out about this.

  • Aidan

    November 17, 2018 at 9:29 pm - Reply

    Alpha-Gal Meat Allergy is actually a Sugar Protein & it will be in 100% of these Patients no doubts…Lets test for Alpha-Gal Meat Allergy IgE Panel in all these Patients & also run (RAST) testing in all of them & bring Dr. Commins from UNC North Carolina & his partner onboard & do some serious testing & also in-depth skin food testing for Meats, Pork Chicken Dairy & Sugar the processed Sugar

    • Ej

      November 17, 2018 at 9:48 pm - Reply

      What does alpha gal have to do with this? Alpha gal is a meat allergy that results from certain ticks. Nothing to do with ME. I have ME and tested negative for alpha gal.

      • Aidan

        November 20, 2018 at 4:32 pm - Reply

        The test for Alpha Gal Meat Allergy is not 100% accurate some test Negative but have (AG) all along & skin testing also is not 100% accurate as well & (AG) is also in Sugar, medicines vitamins minerals & countless home & hygiene ingredients…Even with eliminations diets, there is not a treatment for (AG) presently

  • Private

    November 17, 2018 at 9:37 pm - Reply

    Does the type matter? If we had a long-term partner with the nasty type but never caught it (that we know of), could that factor in?

    • Cort Johnson

      November 17, 2018 at 11:59 pm - Reply

      Interesting question. I have heard there are variants of EBV and other herpesviruses – some more damaging than others. The thing with these viruses is that just about everyone has them. It could depend on your first exposure to the virus. If you were exposed early in your life you likely fought it off with ease – and your immune system was well adapted to fight it off again. If you were exposed later in life then your immune system likely had much more difficulty fighting it off – as apparently happened with your partner.

      The potential issue with dUTPase and ME/CFS is an immune hole in ME/CFS which allows the virus to partially reactivate before it gets shut down. My guess is that immune hole is probably much bigger in those who were exposed after they were children.

      • Gijs

        November 18, 2018 at 10:56 am - Reply

        So ME/CFS will be an abortive lytic infection after all (?), like Scheibenbogen e.a. suggests.

        • Cort Johnson

          November 18, 2018 at 4:51 pm - Reply

          Yes, possibly in a subset of patients – not everyone – but perhaps a significant subset.

  • JC

    November 18, 2018 at 2:40 am - Reply

    very interesting.

    wasn’t this lerner’s original theory (non-lytic replication) for why antivirals seem to help some? what effect, if any, do current antivirals have on this sort of dUTPase production?

    • Cort Johnson

      November 18, 2018 at 4:56 pm - Reply

      Dr. Lerner was actually involved in this research earlier I believe. Knocking the virus down as much as possible would help reduce the attempted reactivation – and thus reduce the spillage of the protein into the blood.

  • joana sanfort

    November 18, 2018 at 9:37 am - Reply

    Thank’s for your information

  • Yomama

    November 18, 2018 at 11:19 am - Reply

    What we need to do is find a way to disable the herpesvirus genetically. Perhaps creating a new strain that latches onto the virus (dangerous in the wrong hands) that turns replication into a non infectious virus? As in, the virus that infects people would start to be unable to replicate into a virus that “fits” the ganglia, thereby being effectively (1) able to be killed and (2) rejected by the ganglia and thus, again, killed. Genetic restructuring is essential. Perhaps looking at “neanderthal” genes already in the bodies of most people (I highly suspect that non hybrid Neanderthal/sapiens were herpes resistant due to the “it doesn’t fit” effect. Fibromyalgia is a horrible effect of this virus.

  • Alex Young aka alex3619

    November 18, 2018 at 2:16 pm - Reply

    I and others have been discussing non-lytic viral infections for years. Its not just herpes viruses that do this, enteroviruses do too. This is not news. What might be news is if they find it in ME in sufficient quantities to be a problem. This is part of the hypothesis behind Chia finding enterovirus in gut lining in ME patients.

    I do wonder however if this might be the large molecule that Ron Davis is looking for? We know its in the protein size range, and it disrupts cell metabolism in our blood. It would be possible to filter dUTPases and then see if our cells work.

    I look forward to reading the paper when it comes out.

    • Cort Johnson

      November 18, 2018 at 4:50 pm - Reply

      Interesting! I hadn’t thought of that and thanks for mentioning Chia’s hypothesis that non-functioning enteroviruses are doing the same in ME/CFS.

      • Lora

        December 9, 2018 at 3:19 pm - Reply

        Interesting I had not read about Chia hypothesis but I really feel that the entro or adenovirues was my trigger ..I think it is worth looking into by Ron Davis by reading yours and other comments Could you post Chia hypothesis here ?

  • Georgia C.

    November 18, 2018 at 2:59 pm - Reply

    Simply put…. Thank you!

  • SBC

    November 18, 2018 at 3:55 pm - Reply

    I had a severe case of EBV and Influenza in 2011 and never fully recovered. In 2012, I shattered my ankle and recovery took nearly a year. The EBV, Inflyenza and the physical trauma to my body took me from working 60 hours a week to being fully disabled and homebound in 2014. My health continues to decline. I hope treatments are available soon to at least improve the quality of life for folks like me.

    • Cort Johnson

      November 18, 2018 at 4:49 pm - Reply

      You are not alone. My guess is that you were introduced to the virus later in life which makes it much harder to fight off. Plus some people with ME/CFS may have an immune hole which makes it more difficult to fight off the virus.

      You can find more out about that here –

      Good luck!

  • Paul

    November 18, 2018 at 5:32 pm - Reply

    This is excellent news let’s hope the funding is big enough.

    I had ebv decades ago apparently, then herpes type 2 10 years ago but then 2 weeks after CMV I slowly got unwell so for me I have 3 repeated herpes virus. Before a trigger for me. Pity no one is working on new antivirals, as far as I am aware? Or are they?

    • JC

      November 21, 2018 at 2:06 am - Reply

      there are anti-herpes drugs in the pipeline but it might be 2-3 years before anything hits the market. brincidofovir seems like the most promising. it failed a phase iii trial a few years ago but it’s shown high efficacy in vitro and the company is preparing another on a different patient subset.

      is there anything in the offing that i’m missing?

      the current antivirals have limited efficacy and, at least valcyte, high toxicity. my sense is that the pipeline is modest, but research by the OSU team, bhupesh prusty, some recent studies on MS and Alzheimers, suggest this might end up being a huge industry down the line.

      • Cort Johnson

        November 21, 2018 at 2:52 pm - Reply

        Glad to hear that brincidovir (CMX 001) is still in play! That drug has such promise! Here’s some more on CMX001

        Here’s from Wikipedia on CMX 001

        “As of 2014, brincidofovir was in Phase III clinical trials for use in humans against cytomegalovirus and adenovirus, after testing for safety in over 1,000 human subjects,[6] and has received FDA Fast Track Designation for treatment of cytomegalovirus, adenovirus, and smallpox.[7] Chimerix announced in December 2015 that the Phase III trials for use of the drug in preventing cytomegalovirus infection in stem cell transplant patients had failed, and in February 2016 shut down two other late-stage trials for use of the drug in preventing infection after kidney transplants.

        As of 2016, the company is planning on returning trials of the drug for use in stem cell transplant patients to Phase II, while continuing to advance a late-stage trial for use against adenovirus infections in patients suffering from weakened immune systems.[8]”

  • Donna

    November 20, 2018 at 6:00 pm - Reply

    So excited to see Dr Lerner’s work continue!!! He has extensive monthly lab data for those virus and ECG results from hundreds of patients going back decades. Also which pt responded to Valcyte, Vistide, and Valtrex to break up subsets. He was still working with Ohio Statevuntil his passing. As a pt involved with discussions on his research, it is exciting to see that the Ohio State team cont. to use Lerner data bank and come up with new research papers. It would have been such a shame to let it all just sit there.

  • Voyager

    November 21, 2018 at 2:48 am - Reply

    Latent viral infections can also alter intracellular calcium metabolism which would be consistent with the Australian TRPM1 study that showed abnormal calcium concentrations.

    The link to viruses is not specific to CFS – the same connection has been made for virtually every other illness – cancer, autoimmunity, and mental illness. It seems that we all harbor viruses and it’s not so much the issue of the specific strain or when you acquired it but rather how well you can adapt to living symbiotically with the virus. This is why stressful events, use of drugs and hormonal changes often trigger CFS.

    Antivirals are very ineffective drugs for latent viral infections, especially EBV. Long term use of antivirals is not only potentially harmful but also likely to be inferior in its effect compared to multiple natural supplements and herbal remedies that have been shown to interfere with viral replication and early protein expression. Many psychotropic drugs, such as antiepileptics and lithium are also believed by some experts to exert their effect by suppressing viral infections within CNS.

    • Adelle

      November 21, 2018 at 8:50 pm - Reply

      That is interesting; the only medication I am on is Clonazepam. Before discovering it, I was in a bad way. I could not sleep. After desperately trying other medications, it was the only one that “allowed” me to sleep.

    • dejurgen

      November 21, 2018 at 11:42 pm - Reply

      I’m very new to this intracellular calcium thing.

      If I understand correctly then getting a full “cycle” of calcium in and sub-sequentially out of the cells does cost energy in the form of ATP. That could be either direct by the Ca2+ATPase pump thing in the cell itself or indirectly by fiddling somewhere with the Na+ concentration by using ATP to fuel Na+ pumps.

      Maybe my understanding of it still is very premature. But if indeed each cycle of letting Ca2+ in end getting it out of the cell costed ATP then we are in the difficult situation that ME patients are short of energy and ATP. That in turn might allow the body to “decide” to keep the gates shut in order to reduce the Ca2+ traffic in order to save ATP. If the gates were firmly shut then the Ca2+ concentration could be about anything. But if only the bi-directional gate were shut as is assumed in the link find as a reference in the paper you quoted, then even a slow trickling of the only remaining pump, that shuffles Ca2+ unidirectional out of the cell may be enough to get Ca2+ concentrations too low in the cell.

    • Colin

      November 23, 2018 at 7:22 am - Reply

      Another Australian study, just published, might be of interest. Here in Brisbane, the Berghofer Institute have completed a phase I trial, on MS sufferers, of a novel, cellular immunotherapy, directed against EBV-infected cells in the brain. See here:

      Some reduction in symptoms, including fatigue levels, was observed.

    • Lora

      December 9, 2018 at 5:07 pm - Reply

      Thanks for posting that article most definately a keeper for me..

  • Adelle

    November 21, 2018 at 9:07 pm - Reply

    Thanks for the article. I am not very scientifically literate, but I feel that this is very relatable to my experience, possibly. I have very high antibodies to many herpesviruses, including EBV, CMV, and HHV-6, and was on an anti-viral regime for a few years that did absolutely nothing. I didn’t get ME/CFS acutely, but I first noticed symptoms when I was 10, after an unusual case of shingles. About 4 years later, I contracted mono, and then again a year later. This article seems to make sense, that malfunctioning herpesviruses are hindering cellular communication. But I guess like always, we will have to wait and see if this leads to anything meaningful.

  • Michelle L

    November 24, 2018 at 11:04 am - Reply

    To me much of this is hard to absorb, but I get the gist mostly, This might of been asked before, I often hear of EBV being a likely trigger to CFS. My question is. If EBV is common in most/all of us, only some of us come down due to it, is it not possible that CFS is the reason we react to EBV? Our systems submit to CFS our immune system alters leaving us open to failing to address other illnesses.
    I do so hope something comes to light over CFS. EBV at 12 CFS for 25 years, unknown trigger for Heart attack 2000, tired of being so tired

    • Cort Johnson

      November 24, 2018 at 3:11 pm - Reply

      My guess is that there may be two or three things going on

      One – since EBV is much harder to fight off when you contact it when you’re an adolescent or later I wonder if some ME/CFS is a natural result of some people simply contacting it later in life

      Two – one study suggested, as you do, that a kind of immune hole is present which gives EBV an extra edge when it comes to at least a subset of people with ME/CFS.

      Three – someone suggested that people who developed ME/CFS after infectious mononucleosis could have been given a course of steroids which dampened their immune response.

  • Lora

    November 26, 2018 at 7:19 pm - Reply

    Thank you Cort for posting this as I also think correlation/link to this as well ! Great info./research article