Article: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! 2021, Ariza

John Mac

John Mac

Senior Member (Voting Rights)
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology.

There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown.

Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome.

New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS.

Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.
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https://www.mdpi.com/2218-273X/11/2/185
 
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Discussion:

It is clear that the lack of a universally accepted clinical criteria has led to multiple discrepancies, problems and confusion as to how to accurately diagnose and stratify patients with ME/CFS. This has severely hampered the pursue of studies to clearly define the environmental and genetic factors that act as triggers or the downstream mechanisms responsible for the development/progression of ME/CFS. Furthermore, numerous studies using small size patient cohorts, which lack the statistical power to achieve reproducible and rigorous results, have further complicated the task of identifying biomarkers/signatures that would be useful for diagnosing patients.

The role of some herpesviruses in the development and evolution of ME/CFS in a subset of patients has also been hampered because of the use of classical serological approaches focused primarily on viral proteins expressed during latency or late in the replicative cycle of these viruses or viral load as indicators for the involvement of herpesviruses in the pathobiology of ME/CFS. Recent studies using more advanced serological approaches as well as mechanistic studies have demonstrated the possible role of the EBV BRRF1 and BLLF3 gene products in ME/CFS pathophysiology. Future directions should focus on exploring the use of these gene products for the development of novel therapeutics and/or as biomarkers with diagnostic application or disease progression. Additionally, additional studies need to be performed in light of the new evidence showing high level of abortive lytic replication of these viruses to determine whether other early herpesvirus proteins could contribute to the disease process. Finally, since there is evidence suggesting simultaneous reactivation of multiple herpesviruses in a large percentage of ME/CFS patients, studies should examine whether or not there is cooperative effects between these viruses as well as other viruses within the virome that could contribute to human disease.​

Especially interesting given the last sentence above and how it relates to some areas of current research.
 
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News item on their research

Ohio State researchers isolate biomarker to test for chronic fatigue syndrome
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Gulf War illness are complex, chronic diseases with overlapping symptoms and no definitive way to diagnose or differentiate between them.

The one symptom they share in common is long-term, disabling fatigue. But widely varying symptoms affecting the immune, endocrine and neurological systems may occur, including muscle and joint pain, concentration and memory problems, headaches, sleep problems, fever, sore throat and tender lymph nodes—symptoms that are common to a number of different illnesses, making diagnosis of ME/CFS even more challenging.

Around 50% of patients who develop ME/CFS report that their symptoms occurred after exhibiting “flu-like” symptoms, leading some researchers to look into the role that certain viruses play in triggering an ME/CFS infection and its impact on the body’s immune system. Viruses such as Epstein-Barr virus, human herpesvirus 6 and varicella-zoster virus, all of which establish latent (persistent) infections in their host, can be periodically reactivated over a person’s lifetime.

Researchers led by cancer biology and genetics professors Marshall Williams, PhD, and Maria Ariza, PhD, at The Ohio State University College of Medicine have looked at the association between these viruses and ME/CFS. They have identified the protein deoxyuridine triphosphate nucleotidohydrolase (dUTPase) as a key modulator of the immune response that contributes to the immunological and neurological abnormalities in some individuals. Their work suggests that the dUTPase protein can be used as a biomarker to identify evidence of the disease observed in a subset of patients, paving the way for early detection and prevention of ME/CFS and related illnesses.

“The impact value of our findings is enormous, when you think about the fact that there is currently no commercially available test to measure the concentration of antibodies against the herpesviruses dUTPase proteins present in patients’ sera,” says Dr. Ariza.

The team is also in the process of developing a single array ELISA test that will allow for the simultaneous quantitation of six different dUTPases, a major milestone that would allow for high throughput screening of a large number of serum samples and aid in diagnosing and, potentially, stratifying patient symptom severity.

“These are very exciting times in our labs, as we currently have NIH funding to validate the dUTPase array ELISA in 4,000 clinical serum from ME/CFS patient cohorts of different severities,” says. Dr. Ariza. “Because it is a noninvasive method, if validated, it could be easily implemented in clinical settings for standard testing.”

Drs. Williams and Ariza are members of an interdisciplinary team of research scientists and clinicians bought together from across The Ohio State University’s vast system of clinical science departments and centers to conduct cutting-edge research in the College of Medicine’s Institute for Behavioral Medicine Research, making up one of the largest contingents of psychoneuroimmunology researchers in the world. Their innovative, high-impact work results from collaborations in areas that include medicine, microbial pathogenesis, nursing, biostatistics, human sciences, microbial infection and immunity, neuroscience, neurological surgery, obstetrics and gynecology, pediatrics, psychiatry and behavioral health, and psychology.
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My bolding
https://medicine.osu.edu/news/biomarker-for-chronic-fatigue-syndrome
 
EBV has too long an incubation to account for the spread in epidemics and many people are too young to have EBV when they get ill.

The herpes viruses have been studied in ME for over 30 years. There may be something to learn and they may be important for a lot of people which would be good, but i do wonder if part of the reason for the lack of progress in ME is because enteroviruses are so neglected.
 
@Mithriel

How many of us know which virus caused our illness? I had a sudden viral onset (extremely elevated anti-thyroid antibodies), but wasn't tested for any viruses that I'm aware of. I had negative PCR testing for various viruses 10 years later- nothing.

I'm dealing with frequent viral re-activations since 2002. I'm confused from all the different angles and research as to what is occurring with our immune system.
 
Mij said:
How many of us know which virus caused our illness?
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I don't think we can, at least in many cases. A lot of common viruses cause a fairly characteristic range of symptoms, but unless a patient is worryingly ill and needs investigations, 'I'm pretty sure it's a virus' often as much as the doctor can say.

There are even two viruses that cause glandular fever symptoms, so unless you're tested – which is unusual, as diagnosis is often straightforward enough that no tests are needed – you couldn't be sure whether it was caused by EBV or CMV.
 
When I relapsed from taking immune modulators, both HHV6 and EBV reactivated. I experienced a terrible 3 months and recovered, but this was when the OI started.
 
Kitty said:
I don't think we can, at least in many cases. A lot of common viruses cause a fairly characteristic range of symptoms, but unless a patient is worryingly ill and needs investigations, 'I'm pretty sure it's a virus' often as much as the doctor can say.

There are even two viruses that cause glandular fever symptoms, so unless you're tested – which is unusual, as diagnosis is often straightforward enough that no tests are needed – you couldn't be sure whether it was caused by EBV or CMV.
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I was actually tested during the infection and later made a habit out of always bringing the test results with me when I see a new doctor, after one once asked in obvious disbelief how I even know that glandular fever started it. (He also happened to tell me it must be neuropsychiatric/neurasthenia.)
 
I had summer flu which is enteroviral and tested positive for infection a few years later. A lot of viruses have characteristic properties.

Since basic research has stopped being a priority in medicine viruses have been neglected. Too many are classed as trivial so not worth bothering about like, say coronaviruses :)

As we know with ME it would be useful if there were simple tests for common viruses. Who knows how many MUS cases have a viral origin and we will never know if no one looks.
 
There was a 2017 paper by Williams, Ariza, et al. that seems to have been a precursor to these findings (Nancy Klimas was also an author on that paper).

Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses-encoded dUTPase: Implications in disease pathophysiology
Peter Halpin 1, Marshall Vance Williams 1 2, Nancy G Klimas 3 4, Mary Ann Fletcher 3 4, Zachary Barnes 3 5, Maria Eugenia Ariza 1 2

https://pubmed.ncbi.nlm.nih.gov/28303641/

The results of this study demonstrate that a significant percentage of patients with ME/CFS (30.91-52.7%) and GWI (29.34%) are simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or the human dUTPase when compared to controls (17.21%).
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Forbin said:
There was a 2017 paper by Williams, Ariza, et al. that seems to have been a precursor to these findings (Nancy Klimas was also an author on that paper).

Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses-encoded dUTPase: Implications in disease pathophysiology
Peter Halpin 1, Marshall Vance Williams 1 2, Nancy G Klimas 3 4, Mary Ann Fletcher 3 4, Zachary Barnes 3 5, Maria Eugenia Ariza 1 2

https://pubmed.ncbi.nlm.nih.gov/28303641/
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Thank you @Forbin i remember this paper. I wonder where they are at with their current research and whether this recent reporting is announcing something coming soon.
 
Thanks Forbin, I don't think we have a thread for that paper. I'll make one.

When I have full-on PEM, I'll typically get a cold sore. For 18 months, I had serial cold sores, as in, I always had one, until I was given valacyclovir tablets. Presumably then, the re-activated viruses are producing the dUTPase when my body is not strong enough to keep them under control.

So, I'm not sure if it's just a down-stream effect that these researchers have identified, and that all sorts of people who aren't in the best of health and who have a latent herpes infection would have higher levels of the dUTPase produced by the herpes viruses.

Maybe, and I haven't read much yet, but maybe it's a nice test to confirm that a person's immune system isn't doing very well, but it is not necessarily a biomarker.
 
Here are all the papers produced by the authors under the NIH grant.
https://projectreporter.nih.gov/project_info_results.cfm?aid=10049715&icde=31258613

The description of this work to uncover biomarkers is covered in the NIH grant project description
The results of this study, will demonstrate that the EBV/HHV-6 dUTPases may act as drivers of the immune activation that occurs in ME/CFS. It may also identify EBV/HHV-6 dUTPase proteins as diagnostic biomarkers for identifying a subset of patients with ME/CFS. Finally, these studies will demonstrate that engagement of EBV/HHV-6 dUTPase proteins with TLR2 is essential for inducing neuroimmune dysfunction and thus, this interaction can be used as a novel target for the development of alternative therapeutic approaches.
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https://projectreporter.nih.gov/project_info_description.cfm?aid=10049715&icde=31258613
 
In a parallel study, these investigators demonstrated that EBV and HHV-6 dUTPases induced the secretion of activin A in hDCs at sufficient quantities to promote the differentiation of naïve CD4+ T cells into a TFH cell-like phenotype [105]. Interestingly, serum from ME/CFS patients was sufficient to drive naive CD4+T cell differentiation into a TFH cell-like phenotype.
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Reference 105: Cox, B.S.; Alharshawi, K.; Lafuse, W.P.; Ariza, M.E. Herpesvirus dUTPases contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by promoting follicular helper T cell differentiation. JCI 2021. Submitted.

Potentially relevant to the reported finding of higher numbers of T helper cells in people with ME/CFS (I have had a finding of higher T helper cells).


There's an awful lot in this review, wrapping up quite a high percentage of current ideas in ME/CFS research, like exosomes, neuroinflammation... Something for everyone. It's beyond me to sift through it and come to a conclusion. It certainly looks as though there is more to come on this, with that follicular helper T cell paper just submitted and the level of enthusiasm in this paper.
 
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