Viruses make a comeback

Following our recent call for grant applications on the viral causes of ME/CFS, Cort Johnson from the Health Rising blog takes a look at some of the existing research investigating links between viruses and the illness.

From Epstein-Barr virus to XMRV, and now to the coronavirus, it seems there’s no escaping viruses in ME/CFS. It wasn’t all that long ago, however, that National Institute of Health funders made it clear that they weren’t interested in viral studies – that vein, they felt, had been tapped out. But time has shown that’s clearly not true.

The ubiquity of long-COVID is sparking a long-overdue reassessment of ME/CFS and the role pathogens play in it. The same Anthony Fauci, MD, who oversaw the destruction of the NIH-funded ME research centres twenty years ago, is suddenly interested in ME/CFS – because of a virus. 

“We’ve been chasing myalgic encephalomyelitis and chronic fatigue syndrome without ever knowing what the etiologic agent was,” Fauci said at the 2021 annual meeting of the American Academy of Neurology. “Now we have an absolutely well-identified etiologic agent (coronavirus) that should be very helpful now in getting us to be able to understand it. I hope we do; it’s been mysterious to us for years. Maybe this will give us a chance at a breakthrough.”

Fauci, it should be noted, was wrong about not knowing the aetiological agent. Studies of Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), Ross River virusGiardia, the first SARS virus and others made it clear long ago that many pathogens can trigger an ME/CFS-like condition.

Crippled herpesviruses 

Take Epstein-Barr virus (EBV). Our ability to fight off this complex virus wanes over time, so that by the time we’re adolescents our immune systems have trouble fighting it off – hence the chronic cases of glandular fever often seen in adolescents.  

Couple that fact with findings suggesting that some people with ME/CFS have an immune hole which makes it even harder to fight off EBV, and you come up with something rather strange: a smouldering EBV infection that is hardly replicating at all, but which is still causing major problems.

For the past fifteen years, two Ohio State University researchers have been methodically producing results suggesting that a significant number of people with ME/CFS harbour a kind of crippled EBV/HHV-6 infection. Unable to replicate, these herpesviruses are instead producing enzymes (dUTPases) that appear to be producing fatigue, flu-like symptoms and more in a significant number of ME/CFS patients.

Epstein-Barr virus rides again

Nuno Sepúlveda, a theoretical immunologist at the London School of Hygiene & Tropical Medicine, is taking a different crack at EBV. Sepúlveda has come on like a storm – co-authoring eight ME/CFS papers in the last two-and-a-half years. In 2019, Sepúlveda proposed that herpesviruses were leaving the immune system of ME/CFS patients stuck in a kind of limbo state. Not able to completely fight off the virus, the immune system remains turned on, chewing up vital energy stores.

Next, in an ME Research UK-funded study, Sepúlveda will piggyback on an earlier finding where he discovered that a heightened antibody response to EBV proteins differentiated ME/CFS patients (especially in those with infectious onsets) from healthy controls.

With the beginnings of a possible biomarker intact, Sepúlveda will take his EBV research to a new level in a study that will compare the antibody responses to EBV-derived proteins in 100 people with ME/CFS, 50 healthy controls and 50 patients with multiple sclerosis.

The goal is to uncover a unique ME/CFS immune signature or biological biomarker. Doing so would cause the disease once known as ‘Chronic Epstein-Barr Syndrome’ to come full circle.

Hibernation-inducing herpesviruses?

In 2020, Philipp Schreiner, Robert Naviaux and Bhupesh Prusty co-authored a paper that threatened to upend what we know about herpesviruses – and ME/CFS. Laboratory experiments showed that subjecting HHV-6-infected cells to stress caused their mitochondria to fragment, and the metabolism of the entire cell to shut down.

At the same time, the cells appeared to emit a substance which, when entering the bloodstream, caused the cells around them to enter into a kind of hibernation state. Adding the serum from ME/CFS patients to the mix caused the same process to occur – possibly putting herpesviruses once again at the heart of ME/CFS.

Ancient retroviruses

Herpesviruses may be with us for life, but they don’t have anything on the human endogenous retroviruses (HERVs) which actually come embedded in our DNA. In fact, 5% to 8% of our DNA is composed of fragments of ancient retroviruses. While the viruses don’t have the ability to activate, they can still tweak our immune systems, and have been associated with diseases such as multiple sclerosis.

That’s where Professor Elisa Oltra and her team at the Catholic University of Valencia in Spain come in. ME Research UK is funding Prof. Oltra’s new research and is essentially getting two studies for the price of one. As well as furthering the charity’s interest in epigenetics, she will also take a dive into HERVs at the same time.

HERVs, epigenetics and ME/CFS, it turns out, have something in common – they tend to show up during times of biological stress. Biological stressors such as infections can change our epigenetic makeup – altering who we are as genetic beings. HERVs are most likely to get activated during times of biological stress as well. Put epigenetics, HERVs and the immune system together and you possibly have a recipe for ME/CFS.

Prof. Oltra believes that epigenetic modifications in ME/CFS may be waking up bits of ancient retroviruses which are then triggering the immune system to activate – causing the symptoms found in ME/CFS.

She’ll first assess the expression of HERVs in women with severe ME/CFS and women with fibromyalgia. She’ll then determine if the ME/CFS-associated HERVs she has found are affecting nerve and muscle cells. Then she’ll validate the results in another larger group containing healthy controls.

Fragmented coronaviruses

Finally, reports that coronavirus vaccines are helping some long haulers (and people with ME/CFS) provide another intriguing possibility: that fragments of the coronavirus that have been left behind are touching off immune reactions in the long haulers.Crippled herpesviruses, herpesviruses-inducing hibernation states, bits of ancient retroviruses coming back to life, viral fragments causing trouble – the viruses, it turns out, never did go away in ME/CFS, they just got more interesting. Stay tuned…

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