“A lot of what’s happening in CFS is probably not happening in the blood.” Amy Proal

Amy Proal

Amy Proal – who has ME/CFS – is the co-founder of PolyBio and the leader of The Long COVID Research Initiative.

If we’re going to get to the promised land, it’s probably going to come through better technology – which is a good thing – as technological advances are exploding seemingly everywhere. Amy Proal – the dynamic co-founder of PolyBio and the mastermind behind the Long COVID Research Consortium – recently interviewed a UCSF researcher, Tim Henrich, who is pushing the boundaries of science in long COVID and other diseases further. (Thanks, Gail, for the link to the interview :))

The Long COVID Research Consortium is going to throw at least $15 million into one of the great questions facing the long-COVID and chronic fatigue syndrome (ME/CFS) fields: could a persisting but hard-to-find virus be causing at least some long COVID and ME/CFS? Proal, who has chronic fatigue syndrome (ME/CFS), has said that viral persistence is “the trend we see the most evidence for.”

Lighting a Spark: Major New Long-COVID Initiative Promises Rapid Movement

Proal has a personal reason to think so. She – but not her fraternal twin – suffered from a series of severe infections between the ages of three and five. Twenty or so years later, her ME/CFS reared its head when she was a premed student in 2004, but then it really bloomed after she came down with infectious mononucleosis. The more viruses you’re exposed to, or as the coronavirus has shown us, the more times you’re exposed to the same virus – the more impacted your immune system may be.

She said, in an interview, “Reactivated Viruses Causing Chronic Fatigue and Long COVID“, with the Mitchell Medical Group, that she remembers being in a pre-med class when the writing on the chalkboard started looking like gibberish.

(Her fraternal twin sister is apparently fine. One of the few differences between my identical twin, who is fine – and myself – is the Giardia infection I contracted a couple of years before becoming ill.)

She noted that researchers are not good at finding viruses buried deep in a patient’s tissues that have adapted themselves to hide out from the immune system. Because the genetic material from the viruses tends to show up less and less in the blood over time, Proal stated that we have to get into the tissues to see if they are present.

These viruses don’t need to replicate to be causing problems. They can change the gene expression of the cell. By stealing resources from them, they can inhibit mitochondrial function. They can express proteins that interfere with the ability of an immune cell to fight off other viruses. (Over the past decade, an Ohio State University team has been demonstrating that a protein produced by EBV called EBV dUTPase may be doing just that in ME/CFS.)

Michael VanElzakker, Proal’s partner at PolyBio, hypothesized that in chronic fatigue syndrome (ME/CFS) small viral infections around the vagus nerve could be impacting its ability to transmit immune signals to the brain but, short of an autopsy, finding evidence of those viruses has been difficult in the extreme. Biopsies are limited to certain tissues and even then can be misleading as only small areas can be assessed. How effective can a couple of biopsies of a 20-foot gut really be?

EXPLORING For Deeply Buried Pathogens

West Nile Virus

Deeply buried pathogens may not show up in the blood – they can’t hide, though, from the new EXPLORE machine.

That’s all changing. Proal recently interviewed Tim Henrich MD at the University of California at San Francisco – one of the top medical research universities in the country. Heinrich’s going to use the EXPLORE PET scanner, developed by researchers at UC Davis, to look for viruses buried deep in the tissues.

The EXPLORE is a beast. Henrich explained that EXPLORE is essentially many PET scanners plus a CT scanner incorporated into one. This monster PET scanner can produce 3-D images of deep tissues in the body. How big of a technology jump is the EXPLORE? It’s 40x’s more sensitive than commercial scanners.

Henrich puts a radioactive tag on a monoclonal antibody that he knows will bind to a virus and then uses the scanner to find where the virus is hanging out.

HIV researchers have had the same question about HIV that EBV researchers do about EBV and other viruses. Where is the virus? Is it still active? Is it producing proteins? Even when the virus has been fully suppressed, it’s still present in deep tissues in the body and, in fact, comes roaring back within weeks of the HIV drugs – even after they’ve been used for decades – being stopped.

The efficacy of this EXPLORE technique was first demonstrated in HIV patients last year. The approach was sensitive enough to illuminate places where HIV protein was being produced, even in people who were on antiretroviral drugs.

Now Henrich and his colleagues have turned their focus to the SARS-CoV-2 virus and are about to begin using the EXPLORE PET scanner to see if the virus is persisting in long-COVID patients. He’ll soon inject monoclonal antibodies that latch onto SARS-CoV-2 proteins into people with and without long-COVID symptoms, and then use a scanner to see where they light up.

If the long-COVID patients light up like a Christmas tree compared to the people without symptoms, that will suggest that increased viral persistence is contributing to their symptoms. Since he’ll be looking throughout the body, he also may be able to uncover areas of the body where pathogen persistence is possibly most problematic. Because the scanner will also be able to uncover areas of damage, he’ll be able to determine if the virus is associated with tissue damage.

Henrich can use the EXPLORE scanner to find anything that can be radio-tagged. For instance, In a study whose results he’s now analyzing, Henrich has tagged a molecule that attaches to activated T-cells – to see where the activated T-cells that play such an important role in the immune response are. Finding higher levels of activated T-cells in the gut, or the brain, or elsewhere will tell him where immune activity and/or inflammation is increased in long COVID.

Whether the T-cell is engaged in fighting off the virus or is activated due to autoimmune processes, Henrich will be able to pick it up – not just in the gut or elsewhere – but across the entire body. Since Henrich will be using the same group of patients for both studies, he’ll be able to tell if T-cell activity tracks with viral persistence. If they don’t, then another possibility opens up – overzealous T-cells are shooting blanks and missing the target. (A preprint of that study was just published – a blog on it is coming up.)

The Gist

  • Co-founder of the PolyBio project and leader of the Long COVID Research Initiative, Amy Proal is no stranger to ME/CFS – having come down with it while a pre-med student. Proal’s history is potentially illuminating – she came down with three severe childhood illnesses and suffered through a bout of infectious mononucleosis – all of which her fraternal twin, who remains healthy today, missed. 
  • Proal has called persistent viruses “the trend we see the most evidence for”, and she and the Long COVID Research Initiative are devoting $15 million to search for them. Deeply buried viruses, though, are hard to assess. Aside from autopsies and the limited biopsies that can be done, they’ve been difficult to find. 
  • Recently, she interviewed Tim Henrich at the University of California at San Francisco, who has found a way to uncover the beasties that may be lurking deep in our tissues. Even if they’re not replicating, these deeply buried pathogens could be altering the gene expression of the cells they live in, tweaking the immune system with foreign proteins, and swiping resources from the mitochondria. 
  • Working with UC Davis researchers who developed a super-PET scanner called EXPLORE, Henrich was able to find, for the first time, deep reservoirs of HIV virus in the body. EXPLORE – which combines together multiple PET scanners and a CAT scan – is  40 x’s more powerful than commercial scanners.
  • In the first effort outside of HIV, Henrich and colleagues are turning EXPLORE’s powerful beams on long COVID. Henrich and his colleagues, Stephen Deeks and Michael Peluso, glommed onto the potential long-COVID pandemic early and have been following long-COVID patients for three years now.
  • Throwing the academic research playbook out the window, they formed the LIINC group (Long-term Impact of Infection with Novel Coronavirus), freely shared their findings, data, and samples, have produced over 20 long-COVID papers, and are part of the NIH’s RECOVER Initiative.
  • The LIINC group has also just finished up a study that screened hundreds of thousands of protein sequences to look for evidence that molecular mimicry is causing autoimmunity in long COVID, are taking a deeper look at inflammation and exhausted immune cells, and are exploring novel approaches using non-traditional anti-inflammatories in treatment trials.
  • Both Proal and Henrich agree that many flavors of long COVID probably exist and that combination therapies will probably be the key to stopping it. If Proal was in charge of things, she’d develop a moonshot initiative to develop the best antivirals possible.
  • Many new technologies are being brought to bear on long COVID – each of which has the potential – since investigators like Henrich appear to be essentially studying ME/CFS – to illuminate ME/CFS as well.
  • The PolyBio Foundation recently announced that Akiko Iwasaki – the keynote speaker at the recent IACFS/ME conference – received a grant to assess pathogen proteins in ME/CFS. The twist is that Iwasaki is using a custom pathogen panel that will include 100 enterovirus proteins – making it the first deep dive into enteroviruses – the first virus ME/CFS was putatively associated with decades ago. 
  • Coming up – Henrich et. al’s paper using the EXPLORE machinery to assess T-cells in long COVID was just published. 
Then there’s the long-COVID gut study. If Henrich finds evidence of viral persistence in the gut, he’ll biopsy the gut to validate his findings. Once he has that tissue, he can determine if the genetic responses to the virus have changed how the cells operate. The same thing is being done with the lymph nodes.

Not many EXPLORE machines apparently exist, but this technology could be used in the same way to determine where the Epstein-Barr virus, or where enteroviruses, or the Lyme bacteria are hanging out as well. Henrich and his colleagues were one of the first to show, in fact, that Epstein-Barr virus reactivation is happening in long COVID. Of the three viruses they assessed (EBV, cytomegalovirus, HIV), EBV was most associated with fatigue in long COVID. The herpesviruses, he said, were of “huge interest”.

EBV and its herpesvirus cousins were the next “low-hanging fruit” that he wants to look at. Antibodies specific to EBV do need to be developed – not an easy process, apparently, but if and when they are, Heinrich and his team would clearly jump at the chance to use them in long COVID, ME/CFS, and other diseases.

A Long-COVID Collaboration Engine – the UCSF’s LIINC Project

Henrich, Dr. Stephen Deeks, and Dr. Michael Peluso at the UCSF team have been tracking COVID patients in the LIINC project (Long-term Impact of Infection with Novel Coronavirus). They started gathering samples early in the pandemic. By May, they knew of COVID patients who were no longer shedding viruses but were still sick – making it clear that long COVID was a thing. Scrambling, they applied for grant after grant, only scoring a hit when they were able to tag a supplemental grant to one of Heinrich’s ongoing NIH grants.

From the beginning, they were committed to sharing their data, samples, expertise, and resources with everyone and collaborating as widely as they could. Calling this “not normal”, Heinrich said the scale of the pandemic required a frameshift. Instead of protecting their findings, they spread them as widely as they could.

Over time, LIINC has shared thousands of samples with other researchers. Since the pandemic began, LIINC’s collaborated on over 20 long-COVID papers. (Compare their rapid response to the NIH’s RECOVER project, which failed to start gathering samples for a year – thus missing out on what the virulent Delta variant was doing to unvaccinated people.) They’re also about to begin their own clinical trials and are part of the NIH’s RECOVER project.

The LIINC group has also just finished up a study that screened hundreds of thousands of protein sequences to look for evidence that molecular mimicry is causing autoimmunity in long COVID. They’ve also moved downstream a bit to take a deeper look at inflammation, exhausted immune cells, and novel approaches to interrupting that inflammation to improve symptoms.

Proal said there’s unlikely to be one type of long COVID, and Henrich agreed many flavors (viral persistence, autoimmune, clotting, etc.) probably exist. She noted that combinations of therapeutics were used to tame the HIV virus – she asked if Henrich thought that was the future of long COVID. Heinrich thought 100% yes. Combination therapies work best in many chronic illnesses. If you can disrupt inflammation at the same time you stop an aberrant clotting cascade, for instance, you’re probably going to have a better impact.

That said, testing combination therapies is hard to do with the FDA’s current structure, and it can be difficult to get different companies to work together. It did, however, happen with HIV.

About those antivirals. In the Mitchell interview, Proal said she thought the best thing that we could do we could do right now – for many chronic conditions – was to develop better antivirals. Drugs like Valtrex and Valcyte are not targeted on the Epstein-Barr virus. If it were up to her – and she ran the National Institutes of Health – the first thing she would do is create a program that fast-tracks research on new antivirals. She said, “There’s a huge potential for the development of new and better antivirals, and if we were to do that, I think we could really make a dent in these cases.”

Technological Advances Bring Hope

The greatest hope for people with complex diseases like ME/CFS and long COVID lies in the technological advances that seem to be happening all around us. Not only is the EXPLORE scanner 40x more powerful than commercial PET scans but note that long COVID was the first disease after HIV that Henrich and colleagues brought it to bear on – and every long-COVID advance has the potential to move the ME/CFS field forward. In fact, given the types of patients that Heinrich is studying, we could say he’s probably studying ME/CFS right now.

Ditto with Dr. David Walt, who’s using a new technology in long COVID which allows him to “literally count the number of molecules present” and is 1,000 to 10,000 x’s more precise than standard ELISA techniques.

“An Explosion in Therapeutics”: the RECOVER Long COVID Biomarker Talk and Its Implications for Chronic Fatigue Syndrome and Fibromyalgia

We have our own creators in the ME/CFS field. Jarred Younger is pioneering two new technologies: a cheaper, easier, and potentially more accurate brain scan using heat mapping, and a new immune cell tracking technology that allows him to track immune cells to see if they’re getting into the brain.

The Younger Interview: Neuroinflammation, a Brain Invasion?, Psilocybin Trial,and More…

The First Major Enterovirus Study in ME/CFS in Decades Begins

Then there’s the latest Polybio project. Funded by Tempi Stiftung via the Johadamis ME/CFS Research Grant, Akiko Iwasaki – the keynote speaker at the last IACFS/ME conference – and Michael VanElzakker will use “advanced technologies” to uncover pathogen proteins in the blood and cerebrospinal fluid of ME/CFS patients.

The clincher here is a focus on enteroviruses like we’ve never seen before. Besides other pathogenic proteins, the study has been custom designed to assess over 100 different enterovirus proteins that no one ever looks for. Finally, after literally decades of questions regarding the enteroviruses – which were the first viruses putatively associated with ME/CFS – we’re going to get a deep dive into the enteroviruses in this disease. John Chia, MD. – who has proposed for over a decade that bits of enteroviruses are causing ME/CFS – is undoubtedly happy at that.

Did The ME/CFS Field Give Up Too Early on Enteroviruses?

  • Coming up – the Heinrich T-cell study finds evidence of systemic inflammation in long COVID.

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