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Old Drug Points To a New Way To Knock the Epstein-Barr Virus Down

A recent study suggested that Epstein-Barr reactivation might be present in substantial number of people with ME/CFS.  Anti-herpesvirus drug protocols in ME/CFS, however, tend to last very long and aren’t always successful.  The same drugs have been used for decades. That, however, could be changing, though.

Some studies remind us to always be ready for surprises – to not think that we know so much. The body is always throwing us curveballs and it turns out that sometimes drug companies can as well. The spironolactone saga in EBV reminds us that important answers to ME/CFS and other diseases might not need to come from some sophisticated R&D drug program but might literally, right now, be found down the aisles of a pharmacy.

EBV Reactivation

The goal – find a new drug that could stop EBV from reactivating.

Sankar Swaminathan MD, Chief of the Division of Infectious Diseases at the University of Utah, has been publishing on Epstein-Barr virus  for almost 20 years. Besides infectious mononucleosis – a common trigger for ME/CFS – EBV has been associated with autoimmune diseases and a host of cancers.

Four years ago, Swaminathan and colleagues went on a search to find a drug not to kill EBV – the bug is too firmly embedded in our cells to hope for that – but to stop it from reactivating. It’s when EBV awakens from its latent state and begins reactivating that it becomes the most dangerous. If Swaminathan could stop EBV from doing that he would have achieved a momentous goal.

He had an important clue. He knew that EBV (and other herpesviruses) produced a protein called SM that played a critical role in the early stages of EBV reactivation. He also knew that current slate of herpesvirus drugs left SM untouched – suggesting the protein presented a new possibility for a new herpesvirus drug.

The Study

Verma D, Thompson J, Swaminathan S. Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function. Proc Natl Acad Sci U S A. 2016;113(13):3609-3614. doi:10.1073/pnas.1523686113

“It’s remarkable that a drug we have used safely in the clinic for over 50 years is also an effective EBV inhibitor. It goes to show how basic research can reveal things we would never have found otherwise”  Swaminathan

His team found a way to target the protein, and then created an assay that allowed them to screen compounds for antiviral activity.

Then came the surprise – spironolactone – a 50 year old drug knocked EBV down. The drug not only stopped EBV from forming the capsid or top layer of EBV that it needs to replicate, but it also blocked the expression of genes the virus used to replicate as well.

aldactone - spironolactone

No one suspected that a kidney drug of all things might hold the key to beating EBV. (Aldactone – brand name for spironolactone)

Spironolactone, though, has never been known as a antiviral. Far from it – it’s a mineralocorticoid receptor antagonist used to treat kidney disease, heart failure and edema.

The researchers found that its mineralocorticoid antagonist properties weren’t suppressing EBV – something else was.  Although, the researchers were unsure just how it was doing it, it was clear the drug doing something to EBV that no other drug had done. It had the potential to open a new era of more effective herpesvirus treatments.

Spironolactone, itself wasn’t the answer. While it’s been used for decades it can have significant side-effects. Besides some potentially toxic effects, it also increases the secretion of salts – something that salt craving ME/CFS patients might not find so beneficial.

The authors suggested that spirolactone’s most important role lay not in the drug itself, but in its ability to pointing to how produce more effective herpesvirus drugs. Noting that the current basket of anti-herpesvirus drugs suffers from problems with side effects and increasing rates of drug resistance, they suggested spirolactone be used “as the template for development of antiherpesvirus drugs”.

“We think there is great potential to modify this molecule so that it can work as an antiviral without having undesired side effects,” Swaminathan.

First, though, they would have to find out how Spironolactone was doing what it was doing.

Mystery Solved –  and the Hunt for a Better Anti-Herpesvirus Drug Begins 

Dinesh Verma 1Trenton Mel Church 1Sankar Swaminathan 2 3Epstein-Barr Virus Co-Opts TFIIH Component XPB to Specifically Activate Essential Viral Lytic Promoters Proc Natl Acad Sci U S A. 2020 Jun 9;117(23):13044-13055. doi: 10.1073/pnas.2000625117. Epub 2020 May 20.

“These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action” Verma et. Al.

Four years later – and at about the same time that an ME/CFS study found direct evidence of EBV reactivation in about a quarter of patients –  the mystery of how a kidney drug came to beat back EBV was solved.

Active Epstein-Barr Infections Found in Large ME/CFS Study

Spironolactone, it turns out, stops or inhibits the transcriptions of 15 genes the virus needs to replicate. The researchers knew that SM – the protein which had lead to the discovery of spironolactone – enhances the activation of those genes. What they didn’t know is that the SM protein does that by ferrying another protein called XPB to EBV’s DNA, at which point XPB turns on the genes that begin EBV’s replication process.

EBV virions

EBV virions (circles). An XPB directed drug might be able to keep EBV under wraps.

XPB, then, provided a new, earlier, possibly more effective target for shutting down EBV. The University of Utah researchers are now trying to find new drugs that target XPB with the goal of keeping EBV and other herpesviruses in their latent states.

Spironolactone, then, didn’t turn out to be the EBV inhibitor the medical world is looking for. The 50 year old kidney drug did, however, provided the clue they needed to start developing a new generation of more effective anti-herpesvirus drug.

The Spironolactone saga shows that  answers to medical issues can come from unexpected places – including old, old drugs – that no one would think to explore.

Novel assays – like the one developed by the University of Utah team – and new data mining techniques will undoubtedly provide surprising new insights in the years to come. Some answers to ME/CFS and other diseases could be in plain sight – if only we can see them.

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21 Comments

  • Mary

    July 22, 2020 at 7:12 pm - Reply

    Thanks for this article ! Another very interesting insight to what can happen when we “think out of the box”. Looking forward to the ever unfolding answers!

  • Winston

    July 22, 2020 at 7:32 pm - Reply

    A wonderful sign that those of us experiencing elevated EBV levels on and off for years may have some abatement of our ME/CFS symptoms to look forward to.

  • Marcie

    July 22, 2020 at 7:51 pm - Reply

    Then came the surprise – spironolactone – a 50 year old drug used not to treat viruses, but heart failure and kidney problems knocked EBV down. The drug not only stops the formation of the capsid or top layer of EBV that it needs to survive, but it also blocks the expression of genes the virus needs to replicate. Cort, this statement taken from your article… so then how does this…so then it talks about XPB and the 2 concepts seem a contradiction to me at least. Can you fill in my gaps? Marcie

  • Nancy B.

    July 22, 2020 at 8:46 pm - Reply

    Spirolonolactone may point the way, but it certainly isn’t an EBV inhibitor, at least in my case. I have extensive, high dose and long term experience with this drug–and not for hypertension. I have just as much problems with ME/CFS using it or not. I have antigens for EBV, but since I didn’t have a PCR test, I don’t know whether mine is active–so cannot comment on whether it has a suppressive effect on active infection. The intense fatigue is still present, regardless.

    Spirolonolactone is widely used off label as an androgen blocker for people with acne–especially hormonal, cystic acne which is refractory to other treatments.

    Some of the not so pleasant side effects are that it is a diuretic and it can make you pee–a lot–and therefore is not considered a good combo if you have POTS. It also, as I mentioned, is an androgen blocker and one of the possible side effect for men is–moobs! There are other ways it can affect males, but being a woman I’m not so familiar with them.

    It also is a potassium sparing diuretic which means you may be peeing out all the other electrolytes, but not potassium. Therefore, you have to be careful how much extra potassium you are consuming in your diet (like bananas). On the other hand, it is expeditious to make sure you replace those other electrolytes.

    Not to discourage everyone, but if Spirolonolatone (Aldactone) may be a useful cousin to EBV treatment–bring it on, researchers!

    • Cort Johnson

      July 22, 2020 at 9:08 pm - Reply

      Thanks. It hasn’t been tested in humans – so, yes, we don’t really know that spironolactone can knock EBV out in humans. The earlier study suggested, I believe, that it can knock it out in the lab. It won’t get tested in humans apparently because of the side effects. Hopefully it is pointing to a better herpesvirus drug – one that is fine-tuned to treat herpesviruses – and not function as a diuretic at the same time.

  • Cort Johnson

    July 22, 2020 at 8:56 pm - Reply

    Yes! I think it’s so interesting that at least part of an answer to EBV was right there! It just took advances in technology and high powered statistical analyses to find it. God knows what else is present that we don’t know about ….yet.

  • Cort Johnson

    July 22, 2020 at 9:01 pm - Reply

    Hi Marcie, This is how I understand it:

    First they knew that SM is an important protein in the EBV replication process.
    Their analyses indicated that spironolactone was able to block it and turn off a lot of EBV genes while doing that.
    But they didn’t know how.
    Further research indicated that SM gets EBV replication going by ferrying a protein called XPF to EBV’s DNA – where it turned on all those genes.
    The best target for a new drug, then, became XPB – since it’s the compound that in the end really gets EBV going.

  • Chris

    July 22, 2020 at 11:40 pm - Reply

    Wow, I take spironolactone for my high blood pressure, because it is the only thing that works. But when I tried going off it I had a terrible time with crashes. Now if I’m feeling shaky I take a little more and it helps. I thought it was the adrenergic effects but this is a whole new view on it. I still am completely disabled, housebound, sometimes bedbound, but it keeps me stable. I also still get POTS during PEMs even with high blood pressure starting out.

    • Cort Johnson

      July 23, 2020 at 12:41 am - Reply

      Interesting. Have you had EBV antibodies checked out?

  • Flopp

    July 23, 2020 at 11:13 am - Reply

    When I read about Spironolactrone I get associations to Danazol.
    As steroids that block testosterone and have estrogenic effects.
    Danazol has also in a few studies been related to effect on EBV, T cells and B cells, and a combination of these. As the focus on ME / CFS is now.
    An interesting connection though, as I got ME / CFS after discontinuing Danazol after many years of use for another disease.

    Some reading about Danazol and EBV:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744141/

  • Chris

    July 23, 2020 at 12:36 pm - Reply

    Not yet. I have to talk to my son. He caught mono and then went on to develop MS, which can run in families with ME/CFS. My best friend had it when we were teenagers so I assumed I was already exposed. This cycle of a virus popping out of hiding, deranged immune reaction possibly caused by mitochondrial dysfunction in immune cells, deranged immune reaction triggering dauer response causing mitochondria to stop making ATP, metabolic trap trapping mitochondria in this state, all at the same time? I am waiting anxiously for them to figure out what the signaling molecule is in the vesicles in serum that trigger the mitochondria to turn off. I have a family doctor now after a few years of having no doctor. Do you know an article about EBV testing and me/CFS that might help us figure that part out?

  • Tracey Anne

    July 23, 2020 at 9:19 pm - Reply

    Chris, you seem to be circling around the same ideas as I am – ‘deranged immune reaction possibly caused by mitochondrial dysfunction in immune cells, deranged immune reaction triggering dauer response causing mitochondria to stop making ATP metabolic trap trapping mitochondria in this state’
    Yes… I’m kind of stuck here. I’ve sorted lots of things – I’d say I have Mast Cell Activation but I’m not going to have some young inexperienced medic having a go to see what happens if they trigger me because they’ll probably finish me off. I don’t need them to tell me something’s wrong – that’s fairly obvious!

    I did have EBV at 17 and it seemed to reactivate throughout my 20’s and early 30’s but it seemed to have calm after that. However I read somewhere that EBV can reside, long term, in the Vagus nerve and cause havoc. An odd thing that happens with me is that if I develop a particular kind of viral illness – not a cold or a flu but something in between that brews up, I get strange vertical ribbons of nausea within my abdomen. I didn’t realise this was unusual.

    Anyway your comment caught my attention because I think those ideas are relevant to my situation. I believe that underneath these deranged systems I’m potentially healthy. I can feel 100% well, at times now, particularly in the morning. I tank in the afternoon but I can pick up again in the evening. I constantly have to monitor what’s going on and dark chocolate is my secret weapon. I did slip in one caffeine tablet (50mg) this morning and waited to see what would happen. No adverse events yet.

    I don’t feel I have an activated EBV infection now – I do believe however that something tipped me over into a different new normal – I sometimes feel that my homeostasis is set too low – so my body could now achieve a higher level of functioning but that isn’t it’s current setting and I don’t know how to re-program it!

  • Jill

    July 23, 2020 at 11:49 pm - Reply

    This is a glimpse of hope for me, Cort. The first time I was tested for chronic active EBV, where greater than 120 was positive, mine was 2,693! I had kidney cancer last year with zero risk factors except the EBV. When I look at my health as a whole, I suspect EBV is the root of everything (or at least the catalyst).

    I did wonder if Chris (above) has had his aldosterone and renin tested. High aldosterone is often the cause of high blood pressure that doesn’t respond to meds, and spironolactone is the treatment (and sometimes surgery, depending on the cause of the hyperaldosteronism). You have to be off spiro for two weeks before the blood test, which is the tricky part. I wasn’t the first time, and I’m retesting next week after being off beta-blockers six weeks and spiro for two. Crossing my fingers it was a false positive!

  • Melissa

    July 24, 2020 at 8:32 pm - Reply

    Nancy B- good reply. Cort you are so great, thank you. For me ivig does it all albeit risky and not good long term.

  • Anton

    August 3, 2020 at 8:09 pm - Reply

    @ Tracey Anne. “I constantly have to monitor what’s going on and dark chocolate is my secret weapon”
    Do you know why its your secret weapon?
    Read below if you want to know why.

    https://pubmed.ncbi.nlm.nih.gov/12490409/

  • anton

    August 4, 2020 at 10:11 am - Reply

    @ Tracey Anne………”I constantly have to monitor what’s going on and dark chocolate is my secret weapon”
    Do you know why dark chocolate is your secret weapon? It is high in a certain amino acid.
    Read below.
    https://pubmed.ncbi.nlm.nih.gov/12490409/

  • Jasmine

    August 12, 2020 at 8:01 pm - Reply

    Melissa, why is IVIG not good for the long term? I thought for immune deficiency people they need it for the life time.

  • Jasmine

    August 12, 2020 at 8:03 pm - Reply

    Melissa, why is IVIG not good for the long term? I thought for immune deficiency people they need it for the life time.
    Cort, Curious why is the side effects of this too much for EBV patients? Aren’t people taking it for other illnesses eg hypertension?

    • Cort Johnson

      August 24, 2020 at 5:38 pm - Reply

      Drug reactions are tricky – particularly in ME/CFS – but certainly some people do fine with IVIG.

  • Jasmine

    September 20, 2020 at 11:24 pm - Reply

    Oh, Cort, I meant Spironolactone. If people with hypertension can take it, why can’t people with ME/CFS take it if they can tolerate it?

  • Armand

    October 13, 2020 at 1:33 am - Reply

    You can use MMS to control/suppress CFS caused by EBV. MMS is Sodium Chlorite (usually 22.4% solution) mixed with HCL (4% hydrochloric acid solution). If you can still find it online, DMSO can also be used to allow MMS to penetrate tissue where EBV hides. I had EBV reactivation which caused chronic fatigue. A diet without gluten, eggs, pork, dairy and less sugar intake is very important as well. Refer to the Medical Medium books by Anthony William for more information. This all controls CFS/EBV. A treatment that prevents EBV reactivation and causes EBV to go back into hibernation would be an even better solution. All CFS sufferers please try this. It works. Good luck…