Epstein-Barr virus

An old drug gave a Utah researcher a clue how to knock EBV down.

A recent study suggested that Epstein-Barr reactivation might be present in a substantial number of people with (chronic fatigue syndrome) ME/CFS.  Anti-herpesvirus drug protocols in ME/CFS, however, tend to last a very long time and aren’t always successful – a sign that these drugs – which were not developed to attack EBV – aren’t very effective.

A new (old) drug in town called spironolactone, however, could be changing things. The spironolactone saga in EBV reminds us that important answers to ME/CFS might not need to come from some sophisticated R&D drug program but might literally, right now, be found on the aisles of your local pharmacy.

Sankar Swaminathan MD, Chief of the Division of Infectious Diseases at the University of Utah, has been studying the Epstein-Barr virus for almost 20 years. His most recent study demonstrated that EBV activates the ACE-2 receptor in such a way as to allow the SARS-CoV-2 coronavirus easier entry into epithelial cells. Linking EBV to the ACE-2 receptor is intriguing given the interesting ACE-2 findings in ME/CFS and postural orthostatic tachycardia syndrome.

Besides infectious mononucleosis – a common trigger for ME/CFS – and 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’s at its most dangerous. Swaminathan 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 the current slate of herpesvirus drugs left SM untouched. That suggested the SM protein was a good target for a possibly, more effective anti-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.

Spironolactone – mineralocorticoid receptor antagonist used to treat kidney disease, heart failure, and edema – wasn’t in anyone’s ballpark as an antiviral drug.  The researchers found that its mineralocorticoid antagonist properties weren’t suppressing EBV, though – something else was.

Plus spironolactone had problems. 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 proposed that spirolactone’s most important role lay not in the drug itself, but in its ability to point to a potentially more effective EBV  drug.  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 in the world this mineralocorticoid drug was doing what it was doing.

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

Dinesh Verma1Trenton Mel Church1Sankar Swaminathan23Epstein-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 anti-herpesvirus 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. Spironolactone, it turns out, stops or inhibits the transcriptions of 15 genes that the virus needs to replicate.

The researchers knew that SM – the protein that had led them to find spironolactone in the first place – 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 where it turns on the genes that begin EBV’s replication process.

XPB then became the new target. The University of Utah researchers are now trying to find drugs that target XPB with the goal of keeping EBV and other herpesviruses in their latent states.

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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