Archive for July, 2020

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.

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

“EBV is an important factor for the development of the disease” in at least a subset of patients.  The authors

A new study is revitalizing a long simmering question about the role of Epstein Barr Virus and other herpesviruses in ME/CFS.

herpesviruses ME/CFS

Herpesviruses have been studied in ME/CFS for decades. Few studies, though, have looked for direct evidence of active infection.

Herpesviruses just never seem to go away, in the ME/CFS field. They’ve been studied on and off for decades in chronic fatigue syndrome (ME/CFS) and yet the research keeps coming.

Why? For one reason, reactivated latent viruses are too juicy a possibility for an illness that often starts with an infection. ME/CFS also produces symptoms similar to those  produced by “sickness behavior”: a process initiated by the brain that’s designed to keep us in bed to stop spreading an infection. Plus enough positive study results have kept the herpesvirus theme alive in ME/CFS.  While negative studies can be found, too many positive studies have kept this inquiry from fading.

The Study

And now we have another positive result. A Bulgarian team (on behalf of the European Network on ME/CFS (EUROMENE)) assessed the prevalence of latent and active Epstein-Barr, cytomegalovirus and human herpes virus 6 in 108 ME/CFS patients and healthy controls (58 ME/CFS; 50 healthy controls).

Besides being larger than many past studies, this study went a step further than most past studies. Most studies have relied on more indirect measures such as antibody tests that assess whether an immune response has been raised to determine whether active herpesvirus infections are present. This study, though, assessed antibodies and used a process called PCR to directly look for signs of herpesviruses (herpesvirus DNA) in the plasma.

While several EBV antibody studies have had conflicting results, I was able to find only published two studies that have assessed active EBV infections using PCR. Neither found evidence of active herpesvirus infections in ME/CFS. One, however, was very small (n=20) and the other was 20 years old.  In 2013, though, Ian Lipkin reported in a CDC talk that he failed to find direct evidence of herpesvirus infection in almost 300 people with ME/CFS.

Foremost Virus Hunter Finds Biomarkers, Few Viruses in Big Chronic Fatigue Syndrome Study

If pathogens are in a latent state they should remain in the cells and not be present in the blood. Almost all of us carry latent or inactive herpesvirus infections in our cells. They are not a cause for alarm. Active herpesvirus infections, in which the pathogen is actively replicating and spreading from cell to cell through the blood, are another matter.

Results

The study did not find evidence of increased active cytomegalovirus or HHV-6 infections in the ME/CFS group.  Two findings, however, suggested that active EBV infections – perhaps similar to those found in infectious mononucleosis/glandular – were significantly more prevalent in the ME/CFS group.

Cell infected with herpesviruses

A cell infected with herpesviruses (green dots) (from National Cancer Institute)

Almost 25% of the plasma samples from ME/CFS patients were positive for EBV DNA.  Almost 2/3rds of those patients also had high levels of antibodies (EBV‐CA IgG class antibodies) that have been linked with active infections.  (This type of antibody latches onto an antigen on the capsid or shell of the virus. These particular antibodies fade quickly after the virus is vanquished from the blood.)

The study didn’t find evidence of active HHV-6 or CMV infections. (Some researchers, however, believe that a smoldering infection that this type of research wouldn’t detect may present in a subset of ME/CFS patients. Also low level HHV-6 infections in the organs may not  show up in the blood.  Nor did the study assess the early EBV proteins that Williams at Ohio State University has been finding in ME/CFS.)

Using both serological tests and PCR, this study provided a robust finding of an active EBV infection in about 20% of the ME/CFS patients tested. The authors asserted that this finding indicated “EBV is an important factor for the development of the disease” in at least a subset of patients.

The EBV ME/CFS Saga Continues

There’s plenty of reason to be concerned about an active EBV infection. Researchers are continuing to explore the role EBV plays in many serious illnesses including multiple sclerosis (MS), systemic lupus erythematosus (SLE), Guillain-Barre Syndrome, several cancers,  rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, schizophrenia, and others.

 

The Epstein-Barr Virus – Could it be Causing Neuroinflammation in ME/CFS?

The EBV saga in ME/CFS is littered with interesting and sometimes conflicting findings. We know that EBV – the main pathogen associated with infectious mononucleosis/glandular fever – is a common trigger for ME/CFS. Several studies also suggest that immune response to EBV may be lacking in some patients; i.e. some people with ME/CFS appear to have trouble fighting it off.  Some studies have found a paltry antibody response to the virus. Other studies, however, have found no evidence of an immune hole.

Over the past decade Ariza and Williams at Ohio State University have methodically been making the case that a smoldering EBV infection is producing fatigue and other symptoms in a subset of people with ME/CFS. A recent study suggested that smoldering infection could be producing neuroinflammation.

The Epstein-Barr Virus – Could it be Causing Neuroinflammation in ME/CFS?

The Autoimmune Virus?

On a broader front, a 2018 study which the lead researcher called “a capstone to a career in medical research” suggested that EBV is a kind of autoimmune accelerator that is turning on genes associated with autoimmune disease – an interesting finding given the possibility of an autoimmune subset in ME/CFS.   Two gene expression studies done ten years ago suggested that EBV was turning on/off multiple genes in ME/CFS patients cells.

Epstein-Barr Virus May Be Turning On Pathogenic Genes in ME/CFS

 

This Euromene study was too small (n=108) to be definitive, but the dual testing approach (PCR and serology) provided confidence in its results. Clearly, the EBV story in ME/CFS – like the EBV story in so many diseases – is not over.  If an active EBV infection is present in a significant subset of patients the next question is what to do about it.

With regards to that question, a recent study has produced some potentially very good news on the treatment front. That blog is coming up next.