Chronic Fatigue Syndrome and the Pathophysiology of Epstein Barr Virus (EBV) Infection

Phoenix Rising - Cort Johnson's Column ...Presenting complex chronic fatigue syndrome (ME/CFS) research in a way we can all understand.

 Monday, May 16, 2011:

Dr. Ronald Glaser - Chronic Fatigue Syndrome and the Pathophysiology of EBV Infection

State of the Knowledge Workshop at the NIH

Dr. Ronald Glaser - Chronic Fatigue Syndrome and the Pathophysiology of EBV Infection 

 

by Cort Johnson

 

 

Dr. Glaser started off by noting that studies have found a strong association between HHV6, EBV and chronic fatigue syndrome (ME/CFS) and then, perhaps in reference to all the attention given to XMRV over the past year and a half..stated that any other viral discoveries (guess who?) must account for the fact that these viruses have been shown to be present in ME/CFS.

Dr. Mikovits, of course, has repeatedly referred to pathogenic ‘co-factors’, e.g., viruses like EBV and HHV6 that complete the picture of an immune-depleting retrovirus that, in an HIV-like fashion, allows other pathogens to proliferate. After the WPI’s recent report of XMRV in B-cell lines, Dr. Mikovits was reported to be in conversation with Dr. Lerner about the EBV-XMRV connection. [/SIZE][/FONT]In any case, the EBV connection is there – it certainly needs better studies – there’s no doubt but that EBV plays a role in some patients.

Epstein Barr Virus was (until XMRV showed up) easily the most studied pathogen in ME/CFS. Able to cause various cancers and the subject of much research in autoimmune and other disorders, EBV has long been shown to be reactivated by stress – and stress has been a major focus of Dr. Glaser’s EBV research and that was his first topic.

“Stress”, EBV and ME/CFS – Some early studies indicated that even in healthy people stressful events were able to trigger high levels of EBV reactivation which were in turn linked to feelings of anxiety and depression. This suggests that the reactivation of EBV, which does take up residence in the central nervous system, could cause some of the mood problems found in ME/CFS. See Carol’s story for a herpesvirus positive patient who was able to drop antidepressants after going off of antivirals. (Stress is not at all simply psychological; it also refers to physical activity, the stress of an infection, etc.).

Dr Glaser noted that virtually every type of immune cell has receptors for, i.e. is regulated by, stress response factors. The two branches of the stress response – the autonomic nervous system and the HPA axis – are, in fact, the main immune regulators in the body; these systems are intimately intertwined. (The idea of intertwining will be a prevalent one in the Workshop; Dr. Kelly will later talk on how the immune system in the body interacts with the brain.)

Can We Say…the Activated Stress Response = Reactivated EBV Subset? - Not all the EBV study results have been positive, and Glaser had an idea why. Not surprisingly, it had to do with one of the main features of the conference – subsets. If EBV is reactivated by a stressor, perhaps, Glazer asked, it would be a good idea to try to determine which patients evinced signs of an upregulated stress response and see if they were the same ones with high levels of EBV reactivation. He then provided a grocery list of stress response factors such as hormones (e.g., cortisol, prolactin, epinephrine, norepinephrine), neuropeptides (NPY, substance P), and cytokines and other immune factors researchers could test for.

This kind of multiple dimensional analysis designed to tease out co-factors and subsets is clearly the way to go in CFS. Perhaps at some point it will be odd to see pathogen studies that just look for pathogens and ignore the factors that may allow them to flourish.

(But why not actually introduce a stressor such as an exercise and then measure EBV levels? Researchers have looked an array of factors after exercise but no one to my knowledge has looked at pathogen reactivation. This seems odd given that infectious mononucleosis (aka EBV) triggers ME/CFS in a significant portion of patients…EBV does reactivate during stress…..exercise is a stressor….)

Still bothered by the notion that when researchers talk about ‘stress’ they might REALLY just mean psychological stress? EBV reactivation has been shown to occur in Antarctic winter expeditioners, astronauts training for spaceflight, swimmers and runners. In fact, a recent study used Valtrex, the same drug used in ME/CFS to combat EBV, to reduce viral reactivation in long distance runners. http://www.medscape.com/viewarticle/482952_4

Given the many studies which show that stressing a system – just about any system – leads to clearer, more significant results, it’s possible that looking at pathogen levels at rest, particularly in the case of ‘stress-responsive’ pathogens like EBV and the herpesviruses, may not be the optimal way to go in ME/CFS. )

Glaser then demonstrated how antibodies to some EBV proteins but not others were elevated in CFS, suggesting that EBV replication was stopped partway in ME/CFS, allowing the production of early proteins that he believes trigger an immune response and the symptoms of ME/CFS. Several papers from Dr. Glaser and Dr. Lerner have suggested that this model of ‘abortive EBV reactivation’ may be occurring in CFS.

An EBV Viral Cascade? – Finally Dr. Glaser noted thatDr. Huber, who achieved some ‘renown’ with her negative XMRV findings has been able to show that ‘latent’ EBV, that is, non-reactivated EBV, can produce gene products that, in some individuals, may be able to activate an endogenous retrovirus (HERV-K18) embedded in our genome which then may be able to trigger a cytokine explosion of sorts. Her pilot study (funded by the CFIDS Association of America) suggested that some people with ME/CFS may have a genetic predisposition for HERV-K18 activation. With a nice big NIH grant studying a nice big cohort (400 patients!) in collaboration with Dr. Taylor (who is also working with Dr. Broderick and who knows who else), she is exploring whether this is occurring in ME/CFS. Her study is due next year.

Dr. Huber’s study from the NIH Project Reporter:

A positive association between CFS and either HERV-K18 alleles or expression patterns would open new avenues for the development of clinical treatments of this chronic disease. CFS is a disease that affects a significant number of people worldwide, yet the underlying mechanism(s) of pathogenesis remains unclear. The herpesvirus EBV and IFN-a have been suggested to be associated with CFS, although these concepts are far from accepted. We propose a novel genetic aspect in the EBV/CFS association, namely the presence of certain HERV-K18 alleles that differ in their superantigen activity.

After his bitter experience with the CFS grant review panel Dr. Glaser had to go outside of CFS to his grant funded but he did get it funded and he’s now studying EBV in mice in a study that goes to 2015.

Our data provide a new perspective on how a latent herpes virus, such as EBV, when reactivated by stress or other factors, could cause immune dysregulation, the activation of NFkB in macrophages and the upregulation of proinflammatory cytokines, with possible implications for EBV-associated clinical symptoms and disease, including EBV-associated tumors. http://projectreporter.nih.gov/proje...4&icde=7795849

A Slow, Slow Pace – The EBV story continues with several ME/CFS researchers looking at it; the Montoya treatment study should be out soon, Dr. Glazer has an NIH grant, Dr. Lerner continues his work, the Lipkin/Montoya study should be very revealing and Dr. Huber has her grant.

It’s encouraging to see ME/CFS researchers get some grants but the pace is very, very slow…one study every couple of years. If a study is positive it then needs to be validated….which takes more years. At this pace it can take a good 7 to ten years for real progress to be made in just one area of inquiry. If the NIH were to support ME/CFS research as it does other disorders, there would be a bevy of EBV researchers that would jump on Glaser’s or Lerner’s findings and push the science forward (as has happened in XMRV). Until that does unless something dramatic happens (the Lipkin/Montoya study?) we’re looking a slow pace of research in this area.

 

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