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NIH State of Knowledge Workshop: Pathogens II (EBV and Enteroviruses)

Posted by Cort Johnson

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

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.

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.

Epstein barr virus and chronic fatigue syndrome“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.

HERV-K-18-CFSAn EBV Viral Cascade? – Finally Dr. Glaser noted that Dr. 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 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 NF?B 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/project_info_description.cfm?aid=7924814&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.

Dr. John Chia – The Pathogenic Role of Enteroviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Dr. John Chia on enteroviruses and chronic fatigue syndromeDr. Chia always gives very well-organized and clear presentations and it was good to see him on the agenda. He’s been handicapped by the fact that he is essentially doing his work alone and thus doesn’t have access to some technologies, but he is remarkably thorough in his approach. Throughout his years studying CFS he’s assessed over 2,500 blood samples.

A Talk with Dr. Chia – I asked him what he was doing right now and he stated that he was doing ‘basic stuff’ and would very much like to do the sequencing Dr. Coffin asked about (to determine the exact enteroviruses involved), but he can’t do that himself.

Dr. Chia believes the medical profession needs to look more closely at the colds and flus we all come down with. He stated that more than 50% of the people who appear to come down with the flu, for instance, aren’t infected by flu viruses but by rhinoviruses (which have some similarity to enteroviruses). He feels that the starting point – identifying the virus – is ‘so important’ , and this makes sense given that finding enteroviruses in the blood, long after the initial infection, can be problematic at times.

(The medical profession treats flus and colds as if the identity of the pathogen is not particularly important, and, of course, for most people it’s not. There is that percentage of people (called CFS patients) who just don’t recover, but even in those people pathogen tests are not done until years later when they meet up with a doctor like Dr. Chia.

Enteroviruses in CFS with Dr. ChiaDr. Chia believes the pathogen identity matters, but some other ME/CFS physicians or researchers do not. Prior to XMRV showing up, Dr. Cheney declared that he was tired of chasing after pathogens and instead began to focus on the ‘terrain’ that allowed pathogens to flourish. Other researchers point to studies which show that a number of pathogens can trigger ME/CFS – suggesting that the pathogen itself may not be critical.

Whether that’s true is really unclear.  Later, we’ll see Dr. Klimas point out that Gulf War Syndrome and ME/CFS patients look almost exactly the same – until you look at how their immune networks are functioning – at which point it becomes clear that they are actually very different!

Dr. Chia’s theory of enteroviral infection is, in a broad sense, similar to Dr. Lerner’s theory of an atypical smoldering infection, in that he posits that immune system activity causes the virus to produce altered and defective, but still possibly potent, versions of itself.

“when the immune system fights it, the virus stops producing [whole new virus], but maintains its survival by producing dsRNA”

A Pivotal Discovery – He feels his lab’s discovery of enteroviral double stranded RNA (dsRNA) was pivotal to his understanding because it allowed him to trace the virus through its full life cycle. If I understood what he said (the tape is quite garble), his scenario of enteroviral infection in chronic fatigue syndrome (CFS) (and other disorders) involves the virus spreading through the body during the acute phase of the illness and then getting hampered by the immune system but leaving bits of ds enteroviral RNA behind – which, perhaps after exercise, trigger an immune or other reactions in the tissues themselves.

One problem with treatment is that you can’t kill what’s not alive – and these bits of dsRNA the virus left behind are just pieces of foreign genetic material left in the tissues.

He’s not the first to suggest this. He noted that the presence of dsRNA enteroviral RNA was suspected in the poliovirus cultures in the 1960s and that more recently Chapman et al. have found viral RNA in mouse heart tissues long after the virus appeared to have disappeared from them

Enteroviruses and chronic fatigue syndrome by Dr. John CHia (498x498)Following experimental inoculation of mice with CVB3, we (Kim et al., 2005) and others (Klingel et al., 1992; Reetoo et al., 2000) have shown that viral RNA can be detected in mouse heart muscle for weeks, well past the time that cytolytic virus can be isolated in susceptible reporter cell cultures.

As noted earlier, these truncated bits of viral RNA appeared to be the result of an immune system that kills the virus but leaves viral components behind. Again this appears to be very similar to Lerner’s and Glazer’s theory of an immune system that is just unable to fully complete its mission.

Chapman et al.: “we have shown that TD(terminal deletion) genomes become detectable in the latter part of the acute viral replication period when the adaptive immune system has been activated and has largely cleared the wild type virus from the host. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440640/?tool=pubmed

This, of course, could be why it might be so hard to detect the virus in the blood; it simply doesn’t (or at very low levels) exist in the same form anymore. This is cutting edge work, however. Dr. Chia noted that most of this work has been done on animals and has not been translated into humans. The problem for Dr. Chia, then, is not just CFS; the number of researchers looking at dsRNA in enterviruses anywhere is small and the field is not well funded.

A Pivotal Study – He noted that the enteroviral field in ME/CFS was battered by the Strauss enterovirus finding of 15 years or so ago. He didn’t blame Strauss– who was one of his teachers – but felt there may have been methodological problems to the study (which was never published). Dr. Chia was able to reproduce the findings of the British researchers that the Strauss study invalidated, yet surprisingly there’s been no upsurge in interest in the field. He said he would welcome someone trying to prove him wrong but that hasn’t happened. He’s not in a particularly promising position; the field of enteroviral research is not particularly large (he acknowledged that enteroviruses are not ‘sexy’), and he is looking at one corner of it and in a controversial disorder to boot.

Still, his finding of enteroviral dsRNA in ME/CFS was exciting and he has now has masses of data showing increased levels of enteroviral infection in ME/CFS. One can’t help but think that in a better funded field he would know a lot more about the role enteroviruses play in CFS.

A Drug Suggests Hope – there is some unexpected hope on the horizon, though. A hepatitis C drug under development will, he believes, be able to knock off the RNA that is causing havoc in ME/CFS. If it does that, that will open the door not only to better treatment but more research.

“It will be similar enough to the drug that we need…that it will open the door…(hopefully) just as AZT did for AIDS”

Straus and Chronic fatigue syndromeStraus – A Research Review

The mention of Dr. Stephen Straus, an early leader of the NIH effort on CFS, prompted me to take a look at his research. A greatly disliked figure in the ME/CFS community, Strauss was a key player in shaping the government’s early response to ME/CFS.  A measure of his influence can be seen in the outsize response to his negative enteroviral study which, despite never being published, still managed to effectively end research in that area, until Dr. Chia. That, however, was only the beginning.

Dr. Straus’s failed acyclovir trial, using standard treatment protocols for that time (which we now know do not work in ME/CFS), put the kabosh on antivirals in general. An intravenous immunoglobulin (IVIG) trial (unabstracted/1991) apparently did the same for IVIG.  (Dr. Chia will point out at the Workshop that a certain of his patients do very well on IVIG. ) Hepatitis C was knocked out in 1991 (never to return).

A 1991 HPA axis paper that revealed mild adrenal insufficiency helped to kick off what would become dozens of papers examining what turned out to be, yes, mild HPA axis problems in many patients.

A 1992 conference review sported the rather gut-wrenching statement below, which emphasized that progress on the research level will very likely depend on finding subsets in this heterogeneous population – words that are no less true today than almost 30 years ago.

“ Because CFS is not a homogeneous abnormality and because there is no single pathogenic mechanism, research progress may depend upon delineation of these and other patient subgroups for separate data analysis. “

Straus then moved on to the brain in 1992 and 1993, finding little evidence on one small study for attentional or short-term memory problems but then uncovering altered metabolite levels in a cerebrospinal fluid study http://www.ncbi.nlm.nih.gov/pubmed/1282370 that he felt could account for some of the fatigue and which suggested ‘persistent immune stimulation’ was present.

A 1993 lymphocyte study that found evidence of reduced T-cells and responses to antigens suggested to him it was” a consequence of an underlying neuropsychiatric and/or neuroendocrine disorder or because of exposure to antigens or superantigens of an infectious agent.” http://www.ncbi.nlm.nih.gov/pubmed/8095270. (Note that Dr. Huber is currently studying the possibility of superantigen activation in ME/CFS.  Straus’s review of herpesvirus research http://www.ncbi.nlm.nih.gov/pubmed/8387907 later that year concluded that herpesviruses probably do not play a role in CFS.

Straus’s biggest role in CFS may have been his co-authorship (along with Fukuda, Hickie, Dobbins, Sharpe and Komaroff) of the 1994 Fukuda or International definition of CFS that 17 years later, still, somehow dominates the field.

It was back to the brain in 1996 in a fascinating study that which suggested that the brains of ME/CFS patients, were, for want of a better term, ‘sluggish’ post-exercise compared to those of healthy controls and people with depression http://www.ncbi.nlm.nih.gov/pubmed/8960719. The paper stated “We conclude that postexercise cortical excitability is significantly reduced in patients with chronic fatigue syndrome and in depressed patients compared with that of normal subjects.”

A hydrocortisone trial http://www.ncbi.nlm.nih.gov/pubmed/9757853 that showed mild improvement but adrenal suppression in some patients had important implications for many doctors seeking to turn around the mild HPA axis abnormalities seen in their patients. An HPA axis stress test documented more HPA axis abnormalities in 2001 and then Strauss tried another treatment angle with a failed fludrocortisone trial that ended up in the prestigious JAMA journal http://www.ncbi.nlm.nih.gov/pubmed/11150109. This would be another unfortunate trendsetter whose effects Dr. Rowe, the lead author, would bemoan at the SOK Workshop. The problem again was the paradoxical approach of a research community that readily acknowledged subsets were present but then treated all the patients like they were the same once they got them into a study. And so there it was – in black and white in a top medical journal – the finding that fludrocortizone does not work in CFS. Dr Rowe says he uses fludrocortisone in CFS every day. . .

A very large 2001 study (n=744) http://www.ncbi.nlm.nih.gov/pubmed/11531735 looking at symptoms failed to produce concretely identifiable subsets, but emphasized the toll the lack of proper subsets was likely taking on CFS research, stating that “substratification of patients is essential for further aetiological and treatment research”.

In 2002, Straus performed another stress test of sorts, injecting CFS patients with IL-6 to see if cytokines might be at the heart of the cognitive and symptom problems in ME/CFS. Evidence of increased symptom activation suggested that while immune activation might very well be part of the problem, it was not all of it, as cognitive problems remained unchanged. http://www.ncbi.nlm.nih.gov/pubmed/12214788

After 2002, Straus mostly stopped participating in ME/CFS research. His final (small) study before his death suggested people with CFS (as well as those with rheumatoid arthritis and polymyosistis) have reduced aerobic capacity. http://www.ncbi.nlm.nih.gov/pubmed/19627955

The CDC did look at symptom patterns and made a stab at subsets during the ‘Pharmacogenomics era’ but they also employed a random sampling methodology that made it difficult to build up the large sample sizes needed.

Conclusion – The Straus studies, some of which were surprisingly small, had an outsize influence on the field. Straus’s studies opened up ground or validated findings of altered brain metabolite levels, reduced cortical excitability, altered exercise metabolism and immune system dysfunction in CFS.

Strauss’s studies also negated several treatments that are commonly used today by some doctors to positive effect including antivirals, fludrocortisone, hydrocortisone and IVIG. Strauss was also a key figure in asserting the herpesviruses were probably not a major factor in ME/CFS.

Some of Strauss’s mistakes in the treatment arena can be attributed to his unwillingness or inability (low sample sizes?) to look for subsets – a problem that is hardly less common now. If blame must be placed for the research community’s unwillingness to follow their own advice and make a serious effort at finding subsets, where should the blame be placed? Obviously at the federal level – at both the CDC and the NIH – and at Stephen Strauss, who was entirely aware of the dangers that failure to identify subsets posed to making progress on ME/CFS research level, and yet did nothing about it.


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