“Hopefully this will finally make people change their attitudes to this disease.” Dr. Judy Mikovits
The news had been in the air for the last week; the Whittemore Peterson Institute was going to publish something big – really big – on Friday. As early as Monday discussions on the internet focused on an unusual retrovirus called XMRV (Xenotropic Murine Leukemia Virus Related Virus).
Then early Thursday the news was out – a retrovirus had been found in many if not almost all ME/CFS patients. The WPI choreographed the announcement well; stories shot up on the hundreds of media outlets including Wall Street Journal, NY Times, NPR, Scientific American, Nature, etc. The story quickly became the number one e-mailed story on the New York Times.
It was big news indeed – after two decades chronic fatigue syndrome (ME/CFS) was back in the news in a big way. Ironically the last big splash like this in the 1990’s featured a retrovirus in ME/CFS that didn’t pan out and left a young researchers career in tatters. One has the feeling that that is not going to happen this time.in
A deep bench
One reason is the extraordinary depth of the research team involved in these findings. It’s not often that the head of the NCI’s AIDS and Viral Cancer Center of Excellence has any reason to utter the words “chronic fatigue syndrome” to the national media.
But here was Dr. Stuart Le Grice not only uttering the words but likening this stage of the fight to the early HIV epidemic and its partners pledging the National Cancer Institutes best at unraveling just what is going on.
Besides Dr. Grice (not an author of the study) we had Dr. Ruscetti from the National Cancer Institute and the discoverer of XMRV, Dr. Silverman from the Cleveland Clinic chiming in. Clinic. To top it off the study was published in Science, the most prestigious and oft cited scientific journal in the world – an extraordinary event for the ME/CFS research community.
“These compelling data allow the development of a hypothesis concerning a cause of this complex and misunderstood disease, since retroviruses are a known cause of neurodegenerative diseases and cancer in man,” Francis Ruscetti, Ph.D., Laboratory of Experimental Immunology, NCI.
The big picture
ME/CFS patients have never seen anything like this. And in fact it isn’t all about them. Among the stranger findings emanating out of the Whittemore Peterson Institute is the fact that this retrovirus, which had heretofore been associated only with prostate cancer in some neurological diseases was founded on most 4% of the healthy controls blood.
This suggests that about 10 million Americans could be carrying a ticking bomb. It also suggests that anyone who’s having a blood transfusion could be at risk. Those two things got enough of the National Cancer Institute’s attention that it quickly convened a workshop in August on how to deal with this problem.
The study released by the Whittemore Peterson Institute found that two thirds of chronic fatigue syndrome (ME/CFS) patients were carrying a recently discovered retrovirus called XMRV that is associated with severe cases of prostate cancer. They were lead to this discovery by the fact that both chronic fatigue syndrome and prostrate cancer patients often have a dysfunction in an important immune enzyme called RNase L. When they looked at the ME/CFS patients they were astonished to find that most of them carried the virus as well.
In fact the prevalence of this virus in ME/CFS may have been understated. In telephone calls Dr. Mikovits reported that the WPI was finding antibodies to the retrovirus in fully 95% of their ME/CFS samples. The fact that the few fibromyalgia patients tested also tested positive for the virus suggests that it may be found in other neuro- immune diseases and the WPI will be testing that possibility.
“I can’t wait to be able to tell my patients. It’s going to knock their socks off” Dr. Judy Mikovits
The new (old) AIDS
AIDS and chronic fatigue syndrome were often mentioned together earlier in our diseases history. The infectious onset , the chronic course, the devastating nature of the illness, the inability to identify a pathogen and the fact that HIV had just arrived on the scene as well – all made both lay and professional people think ‘retrovirus’.
Twenty five years later the WPI is asserting that, yes, ME/CFS patients are infected with a retrovirus – in fact, one of only three human infectious retroviruses in existence. In some ways it fits very well; all retroviruses disrupt the immune system in such a way as to allow other viruses to flourish. Several studies have, of course, found highly increased rates of opportunistic viral infections in ME/CFS – a common, though more devastating finding in AIDS.
The Science study found that 67% of patients and 4% of the controls from across the country tested positive for XMRV using PCR testing. Who were these patients? They came from areas where there had been outbreaks and all the patients met both the 1994 definition of CFS and the Canadian Consensus definition. They were also quite disabled.
Researchers often ‘gild the lily’, so to speak, on their first studies by enrolling the sickest patients in order to ensure that they get positive results. The indication that the WPI used very disabled patients suggests that they did this and brings up the question whether the virus will also be found in less ill patients. The fact that the WPI used the Canadian Consensus Definition means that these patients must display postexertional malaise (i.e. they must experience symptom flares after exercise).
Citing unpublished antibody testing Dr. Mikovits suggested XMRV prevalence in the ME/CFS community may in fact be much higher. Antibody testing of 330 patients indicated that fully 95% of patients tested positive for antibodies to the XMRV virus.
Antibodys are factors produced by B-cells in response to an infection. Researchers use antibody’s to chart whether a person has been exposed to a pathogen. Remarkably the the extent of XMRV section in the controls remained constant at 4%. (PCR tests can underestimate the prevalence of infection if the viruses hang out in areas not easily accessed by the peripheral blood – such as the central nervous system. Again we don’t know who these patients were.
Dr. Cheney noted that his office contributed 14 samples including three controls. Since the findings from his office are very similar to the final findings he stated “I am pretty sure her findings will generalize to other CFS cohorts that are well-defined like mine.” Dr. Cheney believes that people who meet criteria for CFS with or without FM or MCS or chronic Lyme will probably test positive. In the New York Times article Dr. Mikovits stated she believed ALL ME/CFS patients will test positve for XMRV.
XAND (X Associated Neuro-Immune Disorder) Dr. Mikovits statement that the few fibromyalgia patients that had been tested tested positive for the retrovirus suggests that XMRV infection may be a factor in several several poorly understood (and poorly accepted) illnesses.
The WPI’s actions to date should lead us to expect that XMRV infection hardly stops at chronic fatigue syndrome. The name given the disorders caused by XMRV infection – XAND – should lead us to expect that ME/CFS may make up only one subset of this retroviruses victims. Expect the Whittemore Peterson Institute at some point to assess XMRV prevalence and possibly related disorders and other neuro- immune illnesses.
The XMRV virus is the key to the viral cascade that the Whittemore Peterson Institute has identified in so many of its patients a central question involves how did that did that key get in the door? Viruses don’t just jump up and attack people – they need to be transmitted. Its clear that this virus is not spread through the air which means it needs to be transmitted from human to human either via the saliva, blood, semen or mother’s milk or some other way.
“NCI is responding like it did in the early days of HIV” Stuart Le Grice, head of the Center of Excellence in HIV/AIDS and cancer virology at NCI
The cause? Don’t pop the bubbly yet
It’s important not to take these new findings about the XMRV virus as anything more than an exciting new development. We need confirmatory studies, then studies to see if the virus is contributing to the cause of illness persistence and symptoms.”
Nor do they know if it’s the cause of ME/CFS. Dr. Mikovits is clearly leaning towards that idea but the WPI is careful to state that that has not been proven. Until we know better the XMRV is simply another virus – albeit with intriguing possibilities – that has been found in ME/CFS patients.
It will take much more study as well as independent verification of the WPI’s results before we can say how significant this virus is. Among others the WPI needs to show that high viral loads are present and that they’re correlated with are with symptom expression; i.e. that the patients with the highests viral loads are the worst off.
Only then can we really start to relax (and really cheer) about this finding. The good news is that XMRV seems to have caught the publics and the scientific community’s eye; hopefully those studies will be finished sooner rather than later.
XMRV – the nitty gritty
There were two types of viruses; DNA and RNA viruses. Retroviruses are single pieces of RNA enveloped in a capsule which penetrates cells and then gets its RNA transcribed into DNA and then inserted into the cells DNA. Once that happens the virus uses cell’s DNA to produce more viruses which then bud from the cell and go on to infect other cells.
Interestingly retroviruses do not usually kill the cells they infect. Because retroviruses sometimes insert themselves into a portion of the genome that regulates cellular growth they may have a higher than normal potential of causing cancer. XMRV is a gammaretrovirus that has those properties in mice and may have them in humans as well.
The XMRV gamma retrovirus was first discovered in 2006 when researchers at the University of San Francisco and the Cleveland clinic found that it clustered in cancerous prostate cells.
XMRV prevalence in the most rapidly growing cancer cells triggered alarms that it was driving a particularly aggressive form of prostate cancer. XMRV has not been proven to cause prostate cancer – those studies have not been done – at the moment it is associated with a form of prostate cancer.
RNase L is an enzyme in the interferon pathway that targets viral RNA and destroys it. A genetically defective form of RNase L. is associated with an increased risk of prostate cancer. The men in the first XMRV study had this defective form of RNase L. ME/CFS patients do not carry this genetic defect but a subset of patients do carry a dysfunctional RNase L enzyme that also appears to inhibit the enzyme’s ability to destroy pathogens.
A followup study suggested that having a genetically derived dysfunctional RNase L enzyme resulted in increased XMRV replication. (It was the RNase L connection that prompted Dr. Mikovits to send ME/CFS blood samples to Dr. Silverman, the discoverer of the XMRV virus, at the Cleveland clinic.)
A 2009 study, however, which found that XMRV is not more common in patients with genetically derived RNase L. defect cast some doubt on the RNase L/XMRV connection. The WPI’s studies also found that RNase L dysfunction is not required to have an XMRV infection and Gordon Medical Associates – a laboratory collaborating with Dr. Mikovits on XMRV – stated that the RNase L test does not have ‘clinical value’ nor is useful in directing treatment in patients with XMRV infection.
No one to my knowledge has said that ME/CFS men have an increased rate of aggressive prostate cancer. WPI researchers did show XMRV infected cells from ME/CFS patients in the lab were able to infect prostate cells. Chronic fatigue syndrome patients do not, however, typically harbor genetic defect that increases the risk for aggressive prostate cancer. The RNase L dysfunction they display does not appear to increase their risk of having aggressive prostate cancer.
The DeFreitas retrovirus?
The WPI conclusively stated that XRMV is not the retrovirus Dr. Elaine DeFreitas believed she uncovered in ME/CFS patients in the early 1990’s
Ground zero in the immune system
Natural killer cells may be ground zero in the immune dysfunction found in chronic fatigue syndrome (ME/CFS). These cells, which man the first lines of our immune response, troll the body looking for invaders and infected cells and destroying them and then raising the alert. Again and again studies have found dysfunctional natural killer cells in ME/CFS. Anecdotal reports from the WPI indicating that the natural killer cells in ME/CFS patients are loaded with this virus suggest a possible cause to one of the most significant dysfunctions in this illness.
See the Puppet Master? Triggering Factors and Other Diseases?
The fact that the viruses isolated from ME/CFS patients were almost genetically identical even in patients from different areas suggests that the virus is a relatively ‘recent’ (in biological terms) escape and that its rate of replication within any one individual may be relatively low. Every time a virus replicates (ie redoes its genome) the possibility of small genetic alterations is present.
Generally the more anrouters and replicates the more it changes over time. The fact that the viruses are so similar from individual to individual suggests that the virus is not replicating very quickly. The researchers went to some pains to make it clear that the virus jumped from mice to humans and there’s no evidence it is a laboratory escape .
The scientists are excited, everyone is working on it, so we know we are going to get a lot of help. It’s an entirely new field of medicine” Dr. Judy Mikovits
The Long Road
Retroviruses were pretty hot item in the early 1990’s. Three studies, one by the CDC in 1993, one by Dr. Gow (full paper here) of the University of Glasgow (still an ME/CFS researcher) in 1992 and one by Japanese researchers in 1993 found no evidence of Dr. DeFreitas’ retrovirus or other retroviruses. Dr. Komaroff failed to find evidence of a spumaretrovirus. A 1994 CDC study found no evidence of six retroviruses in ME/CFS. study. The next retroviral study cited by PubMed for ME/CFS was the 2000 CDC exploration of the p15 retroviral element.
But some controversy lingered about the original DeFreitas study. Gow and the CDC produced different results – which Dr. DeFreitas reportedly argued meant that there were problems with the primer. There have been some suggestions that Dr. Mikovits (and hence Dr. Silverman originally) uncovered Dr. DeFreitas’ retrovirus.
Dr. DeFreitas was looking for genetic sequences she believed belonged to a HTLV-II virus and Dr. Silverman uncovered sequences belonging to a gammaretrovirus. Could they be similar? Only time will tell.
After that small flurry of retroviral studies didn’t pan out the scientific community mostly begged off the viral hunt in ME/CFS. Part of the reason was just our bad luck. HIV was killing people by attacking T-helper cells, the masterminds of the late immune response.
T cells were and are a hot item in the medical research community, and for good reason; it’s the late immune response that is primarily responsible for finally knocking down a pathogen. ME/CFS patients T-cells showed little evidence of substantial dysfunction; ergo infection was probably not the problem in chronic fatigue syndrome.
The natural killer cells in the early or innate immune response are, however, severely affected in ME/CFS. The early early immune response is responsible for identifying pathogens and engaging them a holding action until the cytotoxic T-cells come to the rescue. Natural killer cells weren’t getting much respect back then but they are now and a new class of drugs aimed at the early immune response will reportedly hit the market in the next couple of years.
If AIDS wipes out T-helper cells, it may be that XMRV in ME/CFS patients knocks out natural killer cells; AIDS and ME/CFS patients may suffer from a similar problem but in different parts of the immune system.
Once the innate immune response research got cranking it took some remarkable findings in the late 1990’s and the early 2000’s regarding the RNase L enzyme and ME/CFS to eventually to turn Dr. Mikovits head toward Dr. Silvermans work on XMRV.
Questions and concerns
When researchers use PCR to detect specific genetic sequences (ie. very very small bits of DNA) in cells -as the WPI researchers did – laboratory contamination is always a consideration. The concern grows when the DNA comes from a virus associated with mice; mice, after all, are very common in medical research laboratories. DNA is everywhere; floating on bits of dust in the air, collecting on surfaces. Could the DNA the WPI identified actually be from viruses that laboratory mice naturally harbor?
According to John Coffin of Tufts University this doesn’t seem likely. Genetically XMRV varies substantially from other mouse viruses. The fact that the samples were gathered from different sections of the country further cuts into the contamination question.
The WPI researchers were also able to grow live viruses from ME/CFS patients cells and their antibody tests indicated ME/CFS patients had mounted an immune response to this specific virus. One important question regarding XMRV’s role in ME/CFS will center on the degree of viral load present; is the virus present in large numbers. If so where is it present and how active is the infection?
The Dubbo and Renee Taylor studies have conclusively shown that other infections (EBV, parovirus B-19, ) can and do trigger cases of ME/CFS. The Dubbo studies also suggest that patients are able to fight off and clear those pathogens but that high levels of cytokines early in the infectious process appear to set the stage for what becomes ME/CFS. Finding a place for XMRV in this scenario is going to be intriguing.
We know that not everyone with XMRV infection comes down with ME/CFS. Do high cytokines plus a latent XMRV infection (plus amyloid proteins?) set the stage for ME/CFS. Another researcher suggested that XMRV infection could play a factor in many other diseases.
Given the retroviral nature of this pathogen this might not be so surprising. Retroviruses do not typically kill the cells they inhabit. Instead they apparently alter their functioning. Through its effects on T helper cells HIV opens the door to many different types of pathogens.
(Dr. Mikovits reported that 40% of Autism patients thus far tested are positive for XMRV. Check it out in this article in the Huffington Post)
Dr. Reeves has said the findings are “unexpected and surprising” and that it is “almost unheard of to find an association of this magnitude between an infectious agent and a well-defined chronic disease, much less an illness like CFS”. We have all assumed, given the vague definition, that chronic fatigue syndrome is something of a wastebasket diagnosis and that the disease contains many subsets.
Dr. Peterson has stated that he believes the ‘Incline Village Type cohort’ he’s focused on makes up somewhere around 25% of diagnosed patients. Now we’re presented evidence suggesting that at least two thirds and perhaps a much higher percentage of patients are infected with a retrovirus.
If this work is corroborated it’s a paradigm shifting moment in more ways than one. In fact as was discussed earlier notes could set the stage for a reassessment of several different neuro- immune disorders.
“There is a group who are young, healthy, active and engaged, and all of a sudden they are laid low by something. Everyone tells the physicians these are people who are functional and productive, and this is totally out of character. They are frustrated and often quite disheartened. You feel that medical science hasn’t caught up with their illness yet.” Dr. Schaffner (Vanderbilt University)
Dr. Reeves also stated “Until the work is independently verified, the report represents a single pilot study,” ME/CFS patients can take caution from other ‘breakthroughs’ that fails to be replicated. He’s quite correct about that but then again no other research efforts have been backed by the kind of firepower.
These weren’t your garden-variety ME/CFS researchers – the researchers involved in this paper all have substantial track records outside of chronic fatigue syndrome and hail from very prominent and rather conservative research institutions. One has to believe that they’ve dotted all their i’s and crossed all their T’s. (They wouldn’t have gotten published in Science had they not.)
Dr. Reeves appears to be feeling some heat. He burst the bounds of researcher etiquette when he stated that “My expectation is that we will not” be able to replicate the findings. He noted that he was surprised that Science accepted a paper because he didn’t know who these patients were. At first he seemed to have a point; the Science papers only description of the patients was that they were from ‘well-characterized” cohorts.
But Pat Sonnett has pointed out that accompanying data stated the “Banked samples were selected for this study from patients fulfilling the1994 CDC Fukuda Criteria for Chronic Fatigue Syndrome (S1) and the 2003 Canadian Consensus Criteria for Chronic Fatigue Syndrome/myalgic encephalomyelitis (CFS/ME) and presenting with severe disability; these patients did meet all the criteria for studying ME/CFS.
Expect Dr. Reeves to find lower and possibly much lower rates of infection in his study because he is test ing samples from patients who met the Empirical Definition or the 1994 definition and because of his sampling procedure. The CCD requires that postexertional malaise and cognitive problems be present for someone to be diagnosed with chronic fatigue syndrome. None of the other definitions require those two factors to be present.
If Dr. Reeves attempts to replicate this study using the Empirical Definition (ED) expect much lower rates of infection because the ED virtually eliminates postexertional malaise (PEM) as a significant factor in diagnosing ME/CFS. Expect lsomewhat lower rates of infection if he uses the 1994 definition because PEM is present but not required in the 1994 definition.
Expect possibly even lower rates of infection because Dr. Reeves uses a random sampling procedure which tends to pick up less ill patients. The WPI used severely disabled patients for their first study but a surprisingly high proportion of the patients the CDC uses in their studies had never even seen a doctor.
All these factors suggest that the CDC could find a very much lower percentage of infected patients in their replication study. A fourth factor is the looming presence of a new, more accurate test – possibly in the next few weeks. The WPI has suggested that this test will find the virus in more patients than the old test; researchers is using the old test be underestimating prevalence.
Dr. Reeves also noted that the study did not state the ages or sex of the patients and controls or duration of the disorder or type of onset. But he’s being a bit disengenuous. While Dr. Reeves is careful to match the ages, sex, etc. of the patients in his studies with his controls he has shown little ability to segregate his patients according to age, sex, duration of illness or type of onset. None of those factors appear to make the slightest difference in his laboratory findings and shouldn’t with regard to these findings.
Dr. Reeves also noted that CFS is a heterogeneous disease and likely arises from a combination of many factors – a almost ironic statement given that Dr. Reeves has done more than any other researcher to make this disorder even more heterogeneous. If this virus is ground zero for not only for ME/CFS but for other neuro-immune illnesses, however, uncovering how it creates such a heterogeneous mix of illnesses will be one of the key challenges for researchers.
At least from a patient standpoint it’s uncomfortable to hear comments like these from someone who’s in charge of replicating these results. Certainly the CDC should be expected to do a professional job in their replication efforts but given patients distrust of the group it’s good to know that other laboratories will also be attempting to replicate these findings.
The CDC didn’t need to miss this opportunity. In fact it was almost in their hands. The CDC after all believes the interferon pathway in the central nervous system is the key immune element in chronic fatigue syndrome and RNase L – the factor that lead Dr. Mikovits to XMRV – is a key antiviral component of the interferon pathway.
(The CDC came to the interferon conclusion after interferon alpha treatments for hepatitis patients were shown to create a very CFS-like condition. Interferon research papers are marked prominently on their website).
Once one believes that RNase L dysfunction is an important component of ME/CFS testing for XMRV is a pretty easy next step. (Indeed one wonders why Dr. De Meirlier didn’t jump on this earlier). Possibly because the CDC long ago discarded the importance of a viral component in this disorder they never bought into the RNase L paradigm.
(They have never included it in any of their studies. Nor for that matter have they included the other important immune factor – natural killer cell dysfunction – in their studies. Although the CDC may have focused on the right immune pathway, if the WPI is right they focused on the wrong part of it.
“This is going to create an avalanche of subsequent studies.” Dr. Schnaffer (Vanderbilt)
Game Changer- Only time will tell how significant this finding will end up being but it’s clearly already realigning the ME/CFS research playing field. Dr. Reeves stated that the CDC is already attempting to replicate the study findings. The National Cancer Institutes quickly convened workshop, the presence of this study in such a prominent medical journal, and the incredible news coverage that have accompanied these findings hopefully suggest that something fundamental has changed.
The widespread interest in this study will surely translate into greatly increased funding for research into XMRV and hopefully into more immune research in chronic fatigue syndrome as well.
What to expect next
- Replication – expect a double blinded study from an independent laboratory (or laboratories) that attempts to replicate the WPI’s findings. Dr. Reeves has indicated this study is already underway at the CDC.
- From Dr. Cheney’s remarks it appears that a study determining the rate of infection in family members and close contacts of ME/CFS patients is underway.
- An animal model researchers can use to more completely understand the viruses effects.
- Some sort of pronouncement at some point regarding the safety of the nation’s blood supply.
- Much more information from the Whittemore Peterson Institute as it becomes available (see below).
A note from Andrea Whittemore-Goad
“What we ask is that you understand this initial finding is a catalyst , things have been moving very fast moving but we still need patience. Please if you are interested in participating in research leave your information at firstname.lastname@example.org and please become a Friend at Friendsof Whittemore Peterson Institute facebook page . We are doing our very best to get a link up asap. Please keep looking for updates at the website and we hope we can help you and many others very soon.” Andrea Whittemore-Goad