The discovery of a potential retroviral link to ME / CFS, which is estimated to affect some 17 million people worldwide, has certainly caught the world’s attention — no bad thing for an under-researched and often-overlooked illness! The scientific report, entitled “Detection of infectious retrovirus, XMRV, in the blood cells of CFS patients”, appeared online in Science, one of the most prestigious scientific journals in the world, on 8th October 2009 and described the findings of a consortium of researchers from the Whittemore Peterson Institute (WPI, located at the University of Nevada, Reno), the National Cancer Institute (part of the National Institutes of Health) and the Cleveland Clinic, Ohio.
ME Research UK welcomes good-quality outline applications from Research Units anywhere in the world for funding to replicate and/or extend the work on the possible links between XMRV and ME/CFS. Applications will be processed rapidly, and the peer-review process expedited, for such applications.
The headline finding of the research paper was that DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus ( XMRV ), could be detected in the peripheral blood mononuclear cells of 68 out of 101 ME / CFS patients (67%) compared with only 8 out of 218 healthy controls (3.7%). The extent of this difference in proportions is unusual, as it is the norm for scientific researchers to find relatively small yet significant differences between patients and closely matched control groups; in the modern world, novel associations of such magnitude are rarely found between long-standing chronic illnesses and infectious agents. In addition to the headline finding, the researchers determined that XMRV proteins were being expressed in blood cells from ME / CFS patients at very high levels compared with controls, and through cell culture experiments they showed that patient-derived XMRV was infectious and transmissible. So, as well as being the first to show infection with this novel virus in ME / CFS patients, the researchers appear to have been the first to be able to isolate XMRV particles from the blood, and to show direct transmission of this virus between blood cells — dramatic observations indeed.
What has caught the attention of the scientific world is that these observations seem to fit neatly, at least at a first glance, with what is already known about ME / CFS as a chronic illness. For example, viruses related to XMRV have been reported to be involved in damage to blood vessels and nerves, and natural killer cells (historically low in ME / CFS ) are said to be susceptible to infection by XMRV. Also, the fact that retroviruses like XMRV are known to be able to activate some other (latent) viruses might explain why ME / CFS has been associated with a range of different viral triggers, such as herpesviruses like Epstein-Barr, over the years. Again, as Dr Judy Mikovits and colleagues point out in their paper, some of the most commonly reported features of ME / CFS include neurological symptoms and immune dysfunction with inflammatory cytokine and chemokine upregulation, and some of these observations could be accounted for by infectious XMRV in lymphocytes. The fact that such pieces seem to fit so well together is suggestive only at this stage, however, and a virologist at Tufts University was surely wise to say in New Scientist that while it’s not impossible that infection with this agent might cause a disease with neurological and immunological consequences, we don’t know for sure as yet.
The scientific journey towards this discovery is an extremely interesting one, and includes several strands: prostate cancer, the RNAse L immune pathway, the discovery of the novel virus XMRV, and ME / CFS. XMRV is a human retrovirus similar to HIV, HTLV-1 and a group of endogenous murine leukaemia viruses found in the genomes of wild mice (see the informative presentation on retroviruses by Dr Jones of SAIC-Frederick/NCI-Frederick), and was first identified only in 2006 by Prof. Robert H. Silverman of the Cleveland Clinic, a co-author on the 2009 ME / CFS study. Prof. Silverman initially showed the presence of XMRV in prostate cancer tissue samples (PLoS Pathog, 2006), and subsequent work has confirmed XMRV protein expression in 23% of 334 prostate cancer biopsies (Proc Natl Acad Sci USA, 2009). Importantly, the men with prostate cancer initially studied by Prof. Silverman all had a specific genetic defect in their antiviral defences, the RNase L antiviral pathway which Prof. Silverman had been studying for 30 years, a lifetime’s work of scientific progression described in his fascinating essay, “Journey through the 2-5A/RNase L System ”.
RNase L is the terminal enzyme in the 2,5A synthetase/RNase L antiviral pathway, and plays an essential role in the elimination of viral mRNAs. The enzyme has been the focus of research interest in ME / CFS patients for nearly 20 years, and deregulation of this pathway in subsets of ME / CFS patients has been reported extensively in the scientific literature (reviewed by Nijs and Fremont, 2008 ). In ME / CFS, a wide spectrum of “cleavage” of RNase L can be observed (a phenomenon also seen in multiple sclerosis patients), and such altered RNase L activity profoundly affects cellular physiology, including apoptosis. Overall, an upregulated RNase L pathway in ME / CFS is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of the disorder — and it is because of these and other findings that many researchers have come to view ME / CFS as primarily a disorder of the innate immune system (see Klimas and Kineru, 2008 ). It was thanks to the insight of Dr Judy Mikovits and her team at WPI that the potential connection between RNase L dysfunction in XMRV -infected prostrate cancer and in ME / CFS was recognised, and an exploration undertaken to test for the presence of the virus in the banked blood samples in the WPI tissue repository, the largest ME / CFS sample repository in the world.
What we don’t know
A plethora of unanswered questions arise from this discovery. Chief among these concerns cause and effect: the researchers’ work has shown a suggestive, significant association between the presence of XMRV and a diagnosis of ME / CFS, but this is far from proof that the virus has a direct or even indirect role in the development or maintenance of the illness. This and other points have been well-put in a fine “perspective” in Science by National Academy of Sciences member and expert retrovirologist, Prof. John Coffin, and colleague Jonathan Stoye, who say, “There is still much that we do not understand. Whether the virus plays a causative role in either chronic fatigue syndrome or prostate cancer is unknown.” They go on to point out that XMRV infection might be higher, by co-incidence, in the same locations as clusters of patients; that patients with ME / CFS or prostate cancer might be more readily infected due to immune activation; that XMRV might prefer to proliferate in cells that are dividing rapidly, and that the presence of these cells in these illnesses might simply make it easier to detect infection; and that the mechanism of viral transmission remains unknown, as does the prevalence or distribution XMRV in human or animal populations. In the aftermath of all initial scientific reports of a potentially major find, the unknown wildly exceeds the known — an exciting place for ME / CFS research to find itself.
The next steps
The researchers say that since publication they have continued to refine their test for XMRV, finding that 95% of 330 ME/CFS samples have tested positive for XMRV antibodies in the plasma (showing that these patients have at least been in contact with the virus at some time). They plan to continue their in-depth studies of XMRV to clarify its effe cts on the human immune system, and are clinically validating a blood test for the detection of XMRV in ME / CFS and other human diseases. And they will shortly begin the work of determining if any currently approved drugs, such as AZT, might be useful for suppressing XMRV. If these efforts are successful, human clinical trials to determine the most effective patient treatments in a clinical setting would surely be close behind.
At the same time, other independent laboratories across the world will be attempting to replicate the findings in their own local populations of ME / CFS patients. Since the WPI researchers used samples selected from several regions in the US where “outbreaks of CFS” had been documented (using patients diagnosed on CDC-1994 and 2003 Canadian Clinical criteria ), blood samples from patients in other countries (possibly diagnosed with less stringent criteria) might throw up very different results. Furthermore, it will be particularly important for independent laboratories to conduct double-blind studies to search for XMRV in ME / CFS patients and healthy matched controls, to strengthen the evidence base as a whole.
This is a stunning find — like a comet from a cloudless sky to patients across the world. Yet it is too early to know whether the discovery will change the ME / CFS landscape or not. At worst, the discovery will be just one of a number of false dawns that have arrived over the years — albeit one that has brought, suddenly, the world’s attention to a neglected field largely ignored by mainstream biomedical medicine. In this scenario, XMRV might prove to be simply a passenger virus carried by an immune-depressed ME / CFS patient population, with little or no influence on the illness. At best, however, XMRV might be found to be the casual factor in the development and maintenance of ME / CFS, and a combination of anti-viral drugs will be found to eradicate the viral load from patients. One consequence of this “jackpot” scenario would be a demolition of the existing diagnostic criteria for the “syndrome” CFS (currently a ragbag of common non-specific symptoms, with many causes, shared with other illnesses), as well as the older criteria for myalgic encephalomyelitis. These would be replaced by objective diagnostic criteria based on state-of-the-art methodology — surely a welcome liberation for both CFS and ME patients currently parked in a Diagnostic Terminal. Indeed, the WPI group has already suggested that a new disease entity — X associated neuro-immune disease, or XAND — might arise from the rubble, implying (one assumes) that the one-third of ME / CFS patients found to be “negative” for XMRV in the WPI report would also acquire new, more appropriate diagnoses.
Like Dr Dan Peterson, medical director of the WPI, we are hopeful. As he says, “Patients with ME/CFS (XAND) deal with a myriad of health issues as their quality of life declines. I’m excited about the possibility of providing patients who are positive for XMRV a definitive diagnosis, and hopefully very soon, a range of effective treatment options.”