XMRV Link to CFS Accelerates Scientific Inquiry and Sustains Media Coverage
(Updated most recently on August 24, 2011)
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In the Oct. 8, 2009 issue of Science Express, researchers at the Whittemore Peterson Institute (WPI), the Cleveland Clinic and the National Cancer Institute (NCI) led by Vincent Lombardi, PhD, reported that 67% of 101 chronic fatigue syndrome (CFS) patients tested positive for infection with xenotropic murine leukemia related-virus retrovirus (XMRV), a gammaretrovirus associated with a subset of prostate cancer. Only 3.7% of 218 healthy subjects tested were positive for the virus. Read the joint press release.
On Aug. 23, 2010, a team of researchers from the Food and Drug Administration (FDA), National Institutes of Health (NIH) and Harvard Medical School published a report in the Proceedings of the National Academy of Sciences (PNAS) linking CFS to a related but different group of polytropic murine leukemia virus-related virus (PMLV) sequences.
These published results provided evidence of the association of at least a subset of CFS cases with retroviruses, a hypothesis formed in the mid-1980s and pursued by several independent research groups. XMRV was discovered and detected in a subset of prostate cancer patients’ tumor cells in 2006. Polytropic MLVs had not been linked to other human diseases prior to the 2010 PNAS report. Newer evidence, published in Science on May 31, 2011 suggests that XMRV is a laboratory recombinant of two mouse viruses, and that it is a contaminant rather than an infectious human pathogen. This study and others that cast doubt on the association of XMRV to human disease have generated intense debate about whether XMRV is a productive route of inquiry.
Conflicting Data Warrants More Research
The PNAS paper was not the first follow-up study to the Science paper. Two studies reporting negative results were published in Jan. and Feb., 2010 by researchers in the U.K. A third negative study was reported by Dutch researchers on Feb.25, 2010. A fourth negative study from researchers at the U.S. Centers for Disease Control & Prevention (CDC), Robert Koch Institute (Germany) and Blood Systems Research Institute (U.S.) was reported in Retrovirology on July 1, 2010. A fifth negative study was published on Sept. 13, 2010 in Virology Journal by researchers in China. A group of investigators at Boston-area academic hospitals reported negative findings in the Nov. 15, 2010 issue of the Journal of Infectious Diseases. A study of XMRV in CFS and MS was reported to be negative using PCR by a group in Germany on Dec. 22, 2010. A second negative report from CDC was published on Feb. 22, 2011. It included testing by PCR and serology. A follow-up report from one of these U.K. groups reporting negative data in Jan. 2010 was published in Mar. 2011, with negative results using PCR and serology tests. A team in Japan led by the Japanese Red Cross reported negative results of XMRV tests in both CFS patients and prostate cancer patients on Mar. 17, 2011. They did find a low level of positive antibody results, but were not able to detect XMRV or polytropic MLVs after further testing. The first study looking for XMRV in CFS patients' cerebrospinal fluid samples was published on Apr. 5, 2011; it also did not find any evidence of XMRV.
The most comprehensive follow-up study, using multiple testing methods on freshly collected samples from 100 well-characterized clinic patients, 200 healthy volunteers from the same geographic area and 14 patients identified by WPI who had previously tested positive for XMRV was reported on May 4, 2011 in the Journal of Virology. The team led by senior author Ila Singh, MD, PhD, processed, tested and analyzed all samples in an identical fashion. In spite of these measures and every hope of obtaining a positive result, they could not detect XMRV or polytropic MLVs in any of the samples and therefore could not confirm the link between this family of retroviruses and CFS. An analysis of this study, "The Iteration of X," prepared by CFIDS Association staff was distributed on May 5, 2011. Of note is that the study followed a template published in the Nov. 3, 2010 issue of Viruses, by Dr. Singh that suggests a definitive study of retroviral sequences in CFS.
On May 31, 2011, a paper reporting on testing of 61 CFS patients was published in Science. Of the 61 patients tested, 43 had been previously told they were XMRV-positive based on tests performed at WPI or its commercial lab, VIP Diagnostics. No evidence of XMRV or other MLVs was found, using multiple methods, including some of those reported by Lombardi et al. The senior author of the study, Jay Levy, MD, was one of the early pioneers in CFS research in the 1990s; he is also a co-discoverer of HIV. An analysis of this study was posted to the Association's blog/site, Research1st, on June 1.
Two more studies with negative results have followed the study from Dr. Levy's group. A June 10, 2011 study published in Advances in Virology reported results on 112 CFS patients and 36 healthy controls that were negative by chemihiminescience immunoassay testing. On July 26, 2011, a report in Diagnostic Microbiology and Infectious Disease showed negative results for 85 samples from twins discordant for CFS using four different PCR tests.
The Association has maintained a comparison of the published studies that looked for XMRV/MLVs in CFS patients. The AABB has posted a summary of XMRV studies that also includes studies of prostate cancer and other disease states.
Four papers published on Dec. 20, 2010 in the journal Retrovirology reported potential sources of contamination of studies of XMRV and other murine leukemia virus-related viruses. Experts working in the field, including John Coffin, PhD, an author of two the papers, believe that the case is far from closed: "The argument for lab contamination as a source of XMRV is subtle and indirect, and not, in my opinion, conclusive. This is not the end of XMRV, but it is a warning we have to be very, very careful." An article in BioTechniques.com reports on the challenges of developing sensitive and specific testing methods, while avoiding the risks of contamination. The Journal of Virology study reported low level positive results in an inital batch of samples and found that two brands of Taq polymerase were yielding false positives in 5% of patient and healthy samples. They also identified that a robotic device used to process samples had been contaminated with XMRV months earlier. When these sources of contamination were addressed, they found no positive results using a variety of sensitive testing methods.
In a paper published on Feb. 25, 2011, Garson et al provided data that 2 of 14 integration sites in DNA from prostate cancer tissues are identical to integration sites from experimentally infected DU145 cells. They conclude this is the result of contamination. Writing in Virology Blog, Dr. Vincent Racaniello states that, "Those observations do not directly impugn the veracity of the other 12 XMRV integration sites indentified in the prostate tumor. ... This possibility can and must be addressed experimentally."
Data presented by researchers at the National Cancer Institute, Tufts University and University of California-Davis at the 18th Conference on Retroviruses and Infections Disease (CROI) provide evidence that XMRV may be a laboratory recombinant of two mouse viruses. Science magazine reported this news in its Mar. 11, 2011 issue and shorter article appeared online on Mar. 8. Association scientific director Suzanne Vernon, PhD, summarizes the CROI presentations in "On the Origins of XMRV," based on the conference webcast and abstracts. The research presented at CROI was published in Science on May 31, 2011, concurrent with the study from Dr. Jay Levy's group and an editorial Expression of Concern, issued after authors at WPI refused a request from Science to retract the 2009 paper based on the failure of at least 10 other groups to detect XMRV in CFS patients. The simultaneous publication of the two articles and the journal's request for a retraction attracted considerable debate in the scientific and patient communities and attention from hundreds of media outlets. Some scientists declared the case closed, while others urged patience until NIH-supported studies (see below) could be completed. Science editor-in-chief Bruce Alberts concluded the Expression of Concern with the following statement, "The U.S. NIH is sponsoring additional carefully designed studies to ascertain whether the association between XMRV and CFS can be confirmed. Science eagerly awaits the outcome of these further studies and will take appropriate action when their results are known." In a summary of the three publications, the CFIDS Association reiterated its commitment to await the outcome of these studies and to stand by the results. A news article published June 1, 2011 in the Washington Post reported that NIH director Francis Collins confirmed the studies would move forward according to plans. This information was also posted to the NIH website. More recent developments through early July 2011 are summarized on our Research1st site.
Comments on the initial report in Science, along with a response from two of the 13 authors of that paper appeared in the May 14, 2010 issue of Science. The Sept./Oct. 2010 issue of Virulence includes further description of the methods used by Lombardi, et al. in their original report. The authors also restate; “We have not claimed in our Oct. 2009 publication or in other venues that XMRV is the cause of CFS, only that its detection in a majority of our ME/CFS patient cohort allows us to form a testable hypothesis as to an infectious basis for this devastating disease.”
The authors of the PNAS paper state, “It remains to be shown that the association that we have found, using the methods that we have described, can be generalized to a larger group of patients with CFS. Even if subsequent studies confirm an association between MLV-like viruses and CFS, that will not establish a causal role for these viruses in the pathogenesis of this illness.” The experiments conducted did not include testing for proof of low-grade infection, and the authors recognize that their study did not attempt to fully replicate the Lombardi study in this regard.
Many have sought to explain the so-far discrepant results of XMRV studies. Speaking at a meeting at Tulane University on June 18, 2010*, Dr. Frank Ruscetti, one of the authors of the Science paper, listed the following “reasons for the lack of detection of XMRV” in his presentation:
- Greater sequence diversity than originally believed
- In vivo reservoir(s) of viral replication not identified
- World wide distribution scattered like HTLV-I
- Patient selection and methods applied vary widely
- PCR/other contamination.
These possible sources of discordant data were explored in detail at the 1st International XMRV Workshop held Sept. 7-8, 2010 at the National Institutes of Health. In the opening session, NIH Director Francis Collins, MD, announced that the National Institutes of Allergy and Infectious Diseases (NIAID) had tapped Ian Lipkin, PhD, of Columbia University to coordinate testing of CFS samples from various geographic regions by four independent laboratories under blinded conditions. The study design was discussed by participating labs at a meeting held in early November 2010. Physicians who will recruit and evaluate subjects met in December 2010. This study became the focus of much attention following the three articles published in Science on May 31, 2011. In several media interviews, Dr. Lipkin confirmed his intentions and NIH's support to move forward in spite of some experts' suggestions that the study be cancelled and funds used to support other investigations into CFS.
Other studies at NIH are also taking place. The NCI is evaluating CFS patients at one of its clinics for a study of the different assays used to detect XMRV. The National Heart, Lung and Blood Institute is coordinating a blood safety study (described below).
Research on XMRV in CFS continues at other institutions as well. An NIH grant was awarded in May 2010 to a group at Cornell University led by Dr. Maureen Hanson that will study patients who became ill in Lyndonville, New York in the mid-1980s as children. Dr. Hanson presented preliminary results of a pilot study at the 1st International XMRV Workshop and at a meeting of the FDA's Blood Products Advisory Committee in Dec. 2010. She found sequences of polytropic MLVs in 11 of 20 CFS patients tested, but only 1 of 10 healthy control subjects. 3 of the 11 positive results were obtained from patients who reported having recovered from CFS; the other 8 met Fukuda criteria for CFS. Dr. Hanson’s laboratory is the third independent group to report these sequences in samples from CFS patient and healthy controls, although these results have not yet been published. Dr. Hanson submitted a poster presentation to the 15th Conference on Retroviruses held June 5-8, 2011.
In addition to prostate cancer and CFS, evidence of infection with XMRV has also been looked for in samples obtained from men with HIV, men at risk for HIV infection, individuals with ALS, MS, spondyloarthritis, rheumatoid arthritis, hepatitis C infection, fibromyalgia, lupus, B-cell lymphoma, common types of lymphoid malignancies, transplant patients, fathers of children with autism and children with autism and idiopathic diseases. So far, in these limited studies, no XMRV has been found. A group of researchers in Germany reported finding XMRV-specific sequences in 2-3% of 168 samples from immunocompromised carriers and about 10% of samples from 161 immunocompromised patients. In a study of autistic children in Italy in which all of the autism subjects were negative, 3/97 control subjects were positive by PCR for MLV sequences.
Still Lots to Learn About XMRV and MLVs
XMRV was first described in 2006. There have been more than 170 publications in the peer-reviewed literature about the novel human retrovirus, but there is much that remains unknown about its origins, its prevalence in humans, its transmission and its potential for causing disease. There is no FDA-approved diagnostic test for XMRV or MLVs and researchers studying these viruses use several different methods to detect it in the laboratory setting.
Studies have investigated the utility of various FDA-approved antiretroviral agents against XMRV in laboratory culture with some promising results, but there have not yet been any clinical trials of these medications in either prostate cancer or CFS. Writing in Future Medicine (July 2010), Mikovits, Lombardi and Ruscetti state, “At the moment, the use of antiretroviral drugs in persons with CFS or prostate cancer are biological experiments rather than a clinically tested therapy.” Based on their inability to confirm the link between XMRV and CFS, authors of the Journal of Virology study conclude, “prescribing antiretroviral agents to CFS patients is insufficiently justified and potentially dangerous.” This caution was issued after the May 31, 2011 publication in Science as well.
Blood Safety Issues
Although it is possible that XMRV may be found to be transmissible by blood donation, no country yet tests for XMRV or has banned donation of blood, organs or other tissues from individuals who test positive for XMRV. Several countries have recently revised guidelines for CFS patients. On April 7, 2010, Canada changed its policy for blood donors with a history or current diagnosis of CFS, deferring them from donating for two years. Australia’s Red Cross announced on April 28, 2010 that it will indefinitely defer donors with a history or current diagnosis of CFS. New Zealand has followed Canada's guidelines. Effective Nov. 1, 2010, the United Kingdom permanently defers donors with a past or current history of CFS.
In the United States, the AABB issued a June 18, 2010 bulletin to its membership advising that CFS patients be discouraged from donating blood. The bulletin included information about CFS and a poster for use in blood donation centers. Association CEO Kim McCleary is a member of the AABB’s XMRV Task Force that formed the recommendations regarding blood donation and continues meeting regularly to assess new information and make recommendations as warranted as knowledge about XMRV expands. These recommendations have been fully implemented by the American Red Cross and the majority of America’s Blood Centers. The American Red Cross states that it indefinitely defers anyone who reports a past or present diagnosis of CFS. The AABB Task Force published an interim report in the journal Transfusion ahead of print on Jan. 11, 2011. The AABB recently updated its XMRV fact sheet, part of its emerging infectious diseases library.
At a Dec. 14, 2010 meeting of the FDA's Blood Products Advisory Committee (BPAC), the Committee was asked to vote on the following question: "Do the scientific data support asking donors about a medical history and/or diagnosis of CFS as a basis for indefinite deferral?" Nine members voted "yes" while four voted "no." The 9-4 vote reflects opinion on the issue of whether asking a question was better than using the AABB educational materials to elicit donor disclosure of past/present CFS diagnosis. All BPAC members have indicated that they agree with the indefinite deferral of CFS patients based on all evidence that it will promote donor and recipient safety. The FDA strongly considers guidance from its advisory committees when making policy. No date has been provided for a decision by FDA.
In Oct. 2009, the U.S. Department of Health and Human Services announced that it would conduct studies to assess the potential risks to the blood supply and that will also help standardize tests for XMRV. The studies are being supported by the National Heart, Lung and Blood Institute and coordinated by the Department of Health and Human Services Blood XMRV Scientific Research Working Group, of which Association scientific director Suzanne D. Vernon, PhD, is a member. The studies are organized into the following four phases:
- Phase I: Analytical Panels -- evaluate performance of XMRV nucleic acid test assays
- Phase II: Pilot Clinical Studies -- compare assays using whole blood versus peripheral blood mononuclear cells and evaluate timing of sample preparation
- Phase III: Clinical Sensitivity/Specificity Panel -- assess assay performance on pedigreed clinical samples
- Phase IV: Blood Donor Clinical Panel -- make initial estimate of XMRV nucleic acid prevalence in blood donors and initiate blood donor seroprevalence studies.
At the July 26, 2010 meeting of the Food and Drug Administration’s (FDA) Blood Products Advisory Committee (BPAC), seven groups made informational presentations about XMRV, including researchers at the FDA, NIH and CDC. Results from Phase I were reported. Analytical panels of blinded samples of XMRV and negative controls were tested by six laboratories (including the Whittemore Peterson Institute) to assess results using different methods. All six laboratories were able to detect XMRV in whole blood using nucleic acid testing and four of five plasma RNA assays performed well. CDC’s whole blood assay was the most sensitive under these conditions, while WPI was the only lab reporting an unexplained false positive result on a negative sample. The Phase I study has its limitations and these results should not be extended to other published data.
On Dec. 14, 2010, the BPAC heard nine presentations on XMRV research and testimony from several public witnesses. Results of the Phase II (parts a and b) were presented by Graham Simmons, PhD, on behalf of the HHS Blood XMRV Scientific Research Working Group. On Dec. 17, 2010, the CFIDS Association hosted a webinar featuring Dr. Simmons, Michael Busch, MD, PhD and Steven Kleinman, BSc, MD to provide an update on the activities of the HHS Blood XMRV Scientific Research Working Group, including results of the Phase II study that had been presented to BPAC on Dec. 14, 2010. Collection of samples for Phase III occurred spring 2011 and participating labs tested those samples over the summer. Results are now being analyzed and will be reported in the peer-reviewed literature this fall.
In response to a request from the CFIDS Association about the impact of the publication of four studies about possible routes of contamination in XMRV/MLV research published on Dec. 20, 2010, the Blood XMRV Scientific Research Working Group issued this statement on Dec. 27, 2010:
“The Blood XMRV Scientific Research Working Group has discussed the findings from the four studies published in Retrovirology on December 20, 2010. These studies confirmed the importance of carefully checking XMRV/MLV related-positive results for any evidence of contamination with mouse genetic materials. The Working Group is proceeding with phase III which will evaluate the clinical sensitivity and specificity of multiple laboratory assays that test for the RNA and/or DNA of XMRV/MLVs or antibodies to these viruses. All laboratories have and will continue to apply best practices and check to the best of their ability that no contamination with mouse DNA is present before reporting any positive results. These reports also substantiate the importance of employing tests that not only detect viral DNA and/or RNA but can also detect the virus itself (culture) and/or an immunological reaction to the virus. These tests are reflected in the Working Group planned phase III study."
The AABB updated its statement about XMRV on Feb. 10, 2011. The March 2011 issue of the journal, Transfusion, included updates from the AABB Interorganizational XMRV Task Force and the DHHS Blood XMRV Scientific Research Working Group.
A special report published in Apr. 2011 in Future Microbiology by Roger Dodd, PhD, of the American Red Cross, addresses the issues of blood safety.
"...the issue may perhaps best be analyzed by considering the safety issues relating to ME/CFS separately from those involving XMRV/MLV. It thus seems reasonable to accept that patients with a past or current diagnosis of ME/CFS should not give blood, both for their own protection and as a precautionary measure, given the potential associations of chronic viral infections with the disease."
The CFIDS Association frequently updates this page and resource listing with the latest studies and media coverage of this dynamic high-profile topic. We also included four XMRV programs in our 2010 Webinar Series: on July 15 two top experts gave a webinar on XMRV and its impact on CFS. A webinar on XMRV & Blood Safety featuring infectious diseases expert and transfusion medicine specialist Dr. Louis Katz was held on August 16. Dr. Anthony Komaroff of Harvard Medical School (clinical collaborator for the study from FDA/NIH) gave a webinar on Sept. 16, titled “CFS & the Viral Connection.” These recordings are posted on our YouTube Channel.
The 1st International Workshop on XMRV, sponsored by NIH and Abbott Virology, was held on the NIH campus on Sept. 7-8, 2010. This workshop brought together 225 participants from many of the groups studying XMRV and featured 10 plenary sessions, 20 presentations of new data and 23 poster presentations. Written abstracts are available from the oral and poster presentations. The final question and answer session was webcast to the public and archived. Science magazine, NCI Cancer Bulletin and the CFIDS Association provided written reports on the meeting. A summary of the proceedings prepared by members of the organizing committee was published in Retrovirology on Dec. 22, 2010. While there were no definitive answers about the role of this family of gammaretroviruses in human disease arrived at by the conclusion of the workshop, consensus was reached on several key research issues including the need for greater sharing of samples and methods.
Dr. Stuart Legrice of the National Cancer Institute provided a summary of the XMRV Workshop and NIH's XMRV studies at the Oct. 12, 2010 “Science Day” session of the federal CFS Advisory Committee. The meeting was webcast to the public. On Feb. 22, 2011, Dr. Harvey Alter (NIH), Dr. Shyh-Ching Lo (FDA) and Dr. Fred Gill (NIH) gave a webcast presentation titled, "CFS: Is There A Virus?" as part of NIH's series on Demystifying Medicine.
The XMRV research presented at the 18th Conference of Retroviruses and Opportunistic Infections (CROI) that XMRV may be a laboratory recombinant of two mouse viruses drew attention from Science and Nature. Studies from these sessions are likely to attract more attention when they are published. In an article that ran on the front page of the Chicago Tribune, Robert Silverman of the Cleveland Clinic made the following statement about the possibility that XMRV may be a contaminant. "'I am concerned about lab contamination, despite our best efforts to avoid it,' Silverman wrote in an e-mail, adding that similar cell lines 'are in many, many labs around the world. Contamination could come from any one of a number of different sites.'" Silverman's team first discovered XMRV in prostate cancer cells; he tested CFS samples for the Whittemore Peterson Institute (WPI) and that data was included in the original report in Science.
The National Institutes of Health (NIH) ME/CFS State of the Knowledge Workshop was held on April 7-8, 2011. NIH Director Francis Collins addressed the meeting and several other top Department of Health and Human Services and NIH staff attended all or part of the workshop. Secretary Kathleen Sebelius expressed her support in a letter sent to workshop participants. XMRV-related presentations were given by Judy Mikovits, PhD and John Coffin, PhD, and reflected the diverse perspectives on the evidence so far. A summary of the presentations by Jennie M. Spotila, J.D. is provided here. Other resources from the meeting, including links to the full webcast, are gathered here.
The 15th International Conference on Human Retrovirology, HTLV and Related Viruses was held June 5-8, 2011 in Leuven, Belgium. A session on XMRV chaired by Dr. Robert Silverman (Cleveland Clinic) and Bill Switzer (CDC) was held, with eight oral presentations and 15 posters.
On June 24, 2011, Dr. W. Ian Lipkin, director of Columbia University’s Center for Infection and Immunity, gave a presentation at the Whittemore Peterson Institute titled, “Microbe Hunting.” In addition to describing his center’s approach to pathogen discovery, Dr. Lipkin briefly discussed the multicenter study he is coordinating on behalf of the National Institutes of Health to look for evidence of XMRV in CFS patients and matched healthy controls.
Other recent developments through early July 2011 are summarized on our Research1st site.
The "Frontiers in Retrovirology" conference, Oct. 3-5, 2011 in Amsterdam, will feature a session on endogenous retroviruses and XMRV. Speakers (so far) are Christine Kozak (NIAID), Dusty Miller (FHCRC), Douglas Nixon (UCSF). Abstracts are due July 15.
The CFIDS Association of America congratulates Dr. Judy Mikovits and her team at the Whittemore Peterson Institute and their collaborators at the Cleveland Clinic and NCI for this landmark discovery. The findings themselves and publication of them in a journal of the stature and circulation of Science is a highly significant contribution to the field. Their study and the high-profile publication are important validation of the reality and seriousness of CFS and those who suffer and have been stigmatized too long.
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