History
  Programs
  Leadership
  Annual Report & 990
  What's New?
  Testimonials
  Support Us

XMRV Link to CFS Accelerates Scientific Inquiry and Sustains Media Interest

(Updated most recently on August 23, 2010)

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 family of murine leukemia viruses (MLVs).

These important results provide 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 in 2006 and detected in a subset of prostate cancer patients’ tumor cells in 2009. MLVs had not been linked to other human diseases prior to the PNAS report.

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. by researchers in the U.K. A third negative study was reported by Dutch researchers on Feb.25. A fourth negative study from researchers at the U.S. Centers for Disease Control & Prevention, Robert Koch Institute (Germany) and Blood Systems Research Institute (U.S.) was reported in Retrovirology on July 1, 2010.

None of the negative studies used the same methods as Lombardi, et al., nor did they select patients using the same criteria. 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 own study and the other four investigations of XMRV in CFS have not attempted 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.

Research on XMRV in CFS continues at other institutions. A new NIH grant was awarded in May 2010 to a group at Cornell University that will study patients who became ill in Lyndonville, New York in the mid-1980s as children. Dr. Stuart LeGrice of the National Cancer Institute reported on several studies under way in his laboratory at the July 26, 2010 meeting of the FDA's Blood Products Advisory Committee. Dr. Ila Singh of the University of Utah was a guest on the Aug. 8, 2010 edition of the podcast "This Week in Virology" and she described multiple studies her group is undertaking to understand XMRV and its relationship to human diseases. She is obtaining samples from patients who have tested positive and negative for XMRV by WPI, which she will test under blinded conditions.

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, individuals with spondyloarthritis and children with 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.

Still Lots to Learn About XMRV and MLVs

XMRV was first described in 2006. There have been 55 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.

Dr. Robert Silverman and colleagues at the Cleveland Clinic published a detailed review of the data on XMRV in prostate cancer and CFS in the June 1, 2010 issue of Nature Reviews Urology. They suggest that, “In CFS, XMRV infection of blood cells could trigger immune suppression leading to secondary infections and effects on the central nervous system.” (See figure at right.) Their final paragraph summarizes the current state of CFS studies and implications:

“The presence of XMRV in CFS is a more recent finding that awaits independent confirmation and validation in multiple laboratories; ideally in blinded studies. However, if a role for XMRV in CFS is established it could have far-reaching implications. In particular, while XMRV has not been proven to cause disease, if a link is established with prostate cancer, CFS, or other disease, more effective and more specific diagnostics, treatments and prevention (that is, vaccination) all remain distinct possibilities. Finally, if sufficient risk exists of disease caused by XMRV infection, screening of donated blood to prevent transmission through transfusion might eventually be deemed prudent and necessary.”

Dr. Singh, one of the pioneers in studying XMRV, has indicated that XMRV is present in very small amounts and low copy numbers inside cells, making it challenging to detect. Tests must be very sensitive and very specific and extra care must be taken to eliminate possible sources of contamination from other mouse-related viruses that could cloud results. Based on studies of XMRV in prostate cancer, she indicated that disease stage may have an impact on XMRV's presence and/or the ability to detect it.

Studies have investigated the utility of various 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."

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 that it will indefinitely defer donors with a history or current diagnosis of CFS. New Zealand has followed Canada's guidelines. On June 18, 2010, the AABB issued a 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. The CFIDS Association issued a statement that day commending AABB’s action. 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.

 

The U.S. Department of Health and Human Services announced in October 2009 that it would support studies to assess the potential risks to the blood supply and that will also help standardize tests for XMRV. At the July 26, 2010 meeting of the Food and Drug Administration's (FDA) Blood Products Advisory Committee, seven groups made informational presentations about XMRV, including researchers at the FDA, NIH and CDC. 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, reported results from Phase I of its four-phase study. 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 1 study has its limitations and these results should not be extended to other published data. Presentations made at the July 26 meeting are posted on the FDA's website. Further work on the analytical panels will continue as the other three phases of the study are completed. Results of Phases II and III testing of blinded clinical panel samples are expected by fall 2010.

Coming Up

Watch the webinar

Watch the webinar

The CFIDS Association frequently updates this page and resource listing with the latest studies and media coverage of this dynamic high-profile topic; we have also included three XMRV programs in our 2010 Webinar Series. Most recently, 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. These recordings are posted on our YouTube Channel. The next webinar related to this topic will be held on Sept. 16, "CFS & the Viral Connection," featuring Anthony Komaroff, MD of Harvard Medical School.

The First International Workshop on XMRV, sponsored by NIH and Abbott Virology, will be held Sept. 7-8, 2010 in Bethesda, Maryland. This workshop will bring together many of the groups studying XMRV and offers an opportunity for researchers to develop approaches to study that will help address the many unanswered questions about XMRV and its relationship to human disease. In addition to plenary sessions, 20 presentations of new data will be included in the two-day meeting. The CFS session will be chaired by Drs. John Coffin (Tufts University) and Judy Mikovits (WPI) and the plenary lecture will be given by Dr. Frank Ruscetti (NCI).

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.

Additional Information (updated regularly)

Resources Listed by Source

The CFIDS Association of America

Peer-Reviewed Journals

CFS-specific studies of XMRV

CFS Experts:

Government Agencies/Professional Organizations:

Media:

Citations of Studies of XMRV and CFS (in order of publication date):

Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Science 8 October 2009. 1179052.

Supporting online material for Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Science 8 October 2009.

A new virus for old diseases? Coffin JM and Stoye JP. Science 8 October 8 2009. Erlwein O, Kaye S, McClure MO, Weber J, Willis G, Collier D, Wessley S, Cleare A. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE 5(1):e8519. doi:10.1371/journal.pone.0008519

Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Groom HCT, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, Gow JW, Mattes FM, Breuer J, Kerr JR, Stoye JP, Bishop KN. Retrovirology: 15 February 2010. 10.1186/1742-4690-7-10

Van Kuppeveld FJM, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJG, Swanink CMA, et al. Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ 2010;340:c1018.

Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States. Switzer WM, Jia H, Hohn O, Zheng H, Tang S, Shankar A, Bannert N, Simmons G, Hendry RM, Falkenberg VR, Reeves WC, Heneine W. Retrovirology 1 July 2010.

*quoted with permission from Tulane University

Updated most recently on August 17, 2010