For the second time in five days, a major paper linking CFS to a family of gammaretroviruses has been retracted. The Proceedings of the National Academy of Sciences (PNAS) released a notice of retraction to be published in its Dec. 27, 2011 issue. The notice was included in pre-publication materials circulated to the press by PNAS with a 3:00 p.m. embargo. The notice has not yet been posted on the PNAS site, but Ivan Oransky has posted most of it on his Retraction Watch blog: http://bit.ly/tSMxFu. UPDATE: The full text of the notice is now available on the PNAS site at http://bit.ly/sYDjue.
The retraction notice lists four concerns that led to the action taken and concludes with the following statement:
“…in consideration of the aggregate data from our own laboratory and that of others, it is our current view that the association of murine gamma retroviruses with CFS has not withstood the test of time or of independent verification and that this association is now tenuous. Therefore, we retract the conclusions in our article.”
The paper retracted by Shyh-Ching Lo et al., was the second publication that documented evidence of the presence of murine leukemia virus-like viral (MLV) sequences in blood samples collected from CFS patients. All the authors of the original publication are listed on today’s retraction. The first study linking this family of viruses to CFS, from Lombardi et al., was published in Science on Oct. 8, 2009 and linked XMRV, a member of this virus family, to CFS. That paper was fully retracted by the editor-in-chief in the Dec. 23, 2011 issue of Science.
When the PNAS paper was published on Aug. 23, 2010, the authors from the Food and Drug Administration, National Institutes of Health (NIH) and Harvard Medical School, stated, “Our results clearly support the central argument by Lombardi et al. that MLV-related viruses are associated with CFS and are present in some blood donors.” Dr. Harvey Alter, a Lasker Award-honored physician credited with discoveries leading to the identification of hepatitis C virus, became a hero for his public statements in support of CFS patients and the reality of their suffering. At this spring’s NIH ME/CFS State of the Knowledge Workshop, Dr. Alter moderated presentations given by Dr. Judy Mikovits and Dr. John Coffin, speaking to support or refute the evidence linking XMRV/MLVs to CFS.
Since the August 2010 publication, several groups attempting to validate the XMRV report have conducted assays to detect a broader group of viruses, including the sequences reported by Lo et al. So far, no group has reported positive results. The retraction letter cites the study by Shin et al. published on May 4, 2011 in the Journal of Virology. This is the study led by Ila Singh, MD, PhD, whom many expected would validate the findings based on her positive results for evidence of XMRV in prostate cancer tissues.
The Lo-Alter team’s findings have come under scrutiny as possibly due to contaminants associated with common laboratory reagents. Phylogenetic analysis conducted by Katzourakis et al. and other groups suggest the sequences identified by Lo et al. in samples from CFS patients collected 15 years apart were not consistent with evolutionary change and were likely due to contamination. The work by Katzourakis is cited in the retraction notice by the authors, although they also state, “there has been no evidence of contamination using sensitive mouse mitochondrial DNA or IAP assays or in testing coded samples…”
Results of the NIH-sponsored Blood XMRV Scientific Research Working Group (SRWG) study were published in Science on Sept. 22, 2011. Five patients whose positive results were included in the PNAS paper were part of the SRWG cohort tested by nine independent labs using 19 validated assays. Dr. Lo’s team participated, but did not find any positive results among the patient samples using tests similar to those in the PNAS paper. His assay accurately identified the spike positive controls with high accuracy under blinded conditions. The results from tests on their own patients’ samples are referenced in the retraction notice:
“While this result could be explained by viral clearance over time, it fails to support a sustained retroviral infection in human cells.”
Today’s retraction is the first public word from the Lo-Alter team in several months. Many had hoped they would have reported additional evidence by now, especially after XMRV was reported in Science to be a recombinant created in a laboratory in the early 1990s from two mouse cell lines. Hopes were kept alive by reports at conferences and online about unpublished evidence that supported the involvement of human gammatretroviuses (HGRVs) in CFS, the core of which was the Lo-Alter group’s continued engagement in the field. However, in the retraction notice the authors state,
“Our attempts, through collaborations, to demonstrate antibody in affected patients, to isolate the virus by culture, or to show integration sites in the human genome have failed to support the initial findings.”
UPDATE: Dr. Anthony Komaroff of Harvard Medical School provided the patient samples to Dr. Lo, originally in the early 1990s so he could test them for Mycoplasma. That study, reported in Clinical Infectious Diseases in 1993, was negative. The remaining aliquots from 37 patients were stored (unopened) for 15 years until Dr. Lo tested them for XMRV. Eight patients were recontacted in 2010 for fresh samples, and those results were included in the PNAS paper as well.
Dr. Komaroff is widely respected as one of the most dedicated physician researchers studying CFS and caring for CFS patients over the past quarter-century. As one of the PNAS study authors, he also signed off on the retraction and offered us this additional perspective:
“If the same laboratory cannot reproduce the findings on the same patients that it had previously found positive on two different occasions, then it is necessary to retract the original publication. The reported association between XMRV and these other murine leukemia retroviruses (MLVs) and CFS just hasn’t held up. It is time to move on from that theory.
“At the same time, even in the past two years since this controversy erupted, the evidence that CFS involves abnormalities of the brain and autonomic nervous system, the immune system, and energy metabolism has grown stronger. And there is good evidence that certain infectious agents may trigger CFS (not including XMRV and MLVs). This research points the way to future research.”
Dr. Maureen Hanson of Cornell University had presented reports at conferences indicating she had data from an independent cohort study that supported the Lo-Alter findings, but at the IACFS/ME conference held in September 2011 in Ottawa, she indicated that her results may have been the result of contamination. Dr. Hanson’s work is noted by Lo et al., although they do not reflect the explanation she gave in her presentation at the Ottawa meeting; only an abstract submitted months before the conference is available online. Dr. Hanson’s work is funded by the NIH through an R21 grant; she has not yet published any results in the peer-reviewed literature.
Drs. Lo and Alter are participating in the second multi-lab NIH-sponsored study of XMRV/MLVs being coordinated by Dr. Ian Lipkin at Columbia University. Dr. Anthony Komaroff has participated in the selection of patients for the study, along with five other expert CFS physicians. Sample collection is almost complete and results are expected in the first quarter of 2012. The retraction notice refers to prospect for these study results to be “more definitive” than other studies.
We share their expectation and that held by many others that Dr. Lipkin’s study will be the most conclusive test of this hypothesis so far. It will either breathe new life into the possibility that MLV-related viruses play a role in CFS or it will be the final word that they do not. As stated many times since the May 2011 meeting of the federal CFS Advisory Committee,
“The CFIDS Association stands for rigorous research that leads to better care for CFS patients. The results of NIH-supported research into XMRV will provide answers about whether XMRV is a route to better care. We will support the outcome of those studies, whichever way they lead. We will continue to foster the engagement of scientists interested in viral hypotheses and other well-reasoned approaches to improving diagnosis and treatment.”
We recognize that there continues to be a segment of the community that holds a different view and believes that neither the Lipkin study nor any single study will be definitive and that this line of research requires persistent effort and continued funding. In light of the recent retractions of both original reports providing the only published evidence so far, it is unlikely that such funding support will be forthcoming without presentation of positive evidence through either the Lipkin study or other peer-reviewed publications.
Media coverage of today’s retraction may be light due to reduced staffing between the holidays and today’s U.S. federal holiday, making it difficult for reporters to reach the lead researchers without the assistance of agency press offices. Reports are listed below and will be updated periodically:
- “Second XMRV-CFS paper pulled,” by John Gever for MedPage Today (12/26/11)
- “Authors retract paper on detection of MLV sequences in CFS patients,” by Vincent Racaniello, PhD, at virology blog (12/26/11)
- “Another shoe drops as authors retract PNAS chronic fatigue syndrome-virus paper,” by Ivan Oransky at Retraction Watch (12/26/11)
- “Scholars retract another study linking virus to CFS,” by David Tuller for The New York Times (12/26/11)
- “2 studies on CFS retracted in week,” by Mo Hong’e at Xinhua (Beijing) (12/27/11)
- “And another,” Genome Web (free registration may be required) (12/27/11)
- “Second high-profile XMRV-related paper retracted,” by Amy Dockser Marcus for Health Blog at Wall Street Journal (12/27/11)
- “CFS: Another study pulled from journals,” by Caitlin Bronson at ThirdAge.com (12/27/11)
- “Another XMRV study retracted,” by Heidi Ledford for Nature News Blog at Nature (12/28/11)
- Message from CII director W. Ian Lipkin regarding the XMRV/MLV study of CFS/ME (12/28/11)
- “Authors pull plug on second paper supporting viral link to CFS,” by Martin Enserink for ScienceInsider at Science (12/28/11)
- “Debunked Science: Studies take heat in 2011,” by Jon Hamilton at National Public Radio (12/29/11)
- “This year in virology,” by Vincent Racaniello, PhD, at virology blog (12/29/11)
- “Year in Review,” by Ira Flatow for “Science Friday” heard on National Public Radio stations (Dec. 30, 2011) (audio file)
- “TWiV 164: Six steps forward; four steps back,” by Vincent Racaniello, PhD, Alan Dove, PhD, and Rich Condit, PhD at “This Week in Virology” (podcast) (posted Jan. 1, 2012)
- “Seven Days: Dec. 30-Jan. 5,” Nature (Jan. 4, 2012)
- “TWiV 165: The email zone,” by Vincent Racaniello, PhD, Dickson Depommier, PhD, and Rich Condit, PhD at “This Week in Virology” (podcast) (posted Jan. 8, 2012)
K. Kimberly McCleary has served as the Association’s chief staff executive since 1991.