New Science Papers Contribute More Doubt to XMRV-CFS Connection

Today in the journal Science, two articles were published about xenotropic murine leukemia virus-related virus (XMRV), a retrovirus that was first associated with CFS in a study published in Science in October 2009 by Lombardi et al. These studies add to the mounting number of publications that challenge the reliability of the initial report. Science’s editor-in-chief, Bruce Alberts, issued an “Editorial Expression of Concern” that accompanied the two papers and will be attached to the Lombardi publication. According to Ivan Oransky, executive editor of Reuter’s Health and publisher of the Retraction Watch blog, Science has issued four Expressions of Concern and 10 retractions since mid-2007.

The first study, “Recombinant Origin of the Retrovirus XMRV,” by Tobias Paprotka et al., builds on presentations made in March 2011 at the 18th Conference on Retroviruses and Opportunistic Infections (CROI). It provides data to show that XMRV is a laboratory recombinant of two endogenous murine leukemia viruses that arose during the development of a prostate tumor cell line called 22Rv1. The authors conclude that XMRV originated in the laboratory and does not readily infect or pose a risk to humans. This conclusion is supported by a number of published studies that have used serology to look for evidence of an immune response to XMRV infection. John Coffin, PhD, of Tufts University and the National Cancer Institute, is one of the senior authors on this study. He is a member of the National Academy of Sciences and is considered one of the leading authorities on retroviruses.

The second study, “No Evidence of Murine-Like Gammaretroviruses in CFS Patients Previously Identified as XMRV-Infected,” by Konstance Knox et al., tested newly collected samples from 61 CFS patients diagnosed by Daniel Peterson, M.D. Of the 61, 43 had tested positive for XMRV by the Whittemore Peterson Institute or its commercial laboratory, VIP Diagnostics. This team used a variety of methods to detect XMRV and did not detect XMRV in any of the freshly collected samples. Following on reports from other laboratories, they tested a variety of reagents used to perform polymerase chain reaction and found 9 of 17 to be contaminated with mouse DNA similar to sequences reported by Lo et al. in the Proceedings of the National Academy of Sciences.  They conclude, “We believe that the detection of MLV in human blood in previous studies reflects contamination of reagents used to assess their presence and/or contamination of human samples during laboratory manipulation of the infectious XMRV clone, VP62.”

The senior author on this study, Dr. Jay Levy of University of California at San Francisco, is head of the Laboratory for Tumor and AIDS Virus Research.  He discovered xenotropic murine leukemia viruses (X-MLVs) and is one of the co-discoverers of HIV. In the early 1990s, Dr. Levy and colleagues published two papers about immune activation in CFS and he was affiliated with a CFS clinic at UCSF, as was Dr. Daniel Peterson, the physician who collaborated on the study published today and on the Oct. 2009 study.

These two studies are the result of months of diligent effort by top experts in the fields of virology and retrovirology to understand the origins of XMRV and its potential role in human disease. Multiple collaborators at multiple institutions were involved in the experiments described in these papers published in one of the world’s top journals.

As Alberts states in the Science Expression of Concern, “The U.S. National Institutes of Health [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 further studies and will take appropriate action when their results are known.”

Alberts’ statement is consistent with the statement made by CFIDS Association CEO Kim McCleary at the May 10, 2011, meeting of the Department of Health and Human Services Advisory Committee: “The Solve ME/CFS Initiative 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.”

The Solve ME/CFS Initiative issued a Request for Applications on April 6, 2011, and letters of intent are due on Friday, June 3, 2011. All proposals, including those that may relate to the role of XMRV and MLVs in CFS, will be peer-reviewed for scientific and strategic merit and funding decisions will be made in early 2012 at the conclusion of the thorough application and review process.

We will provide additional analysis of the Knox et al. paper and will closely follow further developments and news coverage about these studies and XMRV with updates to our XMRV resources page and the Media Coverage section.


References:

Alberts B. Editorial expression of concern. Science. 31 May 2011: 10.1126/science.1208542.

Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung HJ, Tepper CG, Hu WS, Fivash, Jr. MJ, Coffin JM, Pathak VK. Recombination origin of the retrovirus XMRV. Science. 31 May 2011. 10.1126/science.1205292

Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett, Jr. J, Qui X, Luk KC, Schochetman G, Knox A, Kogelnik AM, Levy JA. No identification of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science. 2011 May 31:10.1126/science.1204983.

Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, Alter HJ. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proceedings of the National Academy of Sciences. 23 August 2010. 10.1073/pnas.1006901107

Levy JA. Xenotropic viruses: murine leukemia viruses associated with NIH Swiss, NZB, and other mouse strains. Science. 1973 Dec 14;182(117):1151-3.

Barker E, Fujimura SF, Fadem MD, Landay AL, Levy JA. Immunologic abnormalities associated with CFS. Clinical Infectious Diseases. 1994. Jan:18 Suppl 1:136-41.

Levy JA. Viral studies of CFS. Clinical Infectious Diseases. 1994. Jan:18 Suppl 1:117-20. Review.

Landay AL, Jessop C, Lennette ET, Levy JA. CFS: Clinical conditions associated with immune activation. Lancet 1991 Sep21:338(8769):707-12

May 31, 2011