XMRV and CFS – the sad end of a story, The Lancet, 4 February 2012

From The Lancet, The Lancet, Volume 379, Issue 9814, Pages e27 – e28, 4 February 2012 doi:10.1016/S0140-6736(11)60899

Scientific papers on chronic fatigue syndrome (CFS) often evoke much debate and emotional reaction, as exemplifiedby the recent discussions in The Lancet on the PACE trial.(1) Also, the potential role of a retrovirus in CFS kindled a fierce controversy which has recently culminated. In 2009, in Science, Lombardi and colleagues(2) described the occurrence of the xenotropic murine leukaemia virus (MLV)-related virus (XMRV), a gammaretrovirus, in white blood cells in 67% of patients with CFS and in 3·7% of healthy controls. This finding was remarkable because infection of human beings with gammaretroviruses had not been observed before. This Science paper was presented as a breakthrough with important implications for prevention and treatment of CFS as well as for transfusion practices. However, the paper yielded a host of criticism because it was felt to fall short in various aspects — eg, the absence of an appropriate description of the patients and methods.(3–5) More importantly, the observations of Lombardi were questioned by three independent studies that were published shortly after the initial publication. In these studies, no XMRV was detected in patients with CFS and healthy controls.(6–8)

Mid 2010, a study from the US Food and Drug Administration (FDA) created further controversy by reporting detection of polytropic MLV-like viruses, but not XMRV, in blood cells of 86·5% of patients with CFS and 6·8% of healthy controls.(9) Although these findings refuted those of Lombardi and colleagues, they were erroneously embraced as confirmation by CFS activists and patients, some of whom were already using antiretroviral drugs to treat their disease.10

In the meantime, many more studies failed to detect XMRV in patients with CFS and controls.(11–16) Additionally, four independent investigations indicated that commercially available PCR reagents and human clinical samples could be contaminated by mouse DNA containing endogenous MLV-like sequences.(17) Furthermore, phylogenetic analysis of XMRV and MLV-like sequences derived from patients with CFS revealed a remarkable lack of genetic variation, which is uncommon in low-fidelity retrovirus replication (which normally leads to highly divergent viral sequences), and suggested that they all originated from XMRV and MLVs present in the commonly used prostate-carcinoma cell-line 22Rv1.(17) Together, these studies raised huge scepticism about the role of XMRV or MLV-like viruses in CFS, and reminded of previous examples of alleged human retroviruses implicated in cancer and other chronic diseases that were later shown to be laboratory contaminants (so-called rumour viruses).(18)

Now, three new publications seem to provide the final nail in the coffin of the XMRV–CFS story.(19–21) Two of these studies — one of which was published in Science — fail to detect XMRV or related MLVs, either as infectious virus or viral sequence, as well as antibodies against these viruses in a large group of patients with CFS, including patients from the original study by Lombardi and colleagues.(19,20) Moreover, comprehensive evidence was presented for the occurrence of contaminating mouse DNA in the Taq polymerase and other commercial laboratory reagents used in that particular study. The third study, also published in Science, provides convincing evidence that XMRV is a spectacular laboratory artefact generated by recombination of two mouse proviruses during passage of a human prostate-tumour xenograft—ie, the progenitor of the 22Rv1 cell line — in mice.(2)

On the basis of the overall evidence that the association of XMRV with CFS is due to contamination of laboratory reagents and the fact that XMRV is not a genuine human pathogen, editors of Science have asked Lombardi and colleagues to voluntarily retract the paper, according to a report in the Wall Street Journal.(22+ However, the news report continued, the corresponding author of this publication, Judy Mikovitch, declared in a response to Science that “it is premature to retract our paper”.(22) Hence, Science editor-in-chief Bruce Alberts has now published an Editorial Expression of Concern about the paper.(23)

In the past, several infectious agents have been associated with CFS but none of these could be confirmed in subsequent studies, leaving the field and patients in the same state of uncertainty as before. Sadly, we have to conclude that the world has witnessed another false claim that gave new hope to patients with CFS, who are desperately seeking a cause for their suffering.

*Frank J M van Kuppeveld, Jos W M van der Meer
Department of Medical Microbiology (FJMvK), Department of Medicine (JWMvdM), and Nijmegen Institute for Infection, Inflammation and Immunity (FJMvK, JWMvdM), Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, Netherlands
f.vankuppeveld@ncmls.ru.nl

We declare that we have no conflicts of interest.

1) The Lancet. Patients’ power and PACE. Lancet 2011; 377: 1808.
2) Lombardi VC, Ruscetti FW, Das Gupta J, et al. Detection of an infectious
retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome.
Science 2009; 326: 585–89.
3) van der Meer JW, Netea MG, Galama JM, van Kuppeveld FJ. Comment on
“Detection of an infectious retrovirus, XMRV, in blood cells of patients with
chronic fatigue syndrome”. Science 2010; 328: 825.
4) Lloyd A, White P, Wessely S, Sharpe M, Buchwald D. Comment on
“Detection of an infectious retrovirus, XMRV, in blood cells of patients with
chronic fatigue syndrome”. Science 2010; 328: 825.
5) Sudlow C, Macleod M, Al-Shahi Salman R, Stone J. Comment on “Detection
of an infectious retrovirus, XMRV, in blood cells of patients with chronic
fatigue syndrome”. Science 2010; 328: 825.
6) Erlwein O, Robinson MJ, Kaye S, et al. Failure to detect the novel retrovirus
XMRV in chronic fatigue syndrome. PLoS One 2010; 5: e8519.
7) van Kuppeveld FJ, de Jong AS, Lanke KH, 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: 1018.
8 )Groom HC, Boucherit VC, Makinson K, et al. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 2010; 7: 10.
9) Lo SC, Pripuzova N, Li B, et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci USA 2010; 107: 15874–79.
10) Phoenix Rising. Treating chronic fatigue syndrome (ME/CFS): XMRV. http:// aboutmecfs.org.violet.arvixe.com/Trt/XMRVTreatment.aspx (accessed June 6, 2011).
11) Switzer WM, Jia H, Hohn O, et al. Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States. Retrovirology 2010; 7: 57.
12) Hong P, Li J, Li Y. Failure to detect xenotropic murine leukaemia virus-related virus in Chinese patients with chronic fatigue syndrome. Virol J 2010; 7: 224. 13 Satterfield BC, Garcia RA, Jia H, Tang S, Zheng H, Switzer WM. Serologic and
PCR testing of persons with chronic fatigue syndrome in the United States shows no association with xenotropic or polytropic murine leukemia virus-related viruses. Retrovirology 2011; 8: 12.
14) Erlwein O, Robinson MJ, Kaye S, et al. Investigation into the presence of
and serological response to XMRV in CFS patients. PLoS One 2011; 6: e17592.
15) Furuta RA, Miyazawa T, Sugiyama T, et al. No association of xenotropic murine leukemia virus-related virus with prostate cancer or chronic fatigue syndrome in Japan. Retrovirology 2011; 8: 20.
16) Schutzer SE, Rounds MA, Natelson BH, Ecker DJ, Eshoo MW. Analysis of cerebrospinal fluid from chronic fatigue syndrome patients for multiple human ubiquitous viruses and xenotropic murine leukemia-related virus. Ann Neurol 2011; 69: 735–38.
17) Smith RA. Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses. Retrovirology 2010; 7: 112.
18) Weiss RA. A cautionary tale of virus and disease. BMC Biol 2010; 8: 124.
19) Shin CH, Bateman L, Schlaberg R, et al. Absence of XMRV and other
MLV-related viruses in patients with chronic fatigue syndrome. J Virol 2011;
published online May 4. DOI:10.1128/JVI.00693-11.
20) Knox K, Carrigan D, Simmons G, et al. No evidence of murine-like
gammaretroviruses in CFS patients previously identified as XMRV-infected.
Science 2011; published online June 2. DOI:10.1126/science.1204963.
21) Paprotka T, Delviks-Frankenberry KA, Cingöz O, et al. Recombinant origin
of the retrovirus XMRV. Science 2011; published online June 2. DOI:10.1126/
science.1205292.
22) Marcus AD. Chronic-fatigue paper called into question. Wall Street J May 31, 2011. http://online.wsj.com/article/SB1000142405270230374530457635
5852212887170.html (accessed May 31, 2011).
23) Alberts B. Editorial expression of concern. Science 2011; published online
June 2. DOI:10.1126/science.1208542.