XMRV and CFS – the sad end of a story

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

by Tony Britton on February 4, 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.

* 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@...

We declare that we have no conflicts of interest.