Wednesday, November 25, 2009

The Role of Viruses in ME/CFS

The Role of Viruses in ME/CFS, XMRV and the MRC PACE Trial – Margaret Williams – 21st November 2009

"On 8th October 2009 the premier journal Science published a paper online showing a direct link between a retrovirus and ME/CFS (Detection of infectious retrovirus XMRV, in blood cells of patients with chronic fatigue syndrome. Lombardi VC, Ruscetti FW, Peterson DL, Silverman RH, Mikovits JA et al) which caused global reverberations.

However, this was not the first time that a retrovirus had been associated with ME/CFS.

In 1991, using polymerase chain reaction and in situ hybridisation, Dr Elaine De Freitas, a virologist at the Wistar Institute, Philadelphia (which is America’s oldest independent institution devoted to biological research) and Drs Daniel Peterson, Paul Cheney, David Bell et al found such an association (Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA 1991:88:2922-2926). It is notable that co-author Hilary Koprowski is a distinguished virologist and Professor Laureate who was Director of the Wistar Institute from 1957-1991; he is a member of the US National Academy of Sciences and is Director of the Centre for Neurovirology at Thomas Jefferson University.

Before publication, the findings were presented on 4th September 1990 by Elaine De Freitas at the 11th International Congress of Neuropathology in Kyoto, Japan.

Ten days later, on 14th September 1990 Dr Peter White (as he then was) and other members of the Wessely School dismissed the findings: “in the vast majority of CFS cases there is a psychological component. About 75% of CFS sufferers are clinically depressed, according to Peter White, senior lecturer in the department of psychiatric medicine at St Bartholomew’s Hospital in London. White said he believes depression is often a cause, rather than a consequence, of CFS…Les Borysiewicz, a clinical virologist at Addenbrookes Hospital in Cambridge (now Chief Executive of the MRC, having succeeded Professor Colin Blakemore) (said) ‘Whatever causes CFS, it isn’t the virus itself’…Anthony Clare, psychiatrist and medical director of St Patrick’s Hospital in Dublin (now deceased), pointed out that…there have been many ‘fatigue’ diseases with shifting causes: ’Neurasthenia, food allergies, now viruses. Some people would always rather have a disease that might kill them than a syndrome they have to live with’ ” (Science 1990:249:4974:1240).

In their PNAS article that was published in April 1991, De Freitas et al noted that chronic fatigue immune dysfunction syndrome (CFIDS) “may be related or identical to myalgic encephalomyelitis” and examined adult and paediatric CFIDS patients for evidence of human retroviruses (HTLV types I and II). As the CFIDS Chronicle article noted, the Wistar team looked at the peripheral blood DNA to see if they could find messenger RNA (mRNA) encoding for a viral segment of the HTLV-II virus.

At that time, known human retroviruses were the human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) which are known to cause AIDS, and human T-lymphotropic viruses HTLV-I which causes lymphoma and HTLV-II which causes leukaemia (Hunter-Hopkins ME-Letter, October 2009). The four segments of the HTLV-II virus are referred to as the env, gag, pol and tax.

After a two year study, De Freitas et al provided evidence for HTLV-II-like infection of blood cells from CFIDS patients (and also to a lesser extent from people closely associated with them). This evidence was further substantiated by patient reactivity to proteins with the molecular weights reported for HTLV-I and HTLV-II antigens.

In their article, De Freitas et al said: “The frequency of these antibodies in CFIDS patients compared with healthy non-contact controls suggests exposure / infection with an HTLV-like agent rare in healthy non-contact people”.

Following the Wistar findings, researchers at the US Centres for Disease Control (CDC) allegedly attempted to replicate De Freitas’ work but failed to do so; this was suggested to be because certain scientists appeared eager to discount any possibility of a retroviral association with CFIDS. De Freitas defended her work and insisted that the CDC investigators had modified her assays, with the result that her work could not be replicated by the CDC.

De Freitas was publicly discredited; her research funding was discontinued and her research abandoned; she was subjected to what appeared to be attempts to destroy her professional reputation. Commenting on the subsequent discovery of XMRV (see below), ME/CFS expert Dr Paul Cheney of The Cheney Clinic was unambiguous: “Her work was unfortunately assaulted by the CDC. Her proposal to fly to the CDC in Atlanta to physically run the assays side by side with the CDC scientists was dismissed by the CDC” ( )."

1 comment:

Anonymous said...

ME Research UK and the Irish ME Trust are to replicate the WPI's xmrv study - & not a weasel in sight.

Independent confirmation of the relationship between XMRV and ME/CFS in Sweden
Investigators Prof. Jonas Blomberg and Prof. Carl-Gerhard Gottfries

Section of Clinical Virology, Uppsala University Hospital, Uppsala, Sweden; Institution for Neuroscience and Physiology at the Sahlgrenska Academy, Gothenburg University, and Gottfries Clinic, Mölndal, Sweden

ME Research UK and the Irish ME Trust are providing joint funding for this important study.

Background and aims
The discovery of a retroviral link to ME/CFS, reported in the major journal Science in October 2009 (Science 2009; 326: 530–1), has the potential to advance the diagnosis and treatment of the illness greatly (see our overview essay XMRV and ME/CFS — A stunning find). The major finding was that DNA from the XMRV virus could be detected in the peripheral blood mononuclear cells of over two-thirds of ME/CFS patients’ samples from the blood bank in the Whittemore Peterson Institute tissue repository, but in less than 4% of healthy control samples. Also, the researchers reported that XMRV proteins were being expressed in blood cells from ME/CFS patients at very high levels compared with controls, and that patient-derived XMRV was infectious and transmissible.

Prof. Jonas Blomberg These findings have caught the attention of the scientific world, but the next steps are equally important. Chief among these is for independent laboratories across the world to attempt the replication of the WPI findings among their own local populations of ME/CFS patients — it is sometimes said that replication studies are where the rubber meets the road in science! Since the WPI researchers used samples selected from several regions in the US where “outbreaks of CFS” had been documented (using patients diagnosed on CDC-1994 criteria and Canadian Clinical criteria 2003), blood samples from patients in other areas or countries might throw up very different results. Will ME/CFS samples from other regions of the US show similar high rates of positivity? And what about European samples?

Prof. Carl-Gerhard Gottfries This replication study is one attempt to answer this question — to establish whether XMRV nucleic acid can be found in peripheral blood mononuclear cells, plasma and serum of Swedish patients and controls. The researchers will retrospectively test previously stored samples from 3 groups of patients (20 Fukuda-defined ME/CFS, 20 fibromyalgia, 20 irritable bowel) and 20 controls. In addition, they will prospectively test samples from 120 ME/CFS patients (defined on the Fukuda 1994 and the Canadian 2003 criteria, similar to patients in the original 2009 report in Science), who will also have functional assessments.

The investigators are well-placed to conduct this confirmation study. Prof. Blomberg is head of the Research Group of Clinical Virology at the University of Uppsala. His research interests include human endogenous retroviruses, the links between endogenous retroviral sequences of the human genome and diseases such as multiple sclerosis and schizophrenia, and the development of real time polymerase chain reactions for common viral infections.

Prof. Carl-Gerhard Gottfries is Professor Emeritus at the Sahlgrenska University Hospital, Mölndal, and founder of the Gottfries Clinic AB which was formed in Västra Götaland in 1998 for patients with fibromyalgia and ME/CFS, and which is now situated in Mölndal. The unit has three doctors, nurses and medical secretaries, and it has also conducted basic clinical research, including trials of immunomodulatory therapy for fibromyalgia and CFS.

The results of this important replication study should be available in the Spring/Summer of 2010.

(don't forget to donate what you can, folks, they need every penny they can get - & MEResearchUK are selling xmas cards!)


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