The role of viruses in ME/CFS:

What, if any, will be the effect of the discovery linking XMRV to ME/CFS on the MRC PACE Trial?

by Margaret Williams

In relation to “CFS”, the most-studied viruses have been the Epstein-Barr Virus (EBV) and the Human Herpes Virus-6 (HHV-6). In relation to “pure” ME, the most studied viruses (and for which there is extensive evidence) have been the enteroviruses, usually Coxsackie B (CBV). Some illustrations from the literature of the role that viruses play in ME/CFS are provided at the end of this paper; all are significant.

There is increasing awareness that the dysregulated immune system that is a hall-mark of ME/CFS allows multiple latent viruses and microbial agents to become reactivated (Co-Cure NOT:12^th November 2009).

Moreover, recent research has shown that even viruses which were hitherto believed not to persist after an acute infectious episode are capable of long-term viral persistence.

Nora Chapman et al from the Enterovirus Research Laboratory, Department of Pathology and Microbiology, University of Nebraska Medical Centre, have shown that human enteroviruses Coxsackie B can naturally delete sequence from the 5’ end of the RNA genome and that this deletional mechanism results in long-term viral persistence, which has substantially altered the previously held view (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440640/?tool=pubmed).

In a specially commissioned piece for the charity Invest in ME, the researchers say:

Dr John Chia, an infectious diseases specialist from Torrance, California, who specialises in ME/CFS, is on record:

The CFIDS Chronicle (Research Update, Summer 1993) explained viruses and retroviruses as follows:

On 8^th 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 4^th September 1990 by Elaine De Freitas at the 11^th International Congress of Neuropathology in Kyoto, Japan.

Ten days later, on 14^th September 1990 Dr Peter White (as he then was) and other members of the Wessely School dismissed the findings:

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:

Whilst none of the CFIDS patients’ blood sample contained detectable HTLV-I gag sequences, DNA from at least two separate bleedings was positive for the HTLV-II gag subregion in 83% of adult and 72% of paediatric CFIDS patients, and the authors pointed out that “similar frequencies of PBMCs (peripheral blood mononuclear cells) expressing retroviral mRNA have been reported for HIV-infected individuals…The clinical histories of these CFIDS patients do not reveal behavioural or genetic factors usually associated with retroviral infection.  Yet our data suggest that not only are these HTLV-II-like genes and HTLV-reactive antibodies associated with CFIDS in patients but that samples from a significant proportion of their non-sexual contacts are positive”.

De Freitas et al were careful to emphasise that

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:

In August 1991, together with co-author Brendan Hilliard, Elaine De Freitas had applied for a world patent that was subsequently issued in April 1992.  Detailed information has been provided by Dr Alan Cocchetto, Medical Director of The National CFIDS Association [National CFIDS Foundation] (http://www.ncf-net.org/forum/revelations.html ).  Cocchetto is clear:

It has been said that De Freitas’s reputation was intentionally destroyed because her research did not support the theory that (ME)CFS is a psychoneurosis, and that her public discrediting caused others to fear following up her work (Co-Cure;NOT: 16^th October 2009).

As Neenyah Ostrom commented:

There undoubtedly seems to be collaboration about policy concerning ME/CFS between the UK Wessely School and Dr William (Bill) Reeves, Principal Investigator of the CDC’s CFS research programme, who is held in the same disregard in the US as Professor Simon Wessely is held in the UK (see below).

Regarding blood donation by people with ME/CFS, it is a matter of record that in reply to a letter dated 21^st December 1991 from the late Joan Irvine, on 16^th January 1992 Dr George Rutherford, Chief of the Infectious Diseases Branch of the US Department of Health and Human Services, replied to her query about blood donation by people with (ME)CFS:

Also on 16^th January 1992, the same Dr William Reeves of the CDC wrote to Joan Irvine about the same issue:

It is worth noting that people in the UK with ME have been permanently excluded from donating blood since at least 1989 (Guidelines for the Blood Transfusion Service in the UK, 1989: 5.4; 5.42; 5.43; 5.44; 5.410).

This was subsequently upheld by the Parliamentary Under Secretary of State The Lord Warner, who confirmed in writing on 11^th February 2004 in a letter to the Countess of Mar that people with ME/CFS
are not permitted to be blood donors. Lord Warner was unambiguous:

Given the (re)-discovery of a direct link between a retrovirus and ME/CFS, the importance of this cannot be over-stated.

Notably, those with a behavioural disorder are not prevented from donating blood.

XMRV (retrovirus associated with ME/CFS)

As mentioned above, in October 2009 the journal Science published a paper by collaborators from the Whittemore Peterson Institute, the US National Cancer Institute and The Cleveland Clinic that demonstrated a direct link between the retrovirus XMRV and ME/CFS (Science: 8^th October 2009:10.1126/science.1179052).

XMRV stands for xenotropic murine leukaemia virus-related virus (xenotropic meaning a virus that can grow in the cells of a species foreign to the normal host species, i.e. a virus that is capable of growing in a foreign environment).

XMRV is a member of the same family of retroviruses as the AIDS virus.  A retrovirus inserts itself into the host’s genetic material by copying its genetic code into the DNA of the host by using RNA and once there, it stays for the life of the host.

It is understood that Mikovits’ discovery was deemed to be of such magnitude by the world’s most prestigious science journal that the authors’ paper (which was submitted on 6^th May 2009) was sent to three times the customary number of referees prior to acceptance and publication.

Shortly before the Mikovits et al paper was published, on 24^th September 2009 the Whittemore Peterson Institute (WPI) announced that Dr Mikovits and collaborator Dr Jonathan Kerr of St George’s, London, had been awarded a $1.6 million five-year grant by the US National Institute of Allergy and Infectious Diseases for research into the causes and diagnosis of neuro-immune diseases (http://www.wpinstitute.org/news/news_current.html ). The Project Number is 1R01A1078234-01A2 and the description provided by the applicants says:

It is worth noting that three days before the Mikovits et al article was published in Science, on 5^th October 2009 Professor Peter White in collaboration with Dr Bill Reeves of the CDC published a paper in which they described endophenotypes of CFS (which White talked about in his presentation at Bergen on 20^th October 2009 – see below).  According to Wikipedia,

In contrast, in their article in Science Mikovits et al deal with science, not speculation:

The published supplementary material confirms:

Commenting on this discovery, Professor John Coffin from the Department of Molecular Microbiology, Tufts University, Boston, a National Academy of Science member and expert retrovirologist who edited the 1997 reference book “Retroviruses” (proclaimed as “outstanding” by the New England Journal of Medicine) who was not involved with the study and who was at first highly sceptical but who was converted by the WPI team’s independent lines of evidence, together with Professor Jonathan Stoye from the UK National Institute for Medical Research, Mill Hill, London (who is Head of the Virology Division at the Medical Research Council), stated:

Announcing their groundbreaking discovery, a press release by R&R Partners on behalf of the Whittemore Peterson Institute said:

Commenting on this further information, ME/CFS expert Dr Paul Cheney said:

On the day that the news broke of the XMRV link with ME/CFS, it was widely reported; prominent sources included AFP; Reuters; Wall Street Journal; Washington Post; New York Times; Nature; Scientific American; New Scientist; NIH News; Science News; NCI Press Release; Scientist, and many national newspapers such as the UK’s Daily Telegraph and The Independent.  Numerous links can be found at http://bit.ly/13nShx.

The Wall Street Journal quoted Judy Mikovits as saying that the XMRV virus creates an underlying immune deficiency which might make people vulnerable to a range of diseases, and it continued:

AFP (Agence France Presse) quoted Mikovit’s co-author Francis Ruscetti of the Laboratory of Experimental Immunology at the National Cancer Institute:

The NIH National Cancer Institute’s press release (“Consortium of Researchers Discover Retroviral Link to Chronic Fatigue Syndrome”) said:

Science News pointed out:

The Scientific American noted:

Ewen Callaway (New Scientist) also quoted Mikovits as confirming that her team had found antibodies against XMRV in 95% of nearly 300 patients they tested, but these further results have yet to be published in a journal.  Antibodies are a more sensitive test than looking for viral genes, as they pick up people who have had XMRV in the past, not just those who still have it.  Callaway noted that Mikovits also pointed out a very significant fact: not only do characteristics of the virus match the symptoms of (ME)CFS, but viruses related to XMRV can cause blood vessels around the body to leak, a common symptom of (ME)CFS. Quoting Jonathan Kerr of St George’s University of London, Callaway said:

The UK’s Daily Telegraph proclaimed on 9^th October 2009:

Also on 9^th October 2009, The Independent’s Science Editor, Steve Connor, reported the ground-breaking research on the front page.  He said that Dr Judy Mikovits, senior author of the study and Director of Research at the Whittemore Peterson Institute in Reno, Nevada, had confirmed that

Of note is that the UK’s NHS Knowledge Service (for several years the NHS has persisted in including ME/CFS in its mental health minimum dataset despite frequent requests to categorise it correctly) said:

On 8^th October 2009 Hillary Johnson, outspoken author of “Osler’s Webb: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic” (Crown Publishing Inc, New York, 1996), was blunt:

Particularly notable was the BBC’s reporting of the comments of Tony Britton, the (lay) Publicity Manager at the UK ME Association: “This is fascinating work, but it doesn’t conclusively prove a link between the XMRV virus and chronic fatigue syndrome or ME”, a statement that should be compared with what was published in Science: “we have discovered a highly significant association between the XMRV retrovirus and CFS” and with the WPI press release: “This finding clearly points to the retrovirus as a significant contributing factor in this illness”.

It is regrettable that the UK ME Association’s Publicity Manager seems not to distinguish between proving a conclusive cause and proving a direct link, a link that certainly satisfied the many prestigious referees who advised the journal Science.

It also satisfied Richard T Ellison III, Professor of Medicine, Molecular Genetics and Microbiology in the Division of Infectious Diseases and Immunology at the University of Massachusetts Medical School (Deputy Editor of Journal Watch Infectious Diseases since 1988), who commented: 

Moreover, as Hillary Johnson reported in the New York Times on 21^st October 2009, Judy Mikovits had worked for the National Cancer Institute for 22 years and she was impressed that Dan Peterson

On 20^th October 2009 Judy Mikovits herself was interviewed; she said:

Interviewed live by Rene Montagne, when asked why people thought sufferers don’t really have a disease, Dr Daniel Peterson, medical director of the WPI, was clear:

Following the (re)discovery of a direct link between a retrovirus and ME/CFS, there has been much internet traffic about the dismissing and ignoring by US agencies of state of Dr De Freitas et al’s work two decades ago that demonstrated a potential retroviral link, particularly in relation to possible transmission via blood products.

This down-playing has been ascribed by some people to (i) a possible UK/US collaboration over the use of biowarfare agents, including borrelia (“US Government Admits Lyme Disease Is A Bioweapon”: Co-Cure ACT: 1^st January 2006: http://www.indymedia.org.uk/en/2005/11/328067.html and http://www.lyme-rage.info/elena/statejun06.html); (ii) the CDC’s apparent determination to prevent at any cost public panic over the emergence of another AIDS-like pandemic and (iii) the wish to protect insurers from having to make payments for another chronic disease, factors that may be instrumental in Dr Bill Reeves’ dismissive comments about the latest discovery of an association between  a retrovirus and ME/CFS:

• the journal Nature reported: “William Reeves, principal investigator for the Centres for Disease Control and Prevention (CDC)’s CFS public health research programme, says the findings are ‘unexpected and surprising’ and that it is ‘almost unheard of to find an association of this magnitude between an infectious agent and a well-defined chronic disease, much less an illness like CFS…Until the work is independently verified the report represents a single pilot study’.  He also notes that CFS…likely arises from a combination of many factors”




• the Los Angeles Times also reported Reeves comments, adding his comment that: “It is extremely difficult to prove causation with a ubiquitous virus like XMRV, and it ‘is even more difficult in the case of CFS, which represents a clinically and epidemiologically complex illness’ he said. Unfortunately, Reeves said, the major flaw of the study is that there is not enough information about how subjects were selected to rule out any bias in choosing them”
  
the New York Times (13^th October 2009) reported Reeves as saying “he was surprised that a prestigious journal like Science had published it….We and others are looking at our own specimens and trying to confirm it…If we validate it, great.  My expectation is that we will not’….Many patients and a community of doctors and researchers who specialise in the syndrome take issue with the (CDC’s) approach to the illness and the way it defines who is affected.  They claim that the CDC includes people whose problems are purely psychiatric, muddying the water and confounding efforts to find a physical cause” (it is the case that the CDC now uses Reeves’ own (2005) definition that does not distinguish between CFS and major depressive disorder, so it is to be anticipated that the CDC will not replicate the Mikovits et al findings).

Against this background, there are mounting calls for the removal of Dr Reeves from his position as principal investigator of the CDC’s CFS research programme (“Support the 500 Professionals of the IACFS/ME – Reeves Must Go”):

Comments such as that by Tom Kindlon from the Irish ME/CFS Association reflect the position of many in the international ME/CFS community:

In her customary robust manner, Hillary Johnson in the US is scathing about Bill Reeves:

Notably, Dr Stuart Le Grice, head of the Centre of Excellence in HIV/AIDS and cancer virology at the National Cancer Institute went on record saying:

In response to an article in Nature by Lizzie Buchen who quoted Judy Mikovits as saying:

In the UK, Simon Wessely is similarly unpopular, and for similarly well-founded reasons.

On 5^th February 1999 that the New Statesman carried an article by Ziauddin Sardar about Wessely (titled “Ill-defined notions”) in which Sardar wrote:

Since at least 1994, when the CFIDS Chronicle published an article titled “The views of Dr Simon Wessely on ME: Scientific Misconduct in the Selection and Presentation of Available Evidence” (Spring 1994:14-18), valid criticisms of Wessely have continued to mount, some of which can be accessed at http://www.meactionuk.org.uk.

In his article in New Scientist on 9^th October 2009 (referred to above), Ewen Callaway noted Professor Wessely’s position regarding the discovery of XMRV in CFS patients:

Wessely’s belief that childhood trauma causes ME/CFS takes no account of those who had a happy, secure childhood within a stable and loving family but who still developed severe ME/CFS.

Similar points are reflected in the many online comments posted to the New Scientist. These were highly critical of Wessely’s dismissive attitude, and provided examples of the adverse impact on patients of his ill-grounded beliefs about ME/CFS, for example:

Other similar comments about Wessely were posted in response to The Independent’s coverage of the XMRV discovery, for example:

In a reply to someone who wrote to him on 12^th November 2009 asking for his response to the XMRV findings, Wessely replied:

“Could be a real breakthrough, even if I still don’t understand how they made the leap from prostate cancer to CFS”, which seems to indicate that Wessely remains ignorant of or else does not understand what Judy Mikovits et al said: “both are linked to alterations in the antiviral enzyme RNase L”, a link that was clearly explained by David Bell in his Lyndonville News, volume 6, number 2, October 2009:

There is international recognition that Wessely

As long ago as 1998, in his article “Dr Simon Wessely: Prophet or Profit?”, Dr Ken Jolly, a GP in New Zealand who had to give up his medical practice because of ME/CFS, published his concern that Wessely et al had come to dominate thinking about ME/CFS even in New Zealand, saying that they had achieved such influence by producing vast volumes of papers on CFS and obtaining funding for their own work. Jolly was forthright:

Dr Jolly then lists some of the more notorious of Wessely’s published views, including Wessely’s belief that CFS is merely the extreme end of normal fatigue which, as Jolly points out, totally ignores the cyclic nature of the disorder that is a pattern commonly seen in autoimmune diseases.  Jolly also points out that Wessely’s claim that ME/CFS patients’ symptoms are caused by hypervigilance towards normal bodily sensations does not explain why the same symptoms are reported by thousands of patients worldwide (who may not even speak the same language). Jolly notes that many physically-based research findings “have frequently been ignored for the (Wessely) model to continue to fit”. Jolly is particularly scathing about Wessely’s view that patients perpetuate their own illness:

As Dr Jolly further noted:

An internet search will quickly reveal that there is extensive outrage about Simon Wessely and his colleagues’ unproven beliefs, not only from ME/CFS patients and their long-suffering families, but also from international medical scientists and clinicians who are not blinded by ideology or vested interests.

In his article in The Independent on 9^th October 2009 (referred to above), Steve Connor also quoted Professor Simon Wessely’s views on the implications of the XMRV discovery:

However, in a Leading Article that same day, The Independent said:

On 29^th October 2009 Professor Coffin told a Department of Health and Human Services Committee that this discovery was of “potentially extraordinary importance”, not least, as Jack Johnson reported (Co-Cure NOT:16^th November 2009), because it means validation and hope for millions of people suffering from (ME)CFS, often thought by many to be nothing more than the product of neurosis and even laziness and, as Jack Johnson pointed out: “CFS has long been thought to be linked to retroviral infection”.

As noted in “Denigration by Design? A Review, with References, of the Role of Dr (now Professor) Simon Wessely in the Perception of Myalgic Encephalomyelitis (Up-date) Volume II (http://www.25megroup.org/denigration%20by%20design/denigration%20contents.htm), it seems that to Wessely and his closest associates, the belief of the moment represents the only truth.

They would do well to remember that in the early 1600s, King James I of England (who was also King James VI of Scotland) wrote a book called “Demonology” and that book helped to send to their death women known as the Lancashire witches.  Countless innocent women were persecuted, tortured and executed as witches, having been forced into admitting things they did not do, the majority being people who suffered from mental illness.

Incredibly, it was not until the 1950s that the Witchcraft Act was repealed in the UK. This must surely serve as a salutary reminder that the belief of the time (currently, that ME/CFS is a behavioural disorder) is not necessarily the truth, even though it might be promoted as the truth.

It is fair to say that the views of Wessely and his close colleagues (including those involved with the PACE Trial) are held in contempt by many people – medical and lay alike – who have to deal with the reality and severity of ME/CFS, yet injustice for those with ME/CFS continues. Cases of untold suffering and despair continue to accumulate, and this is very significantly because of the influence of the Wessely School.

One can but pray that along with his colleagues Peter White, Michael Sharpe and Trudie Chalder, Wessely’s power and influence – unlike that of demonology – will not remain enshrined for the next 350 years and that medical science may at last have provided the means to right the wrongs that the Wessely School have done so much to perpetrate upon those with ME/CFS.

That such wrongs exist in the US is further demonstrated by the testimony of Kenneth Friedman on 30^th October 2009 before the CFS Advisory Committee (Co-Cure NOT:MED: 4^th November 2009).  Friedman, a medical school professor at the Department of Pharmacology and Physiology, New Jersey Medical School, said:

Could it be said that the Wessely School has created a similar environment in the UK and that the MRC PACE Trial is part of that constructed environment, just as the NICE Clinical Guideline and the actions of NICE which resulted in the failure of the Judicial Review were also part of it?

References: The role of viruses in ME/CFS – some illustrations from the literature

1954:  Encephalomyelitis associated with poliomyelitis virus. ED Acheson. Lancet: Nov 20^th 1954:1044-1048.

1955:  Outbreak at The Royal Free. ED Acheson. Lancet: Aug 20^th 1955:394-395.

1959: The Clinical Syndrome Variously Called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia.  ED Acheson.  American Journal of Medicine, April 1959:569-595. (Note that neuromyasthenia is not the same as neurasthenia).

1978: An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, in 1955.  Nigel D Compston. Postgraduate Medical Journal 1978:54:722-724.

1983:  Sporadic myalgic encephalomyelitis in a rural practice. BD Keighley, EJ Bell. JRCP 1983:33:339-341.

1985:  Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection. G Tosato, S Straus et al. The Journal of Immunology 1985:134:5:3082-3088.  (Note that what is now called ME/CFS was then thought to be caused by EBV).

1985: Persisting Illness and Fatigue in Adults with Evidence of Epstein-Barr Virus Infection. Stephen E Straus et al. Ann Intern Med. 1985:102:7-16.

1985: The postviral fatigue syndrome – an analysis of the findings in 50 cases.  PO Behan, WMH Behan, EJ Bell. Journal of Infection 1985:10:211-222.

1987: Post-Viral Fatigue Syndrome. TJ Marrie et al. Clinical Ecology 1987:V:1:5-10.

1987: Coxsackie B viruses and the post-viral syndrome: a prospective study in general practice.  BD Calder et al. JRCGP 1987:37:11-14.

1987:  The Epstein-Barr Virus and Chronic Fatigue.  Irving E Salit. Clinical Ecology 1987:V:3:103-107.

1988: Chronic enterovirus infection in patients with Postviral Fatigue Syndrome. GE Yousef, EJ Bell, JF Mowbray et al. Lancet  January 23^rd 1988:146-150.

1988:  Chronic fatigue syndromes: relationship to chronic viral infection.  Anthony L Komaroff. Journal of Virological Methods. 1988:21:3-10.

1988:  Postviral Fatigue Syndrome.  PO Behan, WMH Behan.  CRC Crit Rev Neurobiol 1988:4:2:157-178.

1988:  Transmissible disease and psychiatry. Magnetic resonance muscle studies; implications for psychiatry. RP Yonge. JRSM 1988:81:322-326.

1988:  Human enteroviral infections.  EG Dowsett. Journal of Hospital Infection 1988:11:103-115.

1990: Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA.  L Cunningham, RJM Lane, LC Archard et al. Journal of General Virology 1990:71:6:1399-1402.

1990: Myalgic encephalomyelitis – a persistent enteroviral infection?  EG Dowsett, AM Ramsay et al. Postgraduate  Medical Journal 1990:66:526-530.

1991:  Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome.  Elaine De Freitas, Paul R Cheney, David S Bell et al. Proc Natl Acad Sci USA 1991:88:2922-2926. 

1991: Enteroviral RNA sequences detected by polymerase chain reaction in muscles of patients with postviral fatigue syndrome. JW Gow et al. BMJ 1991:302:696-696.

1991:  Considerations in the Design of Studies of Chronic Fatigue Syndrome.   Reviews of Infectious Diseases.  Volume 13, Supplement 1: S1 – S140. University of Chicago Press.  Contributing authors include: S. Grufferman,  AL Komaroff,  DS Bell,  DL Peterson,  S Daugherty,  S Bastien.

1991:  Postviral Fatigue Syndrome. British Medical Bulletin 1991:47:4: 793-907. Churchill Livingstone.

1993: Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy.  NE Bowles et al. Journal of Medicine 1993:24: 2&3:145-180.

1993: Enteroviruses and postviral fatigue syndrome. PO Behan, JW Gow et al. CFS: CIBA Foundation Symposium: 1993: 146-159.

1994:  Changes in the 2-5A Synthetase/RNase L Antiviral Pathway in a Controlled Clinical Trial with Poly(I)-Poly (C₁₂U) in Chronic Fatigue Syndrome. Robert J Suhadolnik, Daniel L Peterson, Paul Cheney et al. In Vivo 1994:8:599-604.

1994: Chronic Fatigue Syndrome: Current Concepts. Clinical Infectious Diseases 1994: Volume 18: Supplement 1: S1 – S167.  Ed. Paul H Levine. University of Chicago Press.  Contributing authors include: Paul H Levine, Alexis Shelokov, Anthony L Komaroff, David S Bell, Paul R Cheney, Leonard H Calabrese, Leonard A Jason, Seymour Grufferman, Hirohiko Kuratsune, Charles Bombadier, Nancy G Klimas, Mary Ann Fletcher, Roberto Patarca-Montero, Benjamin H Natelson, Robert J Suhadolnik, Daniel L Peterson, Dharam V Ablashi, Fred Friedberg, Jay A Levy, Peter O Behan, Wilhelmina MH Behan and Mark O Loveless.

1995: Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. DN Galbraith et al. Journal of General Virology 1995:76:1701-1707.

1995: Comparison of Coxsackie B Neutralisation and Enteroviral PCR in Chronic Fatigue Patients. C Nairn et al. Journal of Medical Virology 1995:46:310-313.

1995:  Detection of Enterovirus-Specific RNA in Serum: The Relationship to Chronic Fatigue. GB Clements et al. Journal of Medical Virology 1995:45:156-161.

1997: Evidence for enteroviral persistence in humans (with CFS). DN Galbraith et al. Journal of General Virology 1997:78:307-312.

1997: Biochemical evidence for a novel low molecular weight 2-5A-dependent RNaseL in chronic fatigue syndrome. Suhadolnik RJ, Peterson DL et al.  J Interferon Cytokine Res 1997:17(7):377-385.

1998:  Enteroviral Infections and their Sequelae.  EG Dowsett. BSAEM; RCGP 1998:1-10. 

2000:  Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. DV Ablashi, DL Peterson et al. Journal of Clinical Virology 2000:16:179-191.

2001: Viral Isolation from Brain in Myalgic Encephalomyelitis (A Case Report). J Richardson. JCFS 2001:9:3/4:15-19.

2001:  Enterovirus in Chronic Fatigue Syndrome. N-T Jou et al. Arthritis & Rheumatism 2001:44:S9:S351.

2001: Prevalence in the Cerebrospinal Fluid of the Following Infectious Agents in a Cohort of 12 CFS Subjects: Human Herpes Virus-6 and 8; Chalmydia Species; Mycoplasma Species, EBV; CMV and Coxsackievirus. Susan Levine. JCFS 2002:9:1/2:41-51.

2001: Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome. Krueger GR et al. In Vivo 2001:15(6):461-465.

2001: G-Actin Cleavage Parallels 2-5A-Dependent RNase L Cleavage in Peripheral Blood Mononuclear Cells – Relevance to a Possible Serum-Based Screening Test for Dysregulations in the 2-5A Pathway.  S Roelens, P Englebienne et al. JCFS 2001:8:3/4:63-82.

2002:  Antiviral Pathway Activation in Chronic Fatigue Syndrome and Acute Infection.  Kenny De Meirleir, Robert J Suhadolnik et al.  Clinical Infectious Diseases 2002:34:1420-1421.

2002: Structural and Functional Features of the 37-kDa 2-5A-Dependent RNase L in Chronic Fatigue Syndrome.  Shetzline SE, De Meirleir K, Peterson DL et al. J Interferon Cytokine Res 2002:22(4):443-456.

2002: The Paul-Bunnell Heterophile Antibody Determinant in Epstein-Barr Virus-Associated Disease.  Roberto Patarca-Montero and Mary Ann Fletcher.  JCFS 2002:10:3/4:51-86.

2002: Ribonuclease L Proteolysis in Peripheral Blood Mononuclear Cells of Chronic Fatigue Syndrome Patients. Edith Demettre, Kenny De Meirleir, Patrick Englebienne et al.  Journal of Biological Chemistry 2002:277:38:35746-35751.

2003: Multiple co-infections (Mycoplasma, Chlamydia, HHV-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. Nicolson GL et al. APMIS 2003:111(5):557-566.

2003: Enterovirus related metabolic myopathy: a postviral fatigue syndrome.  RJM Lane, LC Archard et al. JNNP 2003:74:1382-1386.

2003: Detection of enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease in fibromyalgia and healthy subjects. Douche-Aourik F et al. Journal of Medical virology 2003:71:540-547.

2005: Assessment and Implications of Viruses in Debilitating Fatigue in CFS and MS Patients. Dharam V Ablashi et al.  HHV-6 Foundation, Santa Barbara, USA. Submission to Assembly Committee/Ways & Means, Exhibit B1-20, submitted by Annette Whittemore 1^st June 2005.

2005: The role of enterovirus in chronic fatigue syndrome.  JKS Chia. Journal of Clinical Pathology 2005:58:1126-1132.

2006: Chronic Fatigue Syndrome.  LD Devanur,  JR Kerr. Journal of Clinical Virology 2006: 37(3):139-150.

2006: Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. Ian Hickie et al. BMJ 2006: 333:575.

2006: Antiviral Pathway Deregulation of Chronic Fatigue Syndrome Induces Nitric Oxide Production in Immune Cells that Precludes a Resolution of the Inflammatory Response. Marc Fremont, Kenny De Meirleir et al.  JCFS 2006:13:4:17-28.

2006:  Is HHV-6 a trigger for chronic fatigue syndrome?  Anthony L Komaroff.  Journal of Clinical Virology 2006:37:S1:S39-S46.

2007:  Chronic Fatigue Syndrome is associated with chronic enterovirus infection of the stomach. Chia JK, Chia AY. J Clin Pathol  13^th  September 2007 Epub ahead of print.

2007: Enterovirus infection of the stomach in Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME).  Jonathan R Kerr.  Editorial. J Clin Pathol 14^th September 2007. Epub ahead of print.

2008:  5' terminal deletions in the genome of a coxsackievirus B2 strain occurred naturally in human heart. Virology 2008 Jun 5;375(2):480-91.

2009:  Human Enteroviruses and Chronic Infectious Disease.  S Tracy and NM Chapman.  Journal of IiME 2009:3:1 (http://www.investinme.org/Documents/Journals/Journal%20of%20IiME%20Vol%203%20Issue%201.pdf).