XMRV Study No. 4
- Thread starter Orla
- Start date
Hope123
Senior Member
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Thanks for posting, Orla!
Quick scan, not read yet:
- PCR used
- Blood samples from 1991-1992
-Oxford criteria used for selecting subjects.
Will read later.
Quick scan, not read yet:
- PCR used
- Blood samples from 1991-1992
-Oxford criteria used for selecting subjects.
Will read later.
Esther12
Senior Member
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- 13,774
Kind of study number 4 - assuming the Science paper counts. Alas...
Esther12
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I don't believe the cohort could explain the completely different results the WPI's been getting. Not unless they were massively more selective than they said. I wish the WPI had been more respectful of the early negative results - especially now more are coming out. There was a new Virology blog podcast which sounded unimpressed with them.
<Kind of study number 4 - assuming the Science paper counts. Alas... >
Oops, yes if the mods see this could they change to Study No. 4. ? I was going to put replication no 3 first and then realised that replication wasn't really accurate so left that word out and forgot then that this was really study no 4 then.
Orla
Edit, thanks Mods!
Oops, yes if the mods see this could they change to Study No. 4. ? I was going to put replication no 3 first and then realised that replication wasn't really accurate so left that word out and forgot then that this was really study no 4 then.
Orla
Edit, thanks Mods!
And just to really rub it in McClure and Wessely Editorial:
Editorials
Chronic fatigue syndrome and human retrovirus XMRV
Three studies now refute the original study reporting the link
http://www.bmj.com/cgi/content/extract/340/feb25_1/c1099
Editorials
Chronic fatigue syndrome and human retrovirus XMRV
Three studies now refute the original study reporting the link
http://www.bmj.com/cgi/content/extract/340/feb25_1/c1099
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- Leicestershire, England.
Oxford criteria? Oh come on. 
I guess the deciding battle will be if the CDC can replicate the findings. Should be getting news from them in the coming months I assume?
I guess the deciding battle will be if the CDC can replicate the findings. Should be getting news from them in the coming months I assume?
cfs since 1998
Senior Member
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I thought the Oxford criteria was obsolete?
Oh, it is, the patient samples were from 1991.
Oh, it is, the patient samples were from 1991.
Kati
Patient in training
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So either they didn't have tome to find brand new patient and fresh blood, or they wanted to find out the validity of the Oxford criteria, which just by the name doesn't sound really good does it?
I didn't look deeply in the details of the study, but i suspect that the problems of the study are just about the same, methodology, choice of cohort, primers and not enough DNA. I can just hear Dr Judy from far!!!!
I am not stressing out about this study. The truth will come out.
I didn't look deeply in the details of the study, but i suspect that the problems of the study are just about the same, methodology, choice of cohort, primers and not enough DNA. I can just hear Dr Judy from far!!!!
I am not stressing out about this study. The truth will come out.
Accompanying Editorial
Full text:
Published 25 February 2010, doi:10.1136/bmj.c1099
Cite this as: BMJ 2010;340:c1099
Editorials
Chronic fatigue syndrome and human retrovirus XMRV
Three studies now refute the original study reporting the link
In the linked case-control study (doi:10.1136/bmj.c1018), van Kuppeveld and colleagues describe their failure to find evidence of a new human retrovirus in Dutch patients with chronic fatigue syndrome.1 The study is the latest contribution to a controversy that has surrounded two conflicting publications on the retroviral aetiology of this syndrome.2 3
The saga started, not with chronic fatigue syndrome or a virus, but with an enzyme (RNaseL) that plays a pivotal role in antiviral defences when activated by the interferon released in response to infection. Variants of the gene encoding this enzyme have been linked to an increased susceptibility to prostate cancer, and this led to the identification of a new virus in prostate tissue that was related to, but different from, known xenotropic murine leukaemia viruses4; hence the designation xenotropic murine leukaemia virus-related virus (XMRV). Sequence analyses showed that it is not an endogenous human virus, and the fact that eight clones derived from eight different patients are slightly different from one another confirms it as a new virus that has found its way into a human population.
Abnormalities in the RNaseL gene of patients with chronic fatigue syndrome had been reported in some studies,5 but not in others.6 Nevertheless, this prompted the search for evidence of XMRV in patients with chronic fatigue syndrome. The resulting study claimed that 67% of patients with chronic fatigue syndrome were XMRV carriers, compared with 3.7% of healthy controls.2
The news was received philosophically by most retrovirologists, who are used to claims of associations between retroviruses and diseases that fail to withstand the test of time. Most researchers into chronic fatigue syndrome were also sceptical, mindful of the problems of defining the syndrome, its imprecise boundaries, and almost certain heterogeneity. It was not that they doubted a viral cause in some patients because this had already been shown,7 8 but the possibility that any single agent or risk factor could account for more than two thirds of cases seemed implausible on the basis of what has already been established.9
But if the research community was underwhelmed, people with the syndrome were not. If true, these findings would have transformed the understanding of the illness and opened up new avenues of treatment. Some saw this as a definitive response not only to those few professionals who, they claim, continue to doubt the reality of the syndrome, but also to the larger number of professionals who believe that, irrespective of causation, rehabilitative treatments can reduce symptoms and disability. It is depressing that the first, untenable, view is too often confused with the second, a perspective that offers hope to patients and is backed by evidence.
First and foremost, however, as with any discovery, the data must be unequivocal, and the finding has to be confirmed by others. In January 2010, our own group found no evidence of XMRV in a well characterised cohort of 186 patients with chronic fatigue syndrome in the United Kingdom.3 Van Kuppeveld and colleagues study adds to this negative evidence. Although the study is small, the patients are well defined and matched in age, sex, and geographical location. The polymerase chain reaction used to amplify XMRV gene sequences has been well controlled and its sensitivity is sufficient to detect low virus copy numbers. XMRV was not detected in this Dutch cohort, a result that comes in the wake of a third study published this month,10 which also failed to identify XMRV in 170 patients with chronic fatigue syndrome.
There has been much talk of different protocols being used in the four studies. These technical differences are irrelevant provided amplification is controlled by inclusion of a "housekeeping gene"to show that a known human gene can be amplified under the conditions usedand the sensitivity of the assay is known, as was the case in all three European studies.
Meanwhile, a different strategy is also being considered to reconcile these different findings: that new blood samples should be taken from patients with diagnosed chronic fatigue syndrome and sent to laboratories capable of carrying out the analysis. This is unlikely to be soon.
Three studies have now generated data that are in stark contrast to those of the original study. However, at least two explanations for this are still possible. The first, and more unlikely, explanation is that XMRV infection is geographically confined to the United States. The second is that the virus is infecting an atypical cohort. This may well be so. Although the patients were not well described in the original study, van Kuppeveld and colleagues provide the additional information reported at a conference last year that the patients in question came from an outbreak of chronic fatigue syndrome at Incline village on the northern border of Lake Tahoe in the mid-1980s. Whether or not this was a genuine cluster was never established,11 but an association with viruses, such as Epstein-Barr virus and human herpesvirus 6, has already been suggested.12 It is possible that XMRV is implicated in the Lake Tahoe episode but does not play a substantial role in
most cases of chronic fatigue syndrome elsewhere.
The results from other US laboratories investigating XMRV and chronic fatigue syndrome are eagerly awaited. If the link fails to hold up, it will be another bitter disappointment to affected patients. Nonetheless, the current debate will still bring critical attention to the causes of chronic fatigue syndrome, and XMRV may turn out to be important in the pathogenesis of other diseases.
Cite this as: BMJ 2010;340:c1099
Myra McClure, professor of retrovirology and honorary consultant in genitourinary medicine1, Simon Wessely, professor of psychological medicine2
1 Jefferiss Research Trust Laboratories, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, London W2 1PG, 2 Institute of Psychiatry, Kings College London, London SE5 8AF
m.mcclure@imperial.ac.uk
Research, doi:10.1136/bmj.c1018
References
Van Kuppeveld FJM, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJG, Swanink CMA, 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:c1018.[Abstract/Free Full Text]
Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009;326:585-9.[Abstract/Free Full Text]
Erlwein O, Kaye S, McClure MO, Weber J, Willis G, Collier D, et al. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One 2010;5:e8519.[CrossRef][Medline]
Urisman A, Molinaro RJ, Fisher N, Plummer SJ, Casey G, Klein EA, et al. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog 2006;2:211-25.[Web of Science]
Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis 1994;18(suppl 1):S96-104.[Web of Science][Medline]
Gow J, Simpson K, Behan P, Chaudhuri A, McKay I, Behan W. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Clin Infect Dis 2001;33:2080-1.[CrossRef][Web of Science][Medline]
White PD, Thomas JM, Kangro HO, Bruce-Jones WDA, Amess J, Crawford DH, et al. Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet 2001;358:1946-54.[CrossRef][Web of Science][Medline]
Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ 2006;333:575-8.[Abstract/Free Full Text]
Hempel S, Chambers D, Bagnall A, Forbes C. Risk factors for chronic fatigue syndrome/myaglic encephalomyelitis: a systematic scoping review of multiple predictor studies. Psychol Med 2008;38:915-26.[Web of Science][Medline]
Groom HCT, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, et al. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 2010 Published online 15 February.
Holmes G, Kaplan J, Stewart J, Hunt B, Pinsky PF, Schonberger LB. A cluster of patients with a chronic mononucleosis-like syndrome: is Epstein-Barr virus the cause? JAMA 1987;257:2297-303.[Abstract/Free Full Text]
Buchwald D, Cheney P.Petersen D, Henry B, Wormsley SB, Geiger A, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpes type 6 infection. Ann Intern Med 1992;116:103-16.[Abstract/Free Full Text]
Full text:
Published 25 February 2010, doi:10.1136/bmj.c1099
Cite this as: BMJ 2010;340:c1099
Editorials
Chronic fatigue syndrome and human retrovirus XMRV
Three studies now refute the original study reporting the link
In the linked case-control study (doi:10.1136/bmj.c1018), van Kuppeveld and colleagues describe their failure to find evidence of a new human retrovirus in Dutch patients with chronic fatigue syndrome.1 The study is the latest contribution to a controversy that has surrounded two conflicting publications on the retroviral aetiology of this syndrome.2 3
The saga started, not with chronic fatigue syndrome or a virus, but with an enzyme (RNaseL) that plays a pivotal role in antiviral defences when activated by the interferon released in response to infection. Variants of the gene encoding this enzyme have been linked to an increased susceptibility to prostate cancer, and this led to the identification of a new virus in prostate tissue that was related to, but different from, known xenotropic murine leukaemia viruses4; hence the designation xenotropic murine leukaemia virus-related virus (XMRV). Sequence analyses showed that it is not an endogenous human virus, and the fact that eight clones derived from eight different patients are slightly different from one another confirms it as a new virus that has found its way into a human population.
Abnormalities in the RNaseL gene of patients with chronic fatigue syndrome had been reported in some studies,5 but not in others.6 Nevertheless, this prompted the search for evidence of XMRV in patients with chronic fatigue syndrome. The resulting study claimed that 67% of patients with chronic fatigue syndrome were XMRV carriers, compared with 3.7% of healthy controls.2
The news was received philosophically by most retrovirologists, who are used to claims of associations between retroviruses and diseases that fail to withstand the test of time. Most researchers into chronic fatigue syndrome were also sceptical, mindful of the problems of defining the syndrome, its imprecise boundaries, and almost certain heterogeneity. It was not that they doubted a viral cause in some patients because this had already been shown,7 8 but the possibility that any single agent or risk factor could account for more than two thirds of cases seemed implausible on the basis of what has already been established.9
But if the research community was underwhelmed, people with the syndrome were not. If true, these findings would have transformed the understanding of the illness and opened up new avenues of treatment. Some saw this as a definitive response not only to those few professionals who, they claim, continue to doubt the reality of the syndrome, but also to the larger number of professionals who believe that, irrespective of causation, rehabilitative treatments can reduce symptoms and disability. It is depressing that the first, untenable, view is too often confused with the second, a perspective that offers hope to patients and is backed by evidence.
First and foremost, however, as with any discovery, the data must be unequivocal, and the finding has to be confirmed by others. In January 2010, our own group found no evidence of XMRV in a well characterised cohort of 186 patients with chronic fatigue syndrome in the United Kingdom.3 Van Kuppeveld and colleagues study adds to this negative evidence. Although the study is small, the patients are well defined and matched in age, sex, and geographical location. The polymerase chain reaction used to amplify XMRV gene sequences has been well controlled and its sensitivity is sufficient to detect low virus copy numbers. XMRV was not detected in this Dutch cohort, a result that comes in the wake of a third study published this month,10 which also failed to identify XMRV in 170 patients with chronic fatigue syndrome.
There has been much talk of different protocols being used in the four studies. These technical differences are irrelevant provided amplification is controlled by inclusion of a "housekeeping gene"to show that a known human gene can be amplified under the conditions usedand the sensitivity of the assay is known, as was the case in all three European studies.
Meanwhile, a different strategy is also being considered to reconcile these different findings: that new blood samples should be taken from patients with diagnosed chronic fatigue syndrome and sent to laboratories capable of carrying out the analysis. This is unlikely to be soon.
Three studies have now generated data that are in stark contrast to those of the original study. However, at least two explanations for this are still possible. The first, and more unlikely, explanation is that XMRV infection is geographically confined to the United States. The second is that the virus is infecting an atypical cohort. This may well be so. Although the patients were not well described in the original study, van Kuppeveld and colleagues provide the additional information reported at a conference last year that the patients in question came from an outbreak of chronic fatigue syndrome at Incline village on the northern border of Lake Tahoe in the mid-1980s. Whether or not this was a genuine cluster was never established,11 but an association with viruses, such as Epstein-Barr virus and human herpesvirus 6, has already been suggested.12 It is possible that XMRV is implicated in the Lake Tahoe episode but does not play a substantial role in
most cases of chronic fatigue syndrome elsewhere.
The results from other US laboratories investigating XMRV and chronic fatigue syndrome are eagerly awaited. If the link fails to hold up, it will be another bitter disappointment to affected patients. Nonetheless, the current debate will still bring critical attention to the causes of chronic fatigue syndrome, and XMRV may turn out to be important in the pathogenesis of other diseases.
Cite this as: BMJ 2010;340:c1099
Myra McClure, professor of retrovirology and honorary consultant in genitourinary medicine1, Simon Wessely, professor of psychological medicine2
1 Jefferiss Research Trust Laboratories, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, London W2 1PG, 2 Institute of Psychiatry, Kings College London, London SE5 8AF
m.mcclure@imperial.ac.uk
Research, doi:10.1136/bmj.c1018
References
Van Kuppeveld FJM, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJG, Swanink CMA, 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:c1018.[Abstract/Free Full Text]
Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009;326:585-9.[Abstract/Free Full Text]
Erlwein O, Kaye S, McClure MO, Weber J, Willis G, Collier D, et al. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One 2010;5:e8519.[CrossRef][Medline]
Urisman A, Molinaro RJ, Fisher N, Plummer SJ, Casey G, Klein EA, et al. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog 2006;2:211-25.[Web of Science]
Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis 1994;18(suppl 1):S96-104.[Web of Science][Medline]
Gow J, Simpson K, Behan P, Chaudhuri A, McKay I, Behan W. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Clin Infect Dis 2001;33:2080-1.[CrossRef][Web of Science][Medline]
White PD, Thomas JM, Kangro HO, Bruce-Jones WDA, Amess J, Crawford DH, et al. Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet 2001;358:1946-54.[CrossRef][Web of Science][Medline]
Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ 2006;333:575-8.[Abstract/Free Full Text]
Hempel S, Chambers D, Bagnall A, Forbes C. Risk factors for chronic fatigue syndrome/myaglic encephalomyelitis: a systematic scoping review of multiple predictor studies. Psychol Med 2008;38:915-26.[Web of Science][Medline]
Groom HCT, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, et al. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 2010 Published online 15 February.
Holmes G, Kaplan J, Stewart J, Hunt B, Pinsky PF, Schonberger LB. A cluster of patients with a chronic mononucleosis-like syndrome: is Epstein-Barr virus the cause? JAMA 1987;257:2297-303.[Abstract/Free Full Text]
Buchwald D, Cheney P.Petersen D, Henry B, Wormsley SB, Geiger A, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpes type 6 infection. Ann Intern Med 1992;116:103-16.[Abstract/Free Full Text]
naive questions:
why are these organizations wasting precious time, money and resources doing these subpar studies? is this normal in the world of science?
listening to coffin (love him!!!) and hoff interviews: XMRV does in fact exist...so how can these studies be finding none.
sorta quoting coffin re: xmrv research today: it's confusing and frustrating but at the same time very exciting.
he paralleled the research being done on xmrv today to that done on hiv in the 80's...very messy...hope it doesn't take 30 years to sort it out.
why are these organizations wasting precious time, money and resources doing these subpar studies? is this normal in the world of science?
listening to coffin (love him!!!) and hoff interviews: XMRV does in fact exist...so how can these studies be finding none.
sorta quoting coffin re: xmrv research today: it's confusing and frustrating but at the same time very exciting.
he paralleled the research being done on xmrv today to that done on hiv in the 80's...very messy...hope it doesn't take 30 years to sort it out.
Esther12
Senior Member
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- 13,774
Fair editorial from Wessely. He's good at coming accross as reasonable when he wants to. Slippery for those who know his past papers, but to most readers it's going to make patients attacking him seem unfair.
cfs since 1998
Senior Member
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I don't think it will. From what Mikovits has told us it seems like at least the drug companies are convinced and still willing to invest in anti-XMRV CFS drugs. If we have successful clinical drug trials these lame replication attempts won't matter. Just like HAART shut up most of the AIDS denialists.
another question: will they start clinical trials if the wpi study can't be replicated and/or validated?
can you extrapolate on what you mean by "just how HAART shut up AIDs denialist? they didn't start up clinical trials until until they had validation/replication of HIV, right?
thanks, lisa
cfs since 1998
Senior Member
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I think they will. You don't need to know the cause of a disease or even the mechanism of action of that drug to do a trial. There are many FDA approved drugs for diseases for which the cause is unknown and fo which the mechanisms of action of the drug is also unknown. I think WPI could raise enough money to fund their own trials if they had to, but it looks like drug companies are already cooperating.
I can't elaborate that much because I was just a kid when the epidemic started, but my understanding is that it wasn't until HAART brought back people from the brink of death before the "HIV causes AIDS" theory was really fully accepted.lisag said:
rebecca1995
Apple, anyone?
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- Northeastern US
Yawn
Wake me up when someone finally does a decent replication study. This one looks like another waste of resources.
Also, this statement--attributed to van Kuppeveld et al in the editorial--is patently false:
Dr. Mikovits said in the ProHealth talk that the cohort of 101 in the Science article came from at least a dozen US states and several foreign countries.
Wake me up when someone finally does a decent replication study. This one looks like another waste of resources.
Also, this statement--attributed to van Kuppeveld et al in the editorial--is patently false:
Dr. Mikovits said in the ProHealth talk that the cohort of 101 in the Science article came from at least a dozen US states and several foreign countries.