A paper that reported finding retroviral sequences in blood from patients with chronic fatigue syndrome (CFS) has been retracted by the authors. Just four days ago the 2009 Science report of Lombardi and colleagues was editorially retracted. As 2011 comes to an end, so does the hypothesis that retroviruses are etiologic agents of CFS.
Readers of virology blog know that in 2009 Lombardi et al. published a Science report indicating they had detected the new retrovirus XMRV €“ first detected a few years earlier in prostate tumors €“ in the blood of a high proportion of patients with chronic fatigue syndrome. Many other laboratories attempted to reproduce this finding, but none were successful.
The next year Alter and colleagues reported finding retroviral sequences in the blood of a substantial number of CFS patients. No viruses were isolated in the Alter study; viral sequences were obtained by polymerase chain reaction (PCR). The viral sequences were not XMRV, but were closely related to endogenous retroviruses of mice called polytropic murine leukemia viruses. (Polytropic means the viruses can infect many species, including mice; xenotropic means that the viruses, though originating in mice, only infect non-mouse species).
The Lo-Alter finding was viewed by many (including myself) as supporting the findings of Lombardi et al., but upon closer inspection it became apparent that they only clouded the situation. The viral sequences reported in the Alter study were not XMRV, and it was not clear why CFS would be caused by such a diverse range of viruses. A second report in 2011 reported MLV-like sequences in a CFS cohort but many other studies failed to find any kind of retrovirus in the blood of CFS patients.
Earlier this year it became clear that XMRV is a laboratory-generated recombinant murine retrovirus: it arose during the passage of a prostate tumor in nude mice in the early 1990s. This finding made it highly unlikely that the virus could be associated with human disease. Lombardi and colleagues then retracted part of the 2009 Science paper that reported viral nucleic acid sequence; they noted that their samples were contaminated with XMRV plasmids. What remained of the paper were serological and virus culture experiments that were not specific for XMRV. Last week the remainder of this paper was editorially retracted by Science.
That left the Lo-Alter findings. The first warning came from the observation made by several laboratories that reagents used to carry out PCR are often contaminated with mouse DNA (an example is Singh’s study). The presence of this adventitious DNA can lead to detection of MLV-like sequences that resemble those found in the Lo-Alter study. The implication was clear: the Lo-Alter findings were wrong, a result of contamination of PCR reagents with mouse DNA.
More doubt came from a report of the Blood XMRV Scientific Working Group, which was assembled to determine if XMRV constituted a threat to the blood supply. In this study, sets of coded samples previously shown to be XMRV positive, as well as samples from healthy controls, were blinded and provided to 9 laboratories for analysis by PCR, virus culture, and serology. Two laboratories reported evidence of XMRV in the coded samples. Only the Whittemore-Peterson Institute identified positive specimens by PCR: two from negative controls, and one from a CFS patient. The Lo laboratory did not detect any positives by PCR, using the same nested assay that they had previously reported in their PNAS paper. The samples tested included 5 specimens that were positive in the Lo-Alter study.
The retraction of the Lo-Alter PNAS paper curiously begins with the assertion that the authors could not detect contaminating mouse DNA in their samples €“ which was most certainly present and lead to their detection of MLV-like sequences.
Although our published findings were reproducible in our laboratory and while there has been no evidence of contamination using sensitive mouse mitochondrial DNA or IAP assays or in testing coded panels…
This failure remains puzzling and unexplained; but as they report in the next paragraph, they appear to have run out of material to distribute to other laboratories for ‘independent confirmation’.
The authors provide three additional reasons why they are retracting this paper. They note that no one has been able to reproduce their findings, including the Blood XMRV Scientific Working Group. They have not been able to find (along with collaborators) anti-XMRV antibody, XMRV virions, or viral integration sites in patient samples. Finally, they mention their finding from the PNAS paper that a second set of samples taken 15 years later from the same CFS patients also were positive for MLV-like viruses. Phylogenetic analyses revealed that these sequences were clearly not descendants of the original strains. The sequence data used to make this conclusion were available for the PNAS publication, so it is not clear why this evolutionary incompatibility was not noted previously.
The authors conclude:
…in consideration of the aggregate data from our own laboratory and that of others, it is our current view that the association of murine gamma retroviruses with CFS has not withstood the test of time or of independent verification and that this association is now tenuous. Therefore, we retract the conclusions in our article.
The retraction of the Lombardi et al and Lo-Alter papers erases the published evidence suggesting involvement of a retrovirus with CFS. While it is theoretically possible that CFS has a viral origin, at the moment there are no data in support of a specific viral etiology. Some have suggested that gammaretroviruses related to XMRV might be involved in CFS. But I don’t see how a lab contaminant can point you in the direction of a bona fide etiologic agent. Contaminants cloud our vision, they do not improve it.
In light of these developments, the ongoing Lipkin study (sponsored by the National Institute of Allergy and Infectious Diseases, involving analysis of a coded panel of samples from 150 well-characterized and geographically diverse CFS patients and controls) seems less compelling. Many laboratories have failed to find any retrovirus in CFS patients, and the two papers central to this hypothesis have been retracted. Will results from one laboratory clear the matter up further? Whatever the Lipkin study finds, it will have to be validated by others – because we trust science, not scientists.
Update: The retraction has been published at PNAS.
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Thanks Professor
Two papers find PMRVs. Mikovits and Ruscetti did not retract and Lo and Alter stand by the integrity of the data. There has been no contamination found in their samples or flaws in their methods.
Is this really the best you can do for the human race Dr Racaniello? You know the other labs failed to clinically validate their assays and looked for VP62 instead of the viruses discovered.
This whole saga so far has destroyed many people faith i the field. There are plenty of good scientists, honest decent and caring, but how can they operate in a world controlled by a powerful few with a political agenda. I really feel sorry for you all. The viruses are going nowhere and you can now watch as more are infected and become sick. Maybe your loved ones will escape of the next 100 years, maybe not.
Lo’s group used the wrong assay from Lo et al.
XMRV was not shown to be born in the cell line 22rv1
All the ME positive labs found PMRVs not XMRV
The Lipkin study is one paper and should not be a substitute for the truth. You cannot set a study up as definitive, but should seek answers. The NIH must not trust the design of that study or they would have published how they have set it up on their website before commencing with testing.
Knowing the viruses are PMRVs and always using the VP62/XMRV excuse the study should not allow any lab to use that to optimise their assay to. Only clinical positives should be used.
The controls can also not be contact controls as it will mess with the results and PBMCs must be pre-screened also to ensure controls are really negative. This did not occur in the infamous 14 patient blood study that annouced to the world that people are safe. If only!
Seems to me that all papers linking XMRV to any disease should be retracted, e.g. the prostate cancer papers were this all started…
Apparently you know more than all the scientists that actually conducted and attempted to duplicate this research. Why don’t YOU write a paper and submit it for publication and peer review? Until then, quit spewing more misinformation.Â
How about you pay attention to the evidence instead. It was not replicated, shown to be contamination or cross contamination or an error. It’s sad. Really sad to see science die. Don’t bother pretending with patients they don’t deserve it and you know they don’t.
That was XMRV/VP42 not PMRVs
I think patients deserve concrete and accurate answers to the causation of their illness. Answers that are substantiated and upheld by the world’s scientific and medical community. This particular virus hunt is not it!
Science is never concrete, it is on balance of evidence. Negative papers using novel assays that are not clinically validated and fail to replicate proven methodology never ever means a hunt for answers is over. The viruses are polytropic not xenotropic.
Just for the record: “Hone-5kl” is another sock-puppet and not representing ME/CFS patients. Because if he were on the side of ME/CFS patients, he would take all his genius knowledge, help his best buddy Dr. Mikovits and solve the disease single-handedly – which he does not do.
So tell me, “Hone-5kl”, why don’t you help your friend Dr. Mikovits? Why do you let her run into the open knife with the Lipkin study?
And oh, by the way: “Hone-5kl”, you are slandering ALL of retrovirology as either to dumb to cross the street or you slander them as vicious bastards because “They KNOW the Truthz!!!1!11!©™” yet hide they hide the truth. But you do not supply any piece of evidence for your slander. Not. One. Single. Piece. Of. Evidence. Nothing. Nada. Just slander. Do you think anybody will believe you? Really?
And while we are at it: I tried to discuss this with you at the mecfsforums, but you rather banned me there. You actively refuse to acknowledge divergenting evidence. You rather believe in made-up proof that only exists in your head. I know, it is hard to hear such criticism and you wish know you could silence me here too. Tough luck censoring me here though.
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“Lo’s group used the wrong assay from Lo et al.”Explain “wrong assay”.”XMRV was not shown to be born in the cell line 22rv1″Sorry, but you sound like a birther.”All the ME positive labs found PMRVs not XMRV”
But it said XMRV in the title of the paper. It isn’t XMRV? Oh my, why didn’t you tell us earlier? And why the f*ck didn’t you post gene-sequences? This isn’t the Eighties after all, you know.”The Lipkin study is one paper and should not be a substitute for the truth.”
I know, for you, only the Mikovits paper is the truth. And everything she says, of course. And their disciples blog. Plus all the knowledge that exists solely in your head and refuses to be published.
” You cannot set a study up as definitive, but should seek answers.”
These are not the robots you are looking for. So certain are you. Always with you it cannot be done. Hear you nothing that I say?
“The NIH must not trust the design of that study or they would have published how they have set it up on their website before commencing with testing.”
Sorry, parsing that sentence failed.
“Knowing the viruses are PMRVs and always using the VP62/XMRV excuse the study should not allow any lab to use that to optimise their assay to.” That sentence does not make sense. Please try again.”Only clinical positives should be used.”You do understand what you talk about? I mean, the general topic? Of finding a novel virus? Yes? No? Maybe?
“The controls can also not be contact controls as it will mess with the results and PBMCs must be pre-screened also to ensure controls are really negative.”Â
And I am really the walrus.
“This did not occur in the infamous 14 patient blood study that annouced to the world that people are safe. If only!”
Yeah! If only! Because are they safe? Are they safe? Are they safe?Â
Provide evidence for your slander of retrovirologists or STFU.
If lipkin finds it why should I believe him!
I cannot believe you said that.
I think Hone-5kl is probably the same person who used to post as Gob987 and later as sciencewatcher. They are a troll and can safely be ignored. Certainly they follow the same arguing strategy. Given how much they have read (and probably written) I would say they are most unlikely to have CFS and they obviously don’t represent the CFS community. All this nonsense about clinical validation -the logic is completely on its head!
This arguement appears to be drifting quite a bit. First, it was definitely XMRV. Then related viruses. Now other infectious agents. The list you have given above is pretty correct, but argues against an infectious cause. Rather it suggests a common response to any illness. I have myself seen and diagnosed patients with CFS after a wide variety of serious illnesses, but some have an identical presentation and illness after other forms of stress too, or even after no particular stress.
Incidentally none of the agents you list (with the possible exception of M. Fermentans) are strict opportunists – they frequently cause illness in the immunocompetent.
So the statement that there is no evidence of any association of any virus with CFS is true – in as much as there is not reliable suggestion of a distinct viral cause that might be amenable to treatment. Instead the suggestion is of a clinical syndrome which can follow any one of a number of medical illnesses, or no medical illness, and may be psychological, or may not be; or may arise as a combination of different factors. There is certainly no evidence of a retroviral CAUSE of CFS at the present time.
I agree with you, but people without any medical knowledge are reading these comments as if they were true. So even though you shouldn’t “feed the troll”, I’m glad people use their time to show other readers how far of the truth some of their arguments are.
Lance the only viruses found were PMRVs. No one knew Silverman messed up.
Lance have a blod transfusion from a patient with neurological ME and let’s see if you get sick.
You seem to have a very strange definition of “clinically validated”.
Just explain one thing to me and everybody else here.. how do Mikovits and/or Ruscetti know for 100% sure their assay is capable of detecting a genuine (novel) human virus (aka no contamination) in the blood of a CFS patient? P or X or whatever, I don’t even care. What’s their reference test?
Tony they didn’t use the assays from Lo et al that identified positive ME patients.
Nothing was born in 22Rv1 – you haven’t read one paper on this.
It was called XMRV because of Silverman data which was incorrect. What was sequenced by the other two retrovirologists is polytropic. The sequences are all in the genbank if you had any interest in looking.
Lombardi and Lo both found PMRV. The negative studies only looked for VP62/XMRV, which is Silvermans incorrect data.
Multiple labs should try to replicate. Always with them they refuse to follow the scientific method. The only other step is clinically validation of novel assays. You do understand this is a virus they know little about and there may be only a handful of assays that can detect them in blood. Instead they should try tissue where gamma retroviruses do propagate.
Tony you sound like you can’t take it anymore.
I’m glad the public is not stupid and does recognise that scientists get sick too.
Duplicated??
No study has attempted to replicate the proven methodology of either paper that found PMRVs. The finding are confirmed by the two papers.
Tony you are another person ignoring the evidence and presenting no argument.
Are you referring to studies not using clinically validated assays?
They used the clinically validated assay from Urisman and adjusted it for blood. They the sequenced a section of what they isolated and found polytropic sequences. They are used an antibody to prove there is an immune response to a MLV virus, that is also impossible to be to an ERV. Furthermore they produced an EM of a virion budding from a human cell and maturing.
There is no disease called CFS. You must be anti-ME and anti any other disease that gets dragged into that fatigue basket.
Lance is you name Mark?
In my view the CDC paper should not have been published without a proper positive control, eg. patient samples known to contain XMRV. If I had reviewed the CDC paper that’s what I would have asked for.
That would also apply to every 00 paper.
I would happily have one safe in the knowledge that I was at no greater risk of getting sick than if I had a transfusion from someone wtihout CFS. (Not that I would be happy to need a blood transfusion in the first place, mind.)
No, my name is Lance.
What a load of nonsense.
So lets appy that logic to my new hypothesis: cornflakes cause headaches. Because you can’t investigate my hypothesis using a validated positive control, i.e. a population that have cornflakes induced headache, therefor my hypothesis must be true. By your logic, as soon as an idea pops into your head it must be true. See how what you have written is wrong?
And no this isn’t just an anti-XMRV arguement – just put oligoadenylate synthetase and west nile virus into pubmed. You’ll see the same thing – initial apparently very certain finding which later can’t be repeated and turns out to be false.
And no I’m not anti any disease – I’m anti people who despite not having the condition latch onto something and post reams of rubbish. You’re getting the hopes up of people who might be ill and not have the energy to read through all the amazing waste of bytes that you write, which contains not a shred of reliable information, and is clear as day written by someone with neither scientific nor medical training. Get out of the way and let genuine sufferers of this condition debate the evidence and move forward rather than wasting time on you and your nonsense “more disproven than anything else in science” theories.
Lance,
You refer to “no evidence for a retroviral CAUSE of CFS. Aren’t
you setting up a strawman as neither the Lombardi nor the Lo papers posited more than an association?
Also, you state that ” there is no(t) reliable suggestion of a distinct viral cause that might be amenable to treatment.”
Have you listened to the panel featuring Dr. Montoya where he describes
the great difficulty that he has had in getting his recent Valcyte study
published
(http://voicesfromtheshadowsfilm.co.uk/mill-valley-discussion/)?
As a patient who has had a significant response to Valcyte, I would
suggest for the good of those you are treating you keep an open mind
about the potential clinical utility of anti-virals as well as the
implications of their efficacy.
Lastly, a few questions for Dr. Racaniello,
You wrote ” it was not clear why CFS would be caused by such a diverse range of viruses.” Please correct me if I’m wrong but I don’t recall anything in the Lombardi or Lo papers about causation.
And why the need to retract an article where the authors could not find flaws in their methodology nor evidence of contamination? Wouldn’t it have been better to have simply let the retroviral hypothesis die a natural death (if that was where this was headed)?
Finally, do you think that the XMRV prostate cancer papers should all be retracted and if not, why not?Â
How this is being handled seems to be more politically driven than science based.
Link to panel discussion with Dr. Montoya: http:\voicesfromtheshadowsfilm.co.uk/mill-valley-discussion/
Why would any scientist expect that they could replicate the results of a study, when they did not replicate the quantitative values of the independent variables that produced the original results? Â No research group has even attempted to replicate the independent variables used by Lombardi et al or Lo et al.We now have the sorry situation, Â of papers being retracted because other groups have not attempted to replicate the methodology used to produce the original results.
There is something of a contradiction here – if a virus is not the cause of CFS then why would treating it make any difference? Anyway there is now no association between any retrovirus and CFS, and no association with any one agent or group of agents. Rather there are links with many different things making direct causative connection unlikely. To suddenly deny that everyone was thinking of viral causation of CFS I feel is misleading. Look at all the people taking anti retrovirals for example. Yes, in papers you have to be careful about your conclusions but the WPI were much less retiring on their website at the time as I remember.
I searched pubmed for all Montoya’s papers and I can only find one article on chronic fatigue which is a report of 12 patients given valcyte (valganciclovir). There was no control group. This is very poor evidence for the use of this drug in CFS and it has significant side effects. “First, do no harm.” Your own response, whilst interesting and meriting further investigation, is not conclusive from a single individual. Why Montoya’s double blind placebo controlled trial has not been published I do not know but there are several small trials of therapies in CFS in the literature so there would seem to be no bar to publishing for other researchers.
My own view is that the prostate cancer papers should also be retracted.
That this is politically driven is, to borrow from Karl Popper, a poor hypothesis as it is not disprovable. To me this seems most unlikely. There is nothing I personally want more than an effective antiviral (or any other intervention) for this terrible condition.
Shane i am very pleased that you are better, even if I have a different view of the reasons. I wish you a complete recovery.
You are conveniently ignoring the fact that both Mikovikts and Lo’s labs could not even replicate their own results! What is sorry is that you continue to believe in this despite such overwhelming contrary evidence.
“I searched pubmed for all Montoya’s papers and I can only find one
article on chronic fatigue which is a report of 12 patients given
valcyte (valganciclovir).”
Did you watch the panel discussion?
As for the dictum “First, do no harm,” standing aside and doing nothing has lead to great harm to many patients.
The disparate treatment of CFS studies (this hypothesis must be dragged into the public square and have the life beaten out of it) say, as compared to the prostate studies does raise questions.
Simon Wessley is fond of stating that CFS patients are responsible for chasing scientists from away from studying CFS. I’d say that the PNAS and other journals are doing a fine job all by themselves. If someone of Dr. Alter’s stature can appear to be pressured into retracting a study or if Dr. Montoya struggles to get anything with CFS on it published when his ‘toxo’ studies get published with no resistance, then what chance does someone starting a career have and why on earth would they get involved in studying “CFS?”
What would you know of the reasons? You’ve dismissed them with literally no information about me other than that I claim to have “responded” to Valcyte. You nothing of my symptoms or my response.
Are you a clinician or psychic?
A panel discussion is not cinical evidence of the validity of a treatment. The “something is better than nothing” argument may seem appealing, but all you have to do is talk to someone who has been greatly harmed by a medical intervention. It is not responsible to prescribe toxic drugs without a reasonable basis for their use.
I cannot comment on Dr Montoya’s difficulty in publishing save to point out that he mentioned three articles in the panel discussion, with the one on pubmed from 2006 that makes four in total. He has about 58 publications, most of these are on toxo. So he has submitted a great many more articles on toxo than on CFS.
The inactivity in research on CFS is another matter altogether. My own view is that efforts should be devoted towards a diagnostic marker of some kind as the main problem with CFS research at the moment is the lack of certainty that you are always studying the same group of patients, or even the same disease. This may be the reason for Dr Montoya’s difficulty to publish. I can see why people do not want to pursue research into CFS. I myself am an academic studying viruses that infect the nervous system and I don’t think I would enter the field, as much as I feel for patients with the condition. The reasons for this are many fold, and include: difficulty defining what the disorder is, contradictory findings in the literature making it very hard to think of good research ideas, the lack of any obvious pathological abnormality making hard to know where to start, the possibility of many many causes requiring massive study sample sizes and hostility from some quarters of you don’t find the “virus of the week” or whatever you’re meant to find.
I think Alter saw the writing on the wall. And don’t forget his lab was unable to replicate their own findings, as was the Mikovits lab, in the blood working group study. I am unconvinced by people shouting “conspiracy!” louder and louder as the evidence for the presence of any of this group of murine derived retroviruses gets weaker and weaker. There seem to be people out there who simply cannot acknowledge that this finding might simply be wrong.
Well you’re posting on a thread that is discussing viruses and CFS, among other things. This implies that you had been treated with valcyte for CFS/ME. If that is the case then I would argue there is insufficient basis for saying the it was definitely the valcyte that made you better because CFS is characterised by a rather variable course and this treatment has not been conclusively shown to work. If that’s not the case then tell us of your symptoms and your response. In any case I am pleased if you are feel better, as you implied, and I think the reasons are much less important.
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Post your e-mail address and I’ll share some of my my with you.
Lance,
There are multiple issues here:
1. Too many definitions, not enough biomarkers
Â
2. Multiple studies that are underpowered; the assumption that viruses can only be found in the sera and/or waiting six months or longer to look for viruses; failure to recognize that multiple pathogens can cause the same disease; failure to subgroup accurately; assays used that were state of the art thirty years ago;Â
3. It could be the ME/CFS is a uncommon reaction to common pathogens. It is quite likely that ME/CFS is a grouping of disparate diseases grouped together for convenience. Â Immune system abnormalities are well documented in subgroups – obvious it is more than just a virus at work because then everyone infected with that virus or viruses would contract ME/CFS. Â
4. Lots of possibilities, very little money.Â
Better to start fresh as Dr. Lipkin is doing with the 200 well-characterized patients in his metagenomics study using next generation sequencing. Will it yield all the answers? Probably not. Will it yield some? Possibly.Â
Hone-5kl apparently thinks you are me (RRM). She’s been calling me Mark over at Jamie’s blog, probably as some sort of intimidation method (“I know who you are”).Â
It’s really a classic case of self-projection: because she uses multiple socket puppets herself, she assumes others would also stoop so low. As I’ve said multiple times, I’ve always posted under my RRM handle on this subject.Â
I am glad to see that you are finally backtracking, from “they couldn’t identify positives” to “they couldn’t identify positive patients”.
Problem is that that authors did report that they also found PATIENT SAMPLES positve using the BWG reported primer set. Instead of just looking at the pretty pictures, you have to also check the text:
“All of the positive PCR products
amplified from the patients’ blood samples using primer set GAGI-
F/GAG-I-R and primer set NP116/NP117 were 413 and 380 bp
in length, respectively.”
Thus, although the shown gel and the genbank sequences were obtained using the NP116/NP117 primer set, they did identify positive patients using the BWG primers according to their paper.
Lance, I agree with you in the sense that there is no potential cause (including possible viruses) for which there is a good clear body of evidence (for it being a cause). I am just taking issue with the fact that the statements I quoted are false. There are plenty of viruses associated with ME and it is still possible that some retrovirus(es) cause ME.Â
I think we ME patients are all just sick of the overstepping of evidence by scientists and reporters every time we turn around. Prof. Racaniello knows better than to state things so sloppily. The aggregate of all these misstatements of fact is that it compounds the damage done by the full-on lies by the real charlatans at CDC, NIH, the UK govt and the Wessely school, thus causing iatrogenic morbidity in ME patients. This is unacceptable, period.
So, you are a clinician with CFS patients and an academic researcher?
btw, I would listen to Mr. Carlson, he knows what he’s talking about.
I thought there was pretty good evidence that antivirals help reduce morbidity in ME.
Let me assure you, there is certainly a strong bias against bona fide ME research, including publishing. For example, it took Prof. Komaroff five years from first submission to publish his landmark ME paper (the most rigorous ME paper ever, imo). While Wessely and other charlatans are free to routinely lie in journals without being questioned, except by patients.
Perhaps turning the focus to the immune response to infection – possibly of viral origin – would bring more enlightenment. There are likely diverse initiators, but the common denominator is probably the response to the insult that brings on the symptoms of CFS.