Origin of XMRV and its Demise as a Human Pathogen Associated with CFS

[Jemal]

Origin of XMRV and its Demise as a Human Pathogen Associated with Chronic Fatigue Syndrome
Oliver Hohn and Norbert Bannert *
Center for HIV and Retrovirology, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany
* Author to whom correspondence should be addressed.
Received: 23 June 2011; in revised form: 4 July 2011 / Accepted: 14 July 2011 / Published: 27 July 2011
(This article belongs to the Section Commentaries)

In summary, taking all data and the many negative studies into account, there is little to support the idea that XMRV is a retrovirus infecting humans and that it has clinical relevance for prostate cancer or CFS. It transpires that XMRV is not a new human tumor virus after all, but rather the latest example of a rumor virus.

http://www.mdpi.com/1999-4915/3/8/1312/

 

[alex3619]

Possibly or Certainly?

"Furthermore, Paprotka et als identification of XMRVs origin and the phylogenetic analysis of known XMRV sequences are further nails in the coffin to the notion that XMRV is a clinically relevant infectious human retrovirus."

Nails in the coffin, hmmm, what is the scientific basis of a coffin? Am I showing bias if I think this is indicative of bias?

"In 2009, attention became more intensely focused on XMRV when Judy Mikovits group at the Whittemore Peterson Institute in Reno, Nevada, reported in Science that 67% of chronic fatigue syndrome (CFS) patients were XMRV positive [3] and that the virus was also present in the blood of 3.7% of healthy controls."

Mikovits ... or Lombardi? This was the Lombardi et al paper, although Mikovits has become the most visible researcher since the original paper. Mikovits is the most high profile figure in the controversy, so they selected her as the person to mention.

"Despite all warnings that the link between CFS and XMRV could
not be confirmed, many patients suffering from this debilitating disease and desperately hoping for a cure started taking anti-retroviral drugs."

The small number of patients, who are being treated by a small number of doctors, are suddenly "many". Can we multiple our dismal research funds that way? How many patients can afford this treatment? How many have medical practitioners who are willing to prescribe the drugs at this point? Not many. At least they acknowledged it is a debilitating disease.

"Paprotka et al. calculated that the likelihood of precisely this recombination pattern occurring independently a second time to create the same XMRV sequence to be extremely low, i.e., only 1.3 10-12. As every XMRV sequence published to date has the same six predicted recombination sites, it is clear that they all originate from this unique recombination event during the establishment of the 22Rv1 cell line."

If you beg the question by presuming that the virus must have arisen in this cell line, or a similar limited option, this calculation looks good. However, if you ask what is the chance this virus arose naturally in the last century, allowing for the likelihood that other viral strains, including endogenous viruses, in the entire vertebrate biome might give rise to XMRV, this figure is a tiny percentage of the natural events from what I can estimate. It also ignores the possibility that XMRV is only one of a family of viruses involved.

"We and others have demonstrated that PBMC have a low susceptibility to XMRV infection and, if infected, release very low levels of infectious virus"

So therefore it is not very infectious in humans, and spreads slowly, with potentially a very long incubation period in humans if it is pathogenic. The history of ME does not look like that ... uh, wait, maybe it does!

"It transpires that XMRV is not a new human tumor virus after all, but rather the latest example of a rumor virus"

They can argue that it is more probable, but "is" sounds like dogma. This is as much spin as science. If they were to argue that the balance of published evidence indicates the likelihood that XMRV is associated with CFS (can I call it ME?) is now lower, then it would be a much better conclusion.

This paper is probably accurate on the facts from what I have read, but it is definitely an opinion piece aimed at supporting a particular view, and not showing anything in the way of balanced argument. For example, there is no discussion of the very different results in patient samples and controls. There is nothing new, which is why it is being published in the commentaries section.

Let me state my position. I do not believe XMRV causes ME. I do not believe XMRV is associated with ME. What I do think is that there is sufficient evidence to justify further study until we have a definitive conclusion - for or against. The Lipkin study may well do that for viral association. I really hope the conclusion is non-ambiguous, either way. I also think that there is a good chance that XMRV and related viruses are both associated and indirectly causal, if not directly. Only further study can prove or disprove that - and the Lipkin study should either disprove association, or start us on a new path of discovery.

Bye
Alex

 

[eric_s]

Even if you think Paprotka et al. disproves XMRV it still doesn't explain what the Lo lab found.

Maybe they should ask one of the Emory students how to find XMRV...

I'm no scientist and i don't know the answer to the XMRV question, but i'm really quite tired of these one sided opinion pieces that try to shut down the research into XMRV/MRV.

 

[RedRuth]

If you beg the question by presuming that the virus must have arisen in this cell line, or a similar limited option, this calculation looks good. However, if you ask what is the chance this virus arose naturally in the last century, allowing for the likelihood that other viral strains, including endogenous viruses, in the entire vertebrate biome might give rise to XMRV, this figure is a tiny percentage of the natural events from what I can estimate. It also ignores the possibility that XMRV is only one of a family of viruses involved.

I'm not sure I understand your reasoning here. What Paprotka et al did was trace the origin of 22Rv1 and their data is compelling. They then infer that because the sequences submitted by the Mikovits group are so similar to 22Rv1 then what they are picking up us 22Rv1 contamination. BTW even though Lombardi was the lead author on the original paper Mikovits is the PI and it's usual to refer to the work as hers.

 

[eric_s]

But Ruth, how could contamination explain the difference between cases and healthy controls in a blinded study? And why are negative controls always negative from what we've heard? Dr. Alter asked the same question at the NIH's ME/CFS State of the Knowledge Workshop earlier this year. I don't see how this could be explained by contamination.

 

[RedRuth]

Well I was just interpreting the Paprotka paper, I'm not sure which blinded study you mean? I'm also not sure what you mean by negative controls, do you mean the no template control?

 

[alex3619]

I'm not sure I understand your reasoning here. What Paprotka et al did was trace the origin of 22Rv1 and their data is compelling. They then infer that because the sequences submitted by the Mikovits group are so similar to 22Rv1 then what they are picking up us 22Rv1 contamination. BTW even though Lombardi was the lead author on the original paper Mikovits is the PI and it's usual to refer to the work as hers.

Hi RedRuth, there is now compelling reason to suspect that this virus is easily transfered from cell culture to cell culture. MLVs have been found in many cell cultures. In a much earlier post I speculated that using only moderate assumptions, but indeed a string of such assumptions, the possible number of recombination events for related MLVs in the last century is about ten to the eighteenth. I would have to be out by more than six orders of magnitude to be wrong in my conclusions, but this implies that there is a good chance XMRV has arisen many times. These viruses are vertebrate viruses, we put too much emphasis on mice, although mice do seem to be a natural vector, with the exception of XMLVs.

If you start with the presumption there is no other XMRV out there, and people are not infected, then the ten to the twelfth calculation looks reasonable. However, if you start with the presumption that XMRV and related viruses are common and can be carried by people (perhaps even if they are not infected, but transfer on their clothes etc.), then you get a different result. Either way is begging the question, and I would prefer to see better evidence.

Which is more likely: that the XMRV virus arose in this one culture in a freak accident, or that the culture was contaminated with XMRV due to vulnerability? Given the ease with which we know MLVs can contaminate culture, I suspect it was contamination of the culture, and not the first time it was created. This is not proof of course, its just a suspicion, but it puts reasonable doubt on the origin claims.

If Switzer would do a follow-up paper to show how other MLV strains can recombine to make XMRV, this would increase the doubt. So far he has only made a vague claim in one paper, so I can't tell if it is accurate.

I have studied some recombination theory a long time ago, almost completely forgotten now, in association with genetic algorithms. What I do recall is that the combined computational power of any substantial subset of the global biome is immense. I also know that these recombination events and their power is not based on chance. There is subtle selective pressure that can turn very low probability events into moderate probability events. Given the size of the biome, and the inadequacy of probabilistic methods for this type of argument, I am not impressed with the probabalistic part of the Paprotka et al argument.

Paprotka has put forward an hypothesis. It might be right, but there are reasons to think it might be wrong. I have no problem with anyone claiming this as a supporting argument toward a recombination claim, but the way it is often commented on puts undue emphasis on it.

There is a further point is worth mentioning. The probability calculations by definition are based on an assumption of equal probability of each potential event. Genetic directed search aside, MLVs have been infecting mice for a long time, and MLLVs have been infecting vertebrates for a long time. I have not researched when this is supposed to have started - what is the timeline for MLVs? That could be interesting. In any case, the entire MLV biome subset will have a long history of co-evolution not just with vertebrate, mammalian and primate species, but with each other. Structure will tend to optimize over time, and some of that will be for optimized evolutionary crossover in an attempt to avoid immune defense. This makes recombination at a whole biome level of MLVs a less than random event in itself. The whole notion of a species of virus is highly problematic - there is too much emphasis on XMRV at the expense of all MLVs.

I think there is a good chance the culture discussed by Paprotka was contaminated by live virus. What level of biohazard security were they using? What about that we already know that MLVs can contaminate cultures under reasonable security? Were any of the lab workers tested for MLVs or XMRV - I seriously doubt it as I don't think this was considered a risk back in the early 90s, at least in part because earlier studies had failed to find any evidence of MLV infection in people.

I am prepared to accept Lipkin's findings unless they are somehow ambiguous - clear results are good, either way, but we don't need more results that are problematic.

This doesn't mean that Paprotka was wrong about the original source of XMRV by the way. It just means that the virus might have arisen from MLV infections and recombination in wild mice or even other species many times - murine endogenous viruses are a quiet reservoir.

All the arguments so far are not conclusive in my view. They are all "maybe" arguments, with alternative explanations. Given the importance that a new human retrovirus could have, especially being ignored for a very long time, we need to be as certain as we can be. Proving that XMRV and MLVs are not infecting people, whether or not it is pathogenic, would be a good start. I just don't want us to stop before the evidence is more clear.

Bye
Alex

 

[eric_s]

To my knowledge Lombardi et al. (the 2009 one) was blinded. Also other studies were blinded, if i remember correctly the Hanson one was. I don't know what the correct scientific term is, but i think they often run control samples that they know are negative. Maybe they use water, another substance, or even blood, i don't know, but the idea is that it should come back negative. And from what has been reported they always stay negative.
In the studies that had a confirmed contamination problem, like Brigitte Huber's or Ila Singh's, the healthy controls had the same rate of XMRV+ results as the cases or in one study they found even more "XMRV" in controls than in cases.

 

[currer]

I'll tell you what. Lets accept this paper, forget about xmrv and the contamination of cell lines.

How many billion of us are there? Too many for the planet.

Why try to save people from the diseases to come.

 

[ukxmrv]

I just don't find Paprotka et al "compelling". They didn't have all the samples to test. Just one or two here and there.

Given the high rate of cultures being found to be contaminated in labs we don't know when the possible contamination occurred.

22rv1 isn't used by the WPI so it's irrelevant anyway.

The lack of diversity was explained by by Gkikas Magiokinis in the Lancet.

Evidence cannot surely be compelling when there are valid arguments against it and so little of substance?

 

[jace]

I will admit that I have posted this response elsewhere online.

The two studies this piece is using as evidence for their argument are deeply flawed.

Knox et al failed to find any evidence, by four different assays, of the VP62 clone of XMRV. Since Knox is heavily invested in HHV6, and since she left the WPI under a cloud, she cannot be considered to have no competing interests. See http://tinyurl.com/3zs2myr

While some scientists, Knox among them, are unable to find HGRVs, generally because of inadequate or too specific methodology (wild HGRVs have sequence diversity, all that the assays used by 0/0 studies pick up is the VP62 clone, used to align the primers), many reputable scientist do not have the same problem (1).

Paprotka Coffin and Pathaks unique recombinant event, that supposedly took place in a hypothetical lab, in tissue of hypothetical lab mice, some time in the early 90s has been bought into question by the work of, among others, Bill Switzer of the CDC (1).

This article is yet another crowd control clone piece. Move along, patients, back to your miserable existence, nothings happening here.

1) http://forums.phoenixrising.me/entry.php?959-XMRV-The-case-against-contamination (excellent piece, fully referenced).

 

[currer]

great post jace. How you can keep calm.....a reasoned response is always stronger!

 

[SilverbladeTE]

I'll tell you what. Lets accept this paper, forget about xmrv and the contamination of cell lines.

How many billion of us are there? Too many for the planet.

Bingo! that's what this is all about: The Integrity of Science And Tehcnology Must Be Protected At Any Coast, Comrades!
I'm betting the conspiracy to make our illness into a "joke" by the psychs and Gulf War Sydnrome crap too, is all about keeping a lid on the possibility vaccines (and perhaps other things as well) have been infecting us all.
Such a thing would shake the veritable "Pillars of Heaven" of our corrupt corporate/dumbass world, and they will not allow such to happen, the mere suspicion/possibility is enough to make them close minds and ranks.

 

[heapsreal]

none of this explains how KDM is finding mlv's in biopsy's but not in blood of some patients, that cant be contamination??

 

[RedRuth]

I will admit that I have posted this response elsewhere online.

The two studies this piece is using as evidence for their argument are deeply flawed.

Knox et al failed to find any evidence, by four different assays, of the VP62 clone of XMRV. Since Knox is heavily invested in HHV6, and since she left the WPI under a cloud, she cannot be considered to have no competing interests. See http://tinyurl.com/3zs2myr

While some scientists, Knox among them, are unable to find HGRVs, generally because of inadequate or too specific methodology (wild HGRVs have sequence diversity, all that the assays used by 0/0 studies pick up is the VP62 clone, used to align the primers), many reputable scientist do not have the same problem (1).

Deeply flawed in what way? Both papers passed the same review process. Trying to call into question Knox's competence and honesty isn't very helpful and anyway by your definition surely everyone involved in this has 'competing interests'. BTW If you want to play, 'who's the most reputable scientist' then Levy trumps Mikovits every time by a long way. Instead of sniping maybe you could explain why you think the Knox et al paper is 'deeply flawed'.

 

[eric_s]

I do think that in the case of Konstance Knox it's right to question her honesty. Did you read Annette Whittemore's letter after Knox et al.? If what is said there is correct, the doubts about Dr.(?) Knox are justified in my opinion. One has to try to see the all facts and when there is a reason for it, i think it is right to also look at the persons involved and not only at the science. What i agree with is that other parties involved might have competing interests as well. But still, if what was reported about Konstance Knox is correct, it went further than that and might have crossed the line to illegality.

What i'm asking myself is, given that many isolates seem to be quite close to VP-62, shouldn't such an assay be able to pick up at least some of these? But i'm no scientist. So my feeling would be that the problem can't be only there.

 

[RedRuth]

I've just read it, unpleasant innuendo which will probably turn out to be an unseemly squabble over money. I really don't think it's justified especially given there are 12 authors on that paper including Professor Levy, one of the most respected and distinguished retrovirologists in the world.

What i'm asking myself is, given that many isolates seem to be quite close to VP-62, shouldn't such an assay be able to pick up at least some of these?

I think the inference is, they are VP-62

 

[currer]

Scientists are human, they squabble all the time. Some of the greatest scientists have been execrable human beings.

 

[eric_s]

I've just read it, unpleasant innuendo which will probably turn out to be an unseemly squabble over money. I really don't think it's justified especially given there are 12 authors on that paper including Professor Levy, one of the most respected and distinguished retrovirologists in the world.

I think the inference is, they are VP-62

If what Annette Whittemore said was not true, i wonder why Konstance Know didn't take any steps against this. I think the things mentioned in this letter are very serious and i can't see what's unseemly about it. Either Annette Whittemore was not saying the truth and then i think this was a criminal act or she was saying the truth and then in my opinion the doubts are more than justified. Money might play a role but it remains to be seen which side's actions were/are influenced by this.

I think at least some of the isolates don't match VP-62 100%, but maybe they are close enough to be considered VP-62, i don't know. But then i wonder why the same group of people don't want to call what Lo found XMRV. There they emphasizse the difference very much.

 

[*GG*]

I'll tell you what. Lets accept this paper, forget about xmrv and the contamination of cell lines.

How many billion of us are there? Too many for the planet.

Why try to save people from the diseases to come.

Who says there are too many people for the planet? Perhaps these people have an agenda of their own? Wasn't it announced that global cooling was going to be an issue in the future, this is from the 70's, and what happened? Oh, now we have Global Warming, I mean Climate Change. The climate changes? who would have figured that. I am skeptical. Perhaps I am selfish, but I have enough on my plate that I am not going to worry about that, not my money or precious energy!

GG