Fresh doubts about connection between mouse virus and human disease: Science Now blog, 8 March 2011

March 9, 2011

From Science magazine's Science Now blog, 8 March 2011 (story by Jon Cohen)

BOSTON – A new finding presented at a conference here last week throws cold water on the impassioned debate about the link between a novel mouse retrovirus and prostate cancer and chronic fatigue syndrome in humans. Yet few believe it will end the controversy, which began in 2006.

In an extensive sleuthing expedition that looked back nearly 20 years, two collaborating research teams contend they have evidence that xenotropic murine leukemia virus-related virus (XMRV) resulted from the chance recombination of pieces of two mouse viruses in lab experiments and that the connections to human disease are spurious. “That nails it,” said retrovirologist Nathaniel Landau of New York University. “Everyone working on this thing has this virus contaminating their stuff. It's been a tremendous waste of time and money.”

Vinay Pathak, a retrovirologist who works at the HIV Drug Resistance Program run by the U.S. National Cancer Institute (NCI) in Frederick, Maryland, presented the new data at the 18th Conference on Retroviruses and Opportunistic Infections. Pathak explained how he became intrigued by a 2009 study that showed how a human prostate cancer cell line was infected with XMRV. He acquired earlier material made to use the cell line – in particular, tumors grown in mice, called xenografts, that were then “passaged” to other mice—and established that the original human tumor could not have harbored XMRV.

More startling still, Pathak's lab found that some of the early samples of xenografts did have a stretch of DNA that was nearly identical to about half of the XMRV genome. A group led by John Coffin, who works at both NCI and Tufts University here, made a similar discovery with different samples of xenografts. When the teams compared notes, they saw that the two sequences perfectly overlapped to form XMRV.

“It was an amazing moment, the kind that happens once or twice in a career,” says Coffin. “It was like seeing a puzzle come together.” As Pathak emphasized in his talk, the DNA sequences in what they dubbed preXMRV-1 and preXMRV-2 are nearly identical to the XMRV sequences reportedly found in humans but suspected to be a lab contaminant by some groups. Retroviruses frequently recombine with each other, which is how the two preXMRV sequences likely became XMRV. Now Coffin is convinced that “it is all contamination.”

A longer version of this article will appear in this week's issue of Science.

8 thoughts on “Fresh doubts about connection between mouse virus and human disease: Science Now blog, 8 March 2011”

  1. You really couldn’t invent this stuff anymore could you? I mean even the best fictional writers would be hard pressed.

    Is it science when so much desperation fuelled hope can be invested in something that proves to be a contamination?

    I really don’t know what to believe any more, really I don’t. And I have remained skeptical throughout – many have not.

  2. There is still no evidence that this retrovirus is a contaminant. These studies are merely a pit stop before contamination claims are silenced.

    This is going round the web and it explains the situation very well.

    There is substantial scientific evidence that HGRVs are human pathogens and none whatsoever that they are not.

    Firstly, XMRV integration sites were first discovered in prostrate DNA taken directly from patients. No cell lines of any kind involved. Cell line contamination not possible there.

    Also, the study in question is unable to say where the cell line has been “Analysis of 15 nude mouse strains indicated that none contained XMRV, but some strains potentially used to passage the xenograft contained both PreXMRV-1 and PreXMRV-2.”

    The abstracts posted in CROI present conclusions as fact when they are no such thing. The DU145 cell lines were screened for the presence of XMRV by Dong et al in 2007, and no XMRV was present as provirus or cDNA. Therefore, if integrated sequences were found within the cells, then the direction of transfer was from the human prostate DNA, which contained those sequence, to the cells in question. Similarly, the apparent appearance of XMRV, after the production of xenografts can be explained by the fact that the PCR system used was not sensitive enough to detect XMRV in the original tissue. We certainly have enough examples of that. The testosterone pellets used in the process however would ensure rapid replication of XMRV to the levels which the PCR system used could detect it.

    This is the reference showing how an increase in the level of NF-kappa B increases the replication rate of XMRV, published in the peer reviewed journal of virology.

    How does an increase in the level of NF-kappa B increase the replication rate of a contaminant?

    This is the reference showing the elevated rate of NF-kappa B in DU145 cells.

    If DU145 cells have XMRV integrated into their DNA, can anyone explain why the XMRV does not transcribe and the fact that DU145 cells do not express XMRV, given the high levels of nf-kappa b and oxidative stress known to exist within these cells?

    Finally, Kim et al. has found that XMRV is capable of making three insertions within a 100 kilobase region, and that the integration points for all of the 472 regions mapped were different. If the nucleotide positions were identical to the two sites identified in Garson et al. contamination must have come from the patient sample, not the DU145 cells.

    Now Kearney et al. has apparently been able, and I will use Alan Dove’s word’s here, “to detect XMRV in infected macaque blood (i.e. she can see it when it’s there) but unable to find it in any clinical specimens, including two that Lombardi et al. had reported as positive.” Now the titres in the infected monkeys would be massively higher than in human PMBC’s, with a natural infection pattern. That is artificial inoculation versus natural infection, and can be used to determine tissue tropism.

    The question is, did Kearney use the Lombardi assay to see if she could locate XMRV, which would be adhering to the scientific method?

  3. “It’s been a tremendous waste of time and money.”

    Thoroughly exploring scientific avenues for millions of people suffering from a debilitating condition worldwide is obviously a waste of time and money.

    (denote: sarcasm)

    The language used here is still speculative and indeterminate.

    Neither arrogance nor ego, nor reputation drives the truth. The truth in science doesn’t have emotion.

  4. can someone PLEASE translate all this into english.

    I mean is it disappointment/relief that XMRV has turned out to be a blind alley? or is it the most monumental political game?

    What with all this and the whole PACE debacle… I just despair.

    1. Here is the translation.

      There is still no evidence to suggest that XMRV is a contaminant. They cannot explain the results as if they were. More positive studies are on the way and they will blow this wide open. Contamination will no longer be mentioned.

      The above article is politics at play. The contaminant in the experiments above went from man to mouse, not the other way around. This is what the evidence shows. The reason they cannot detect the virus in the earlier cell line is because their assay (test) is not sensitive enough. In the later cell lines the virus has been increased due to hormones used in them. This re actives XMRV, increasing the number of infected cells, and making it easier to detect.

      Let’s be really clear. The cell line in question was never used in the two positive ME studies. The results cannot in any way be explained by mouse contamination. This is a new human retrovirus.

      One thing to take away though, is the possibility that they did accidentally create this virus in a lab.

  5. Thanks JT.

    One thing in particular continues to stun me, and that is why o why the original studies have not been replicated to the same extent, by anyone, anywhere else in the world, including in the United States.

    Why do advocates keep coming back to the original Lombard study? Why hasn’t anyone from that study opened up their specific findings, the blood, the cultures, to scrutiny?

    If they had done so, then surely to goodness, none of this ‘politics’ that you and others keep referring to, would ever dominate the headlines.

  6. The authors of Lombardi et al. have done exactly that. Everything is open to scrutiny. How else did Lo et al. confirm the findings of Lombardi et al.

    I realise you will think they found a different virus – PMRV. But XMRV is actually a Polytropic/Xenotropic hybrid.

    Honestly though, this will be over soon, and then we can move onto clinical trials.

  7. Here is one vital piece of information to help everyone understand why so many studies have been negative.

    All the negative studies used a clone of XMRV called VP62.

    Lombardi et al never used it.

    Use of this clone limits the diversity of XMRV they can detect. In other words, they would have to find a person who had the exact same specific version of XMRV as the VP62 clone to get a positive result. If this approach had been applied to HIV, they would have given up looking for that too.

    What they need to do is use a clinical positive sample, which have always been available. Calibrate their assays to that, and viola the virus will be found. Well, that’s the clone, there are many other variables they are not all sticking too.

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