Doubts About Connection Between XMRV and Human Disease

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
rlstanley
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Doubts About Connection Between XMRV and Human Disease

Post by rlstanley » Sat 12 Mar 2011 1:16

http://news.sciencemag.org/sciencenow/2 ... tml?ref=hp

Fresh Doubts About Connection Between Mouse Virus and Human Disease

Science Now

by Jon Cohen
8 March 2011
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.

Claudia
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Location: Connecticut, USA

Re: Doubts About Connection Between XMRV and Human Disease

Post by Claudia » Sat 12 Mar 2011 2:10

Wow, that's really interesting and a great cautionary tale reminder in medical science research and in drawing conclusions too quickly.

5vforest
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Re: Doubts About Connection Between XMRV and Human Disease

Post by 5vforest » Sat 12 Mar 2011 3:03

I don't think this is the end for XMRV.

If the XMRV that places like the Whittemore Peterson Institute are finding is indeed due to contamination, why are ME/CFS patients testing positive for it 70% of the time while only 7% of healthy controls test positive?


http://www.wpinstitute.org/

http://www.wpinstitute.org/news/docs/WP ... 010111.pdf

rlstanley
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Joined: Mon 3 Dec 2007 2:53

Re: Doubts About Connection Between XMRV and Human Disease

Post by rlstanley » Sat 12 Mar 2011 3:55

Snippet from the Science full text article

Negative Data for Link Between Mouse Virus and Human Disease- Science

Science 11 March 2011:
Vol. 331 no. 6022 pp. 1253-1254
DOI: 10.1126/science.331.6022.1253
• NEWS & ANALYSIS
RETROVIROLOGY


“The evidence coming out at this meeting is incredibly impressive, and
the weight of evidence is indicating that this is not a major human
virus in terms of pathogenesis,” says Michael Busch, who heads the
Blood Systems Research Institute in San Francisco, California, and is
part of a working group convened by the U.S. Department of Health and
Human Services to examine whether XMRV poses a threat to the country's
blood supply.

But Busch said that before he concludes XMRV is simply a contaminant,
he wants to see the results of studies they are coordinating between
several labs with samples from agreed-upon patient and negative
controls, as well as blood donors. If most of these fail to find the
virus, Busch says, “it's going to eliminate concerns” that XMRV has
caused these diseases.

Even if XMRV has not harmed humans, Busch says we got lucky. This is
the first accidental generation of a retrovirus that can infect human
cells. “It's a warning shot,” Busch says. “We've created a highly
infectious virus that may transmit to humans.”

5vforest
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Re: Doubts About Connection Between XMRV and Human Disease

Post by 5vforest » Sat 12 Mar 2011 3:59

The scariest part about your above post is the last line. :o

rlstanley
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Joined: Mon 3 Dec 2007 2:53

Re: Doubts About Connection Between XMRV and Human Disease

Post by rlstanley » Tue 22 Mar 2011 23:36

http://www.chicagotribune.com/health/ct ... 6823.story

Research casts doubt on theory of cause of chronic fatigue


Retroviral link to debilitating illness looking shaky, but critics still bank on anti-HIV drugs


Trine Tsouderos, Tribune reporter
March 17, 2011

Snippets:
Cancer biologist Robert Silverman, a key researcher at Cleveland Clinic's Lerner Research Institute who worked on studies that linked XMRV to chronic fatigue syndrome and prostate cancer, told the Tribune his lab had stored a cell line known to harbor XMRV and he was working to determine if contamination occurred. Virologists who have examined work by Silverman and others have raised serious questions about contamination, an unfortunate but not unusual mishap in the field.

"I am concerned about lab contamination, despite our best efforts to avoid it," Silverman wrote in an e-mail, adding that similar cell lines "are in many, many labs around the world. Contamination could come from any one of a number of different sites."
A European research team this week reported being unable to find any evidence of XMRV in the blood of people diagnosed with chronic fatigue syndrome and their healthy peers, the latest in a stream of studies in which researchers looking for the retrovirus in the blood of both sick and healthy people have come up empty. Others have reported no evidence of the retrovirus in the blood of patients who were previously found to be XMRV-positive.

The Tribune reported last year that the original research on chronic fatigue syndrome and XMRV had led some patients to get tested for the retrovirus and take anti-retroviral drugs intended to treat HIV, which causes AIDS. The situation highlights the danger in putting too much stock in one scientific study, even one in a prestigious journal. Studies need to be replicated, and early research is often proved wrong.

The original study, published in Science in 2009, was led by retroviral immunologist Judy Mikovits of the private Whittemore Peterson Institute (WPI) for Neuro-Immune Disease in Reno, Nev. The institute plans to open a clinic that in May would begin treating patients diagnosed with chronic fatigue syndrome and other neuro-immune diseases. Despite the newer research, its leaders strongly deny that contamination could account for their findings.
Mikovits, who once worked at the National Cancer Institute in Frederick, Md., has made increasingly broad statements about XMRV. At the January talk, she showed a slide connecting XMRV to a list of frustrating medical conditions like ALS, Parkinson's disease, multiple sclerosis and dementia. She also linked it to autism. But no published data exist to support those links.

Mikovits also talked about potential treatments, including the powerful anti-retroviral drugs used to treat people who have HIV. These have not been proved safe or effective for people with chronic fatigue syndrome or any of the other conditions listed.

The WPI's director of clinical services, Dr. Jamie Deckoff-Jones, who has chronic fatigue syndrome and has taken anti-retroviral drugs for a year, is using a personal blog to allege a cover-up by researchers seeking to discredit the XMRV link.

"So is there motivation for the cover-up and baseless attacks against Dr. Mikovits?" she wrote in a posting that has been widely circulated on patient forums. "They cannot attack the data because it is impeccable."
Physicians who work with HIV patients say antiretroviral drugs can cause significant side effects and that efficacy cannot be determined through anecdotes.

The chasm between the WPI and its supporters and many in the scientific community is emblematic of a new, modern-day dynamic in which patients keep close tabs on the work of researchers and feel empowered to challenge that work and form strong opinions about the quality of it.

Early on, many in the online chronic fatigue community threw their support behind WPI, believing strongly that XMRV was the cause of their illness. More than 1,000 people have paid for non-FDA-approved XMRV blood tests from a commercial lab associated with WPI and headed by Whittemore's husband, Harvey, according to state records. The tests range from $249 to $450, according to the lab website.
This month, 4,000 scientists and clinicians gathered in Boston for a retroviral conference that included 10 presentations offering evidence that XMRV is a lab contaminant. Mikovits did not attend.

Retrovirologist Jonathan Stoye, who co-wrote a supportive commentary that accompanied Mikovits' original study linking chronic fatigue syndrome and XMRV, said he has since changed his mind.

"I think there are serious problems," said Stoye, who works at MRC National Institute for Medical Research in London.

His co-author, John Coffin, a retrovirologist at Tufts University, agreed the evidence for a link between XMRV and human disease had been seriously weakened.

"I think most people are reasonably convinced that there is not much left anymore," Coffin said. But, he said, "I don't think everything has been nailed down."

Coffin began harboring doubts about Mikovits' study as negative evidence piled up and after he, researcher Vinay Pathak at the National Cancer Institute and their colleagues found what they believe to be the parent viruses of XMRV.

The viruses, according to research Pathak presented at the Boston conference, recombined in a cell line called 22RV1 to create a new retrovirus — XMRV — sometime in the 1990s. The work is in the publication process.

That widely used cell line had been stored in Silverman's lab before he found evidence of the retrovirus in the prostate tissue of patients with a form of prostate cancer.

"22RV1 cells were once previously (more than a year earlier) grown in my lab but were being stored in a liquid nitrogen freezer at the time, and not the same freezer used to store prostate tissues," Silverman wrote in an e-mail. "At the time it was unknown that 22RV1 cells were infected with XMRV."

In the field of virology, contamination has sometimes been mistaken for real results. Greg Towers, a virologist from University College London, notes that the technology used is so sensitive that it takes only one molecule of genetic material to contaminate a sample.

Scientists have been reluctant to shut the door completely on the possibility that XMRV really is tied to human disease. Some questions remain unanswered, said Racaniello, of Columbia University. "I don't think it is time to put a lid on it," he said. "You have to carry the whole thing to its conclusion."

The XMRV story is, to Racaniello, an amazing opportunity for people to watch how science works in real time.

rlstanley
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Re: Doubts About Connection Between XMRV and Human Disease

Post by rlstanley » Wed 23 Mar 2011 5:09

http://newsblogs.chicagotribune.com/tri ... tions.html

03/18/2011
XMRV, Chronic Fatigue Syndrome, and a fuller picture of their dubious connections

snippets

Our story today is about the danger of putting too much stock in one study and forgetting that scientific knowledge is hard won, proven over time, and borne out through many, many studies -- not just one.

The study in question
In this case, a research team peopled with respected scientists looked at blood taken from people diagnosed with chronic fatigue syndrome and healthy people and found evidence of a retrovirus - XMRV - in the blood of both groups. The researchers found evidence of XMRV in the blood of more of the CFS patients than the healthy controls, and they posited that XMRV is linked to CFS.

Their work was published in one of the most prestigious scientific journals in the world, Science, in 2009. It was met with great fanfare and joy from the CFS community, in particular...
Rush to spread "happy" news

Some news outlets - not this one - touted the study as a breakthrough, before further studies could determine if the paper was correct or if XMRV was linked to CFS for sure. Some stories even reported XMRV as the cause of CFS - moving far beyond the paper's conclusions.

The paper's lead researcher, Judy Mikovits, spoke to a CFS patient group. A lab began selling commercial tests for XMRV to patients. Some patients began taking antiretroviral drugs. Some patients put enormous hope in XMRV as the cause of CFS.
If it seems too good to be true...

...Science, they know, does not move ahead based on a single study. It moves ahead slowly as a body of work that, in time, seems to point in one direction. Questions are asked, questions are answered, slowly a consensus is formed and one idea takes hold. Over time, if that hypothesis is proven wrong by further research, the consensus changes.

And that is what has happened with XMRV and CFS.
Further tests came up empty

After the original paper appeared, scientists all over the world started looking in the blood of chronic fatigue syndrome patients and others for XMRV.

They came up, over and over again, empty-handed. No XMRV, again and again.

But that wasn't enough to close the door. Maybe, they posited, their methods weren't sensitive enough. They changed techniques, looked in different populations of people. Still nothing, test after test.

Others wondered how the Science team got its results, if others could not. A flurry of papers showing how contamination in the lab could explain the results appeared.

And so, almost 18 months later, many studies later, many dollars later, a consensus is forming that XMRV is actually a lab contaminant and not a human pathogen infecting millions.
A cautionary, if not comforting, tale

For patients of all sorts, it is worth keeping this story in mind during Google or PubMed searches of medical studies. A single study, in some ways, means nothing without considering the studies that came before and those that come after. The important question is not, "what did this study say?," but "what do the studies say when considered together? Is there a consensus? If so, what is it?
"

rlstanley
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Re: Doubts About Connection Between XMRV and Human Disease

Post by rlstanley » Wed 1 Jun 2011 16:31

http://www.sciencemag.org/content/early ... 2.abstract

Published Online 31 May 2011
Science DOI: 10.1126/science.1208542

Letters

Editorial Expression of Concern

Abstract
In the issue of 23 October 2009, Science published a study by Lombardi et al. purporting to show that a retrovirus called XMRV (xenotropic murine leukemia virus-related virus) was present in the blood of 67% of patients with chronic fatigue syndrome (CFS) compared with 3.7% of healthy controls. A number of studies published elsewhere have failed to replicate these findings.

In conjunction with two new Reports that strongly support the growing view that the association between XMRV and CFS likely reflects contamination of laboratories and research reagents with the virus, Science is publishing an Editorial Expression of Concern about the Lombardi et al. Report.
Bruce Alberts
+ Author Affiliations

Editor-in-Chief, Science, American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005, USA.

Received for publication 17 May 2011.
Accepted for publication 26 May 2011.

Full text: (PDF) http://www.sciencemag.org/content/early ... 2.full.pdf
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Last edited by rlstanley on Wed 1 Jun 2011 16:39, edited 1 time in total.

rlstanley
Posts: 1637
Joined: Mon 3 Dec 2007 2:53

Re: Doubts About Connection Between XMRV and Human Disease

Post by rlstanley » Wed 1 Jun 2011 16:35

One of the reports mentioned in post directly above:
http://www.sciencemag.org/content/early ... 3.abstract

Published Online 31 May 2011

Science DOI: 10.1126/science.1204963

•Report

No Evidence of Murine-Like Gammaretroviruses in CFS Patients Previously Identified as XMRV-Infected


Konstance Knox1,2, Donald Carrigan1,2, Graham Simmons3,4, Fernando Teque5 , Yanchen Zhou3,4, John Hackett Jr.6, Xiaoxing Qiu6, Ka-Cheung Luk6, Gerald Schochetman6, Allyn Knox1, Andreas M. Kogelnik2 , and Jay A. Levy5,*

Abstract

Murine-like gammaretroviruses (MLVs), most notably XMRV [xenotropic murine leukemia virus (X-MLV)–related virus], have been reported to be present in the blood of patients with chronic fatigue syndrome (CFS). We evaluated blood samples from 61 patients with CFS from a single clinical practice, 43 of whom had previously been identified as XMRV-positive. Our analysis included polymerase chain reaction and reverse transcription polymerase chain reaction procedures for detection of viral nucleic acids and assays for detection of infectious virus and virus-specific antibodies.

We found no evidence of XMRV or other MLVs in these blood samples. In addition, we found that these gammaretroviruses were strongly (X-MLV) or partially (XMRV) susceptible to inactivation by sera from CFS patients and healthy controls, which suggested that establishment of a successful MLV infection in humans would be unlikely. Consistent with previous reports, we detected MLV sequences in commercial laboratory reagents. Our results indicate that previous evidence linking XMRV and MLVs to CFS is likely attributable to laboratory contamination.
Full text:(PDF) http://www.sciencemag.org/content/early ... 3.full.pdf
.

rlstanley
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Joined: Mon 3 Dec 2007 2:53

Re: Doubts About Connection Between XMRV and Human Disease

Post by rlstanley » Wed 1 Jun 2011 16:45

.
2nd new paper mentioned in editorial of concern posted above:

http://www.sciencemag.org/content/early ... 2.abstract

Published Online 31 May 2011

Science DOI: 10.1126/science.1205292

•Report

Recombinant Origin of the Retrovirus XMRV


Tobias Paprotka1,*, Krista A. Delviks-Frankenberry1,*, Oya Cingöz3,4,*, Anthony Martinez5, Hsing-Jien Kung5,6, Clifford G. Tepper5, Wei-Shau Hu2, Matthew J. Fivash Jr.7, John M. Coffin3,4, and Vinay K. Pathak1,†
Abstract

The retrovirus XMRV (xenotropic murine leukemia virus–related virus) has been detected in human prostate tumors and in blood samples from patients with chronic fatigue syndrome, but these findings have not been replicated. We hypothesized that an understanding of when and how XMRV first arose might help explain the discrepant results. We studied human prostate cancer cell lines CWR22Rv1 and CWR-R1, which produce XMRV virtually identical to the viruses recently found in patient samples, as well as their progenitor human prostate tumor xenograft (CWR22) that had been passaged in mice. We detected XMRV infection in the two cell lines and in the later passage xenografts, but not in the early passages. In particular, we found that the host mice contained two proviruses, PreXMRV-1 and PreXMRV-2, which share 99.92% identity with XMRV over >3.2-kilobase stretches of their genomes. We conclude that XMRV was not present in the original CWR22 tumor but was generated by recombination of two proviruses during tumor passaging in mice.

The probability that an identical recombinant was generated independently is negligible (~10–12); our results suggest that the association of XMRV with human disease is due to contamination of human samples with virus originating from this recombination event.
Full text:(PDF) http://www.sciencemag.org/content/early ... 2.full.pdf

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