XMRV - Innocent on All Counts?

A bombshell has just gone off in the continuing debate over XMRV, the virus that may or may not cause chronic fatigue syndrome. Actually, 4 bombshells.

A set of papers out today in Retrovirology (1,2,3,4) claim that many previous studies claiming to have found the virus haven't actually been detecting XMRV at all.

Here's the rub. XMRV is a retrovirus, a class of bugs that includes HIV. Retroviruses are composed of RNA, but they can insert themselves into the genetic material of host cells as DNA. This is how they reproduce: once their DNA is part of the host cell's chromosomes, that cell is ends up making more copies of the virus.

But there are lots of retroviruses out there, and there used to be yet others that are now extinct. So bits of retroviral DNA are scattered throughout the genome of animals. These are called endogenonous retro-viruses (ERVs).

XMRV is extremely similar to certain ERVs found in the DNA of mice. And mice are the most popular laboratory mammals in the world. So you can see the potential problem: laboratories all over the world are full of mice, but mouse DNA might show up as "XMRV" DNA on PCR tests.

Wary virologists take precautions against this by checking specifically for mouse DNA. But most mouse-contamination tests are targeted at mouse mitochondrial DNA (mtDNA). In theory, a test for mouse mtDNA is all you need, because mtDNA is found in all mouse cells. In theory.

Now the four papers (or are they the Four Horsemen?) argue, in a nutshell, that mouse DNA shows up as "XMRV" on most of the popular tests that have been used in the past, that mouse contamination is very common - even some of the test kits are affected! - and that tests for mouse mtDNA are not good enough to detect the problem.

• Hue et al say that "Taqman PCR primers previously described as XMRV-specific can amplify common murine ERV sequences from mouse suggesting that mouse DNA can contaminate patient samples and confound specific XMRV detection." They go on to show that some human samples previously reported as infected with XMRV, are actually infected with a hybrid of XMRV and a mouse ERV which we know can't infect humans.
• Sato et al report that PCR testing kits from Invitrogen, a leading biotech company, are contaminated with mouse genes including an ERV almost identical to XMRV, and that this shows up as a false positive using commonly used PCR primers "specific to XMRV".
• Oakes et al say that in 112 CFS patients and 36 healthy control, they detected "XMRV" in some samples but all of these samples were likely contaminated with mouse DNA because "all samples that tested positive for XMRV and/or MLV DNA were also positive for the highly abundant IAP long terminal repeat [found only in mice] and most were positive for murine mitochondrial cytochrome oxidase sequences [found only in mice]"
• Robinson et al agree with Oakes et al: they found "XMRV" in some human samples, in this case prostate cancer cells, but they then found that all of the "infected" samples were contaminated with mouse DNA. They recommend that in future, samples should be tested for mouse genes such as the IAP long terminal repeat or cytochrome oxidase, and that researchers should not rely on tests for mouse mtDNA.

They're all open-access so everyone can take a peek. For another overview see this summary published alongside them in Retrovirology.

I lack the technical knowledge to evaluate these claims, no doubt plenty of people will be rushing to do that before long. (Update: The excellent virologyblog has a more technical discussion of these studies.) But there are a couple of things to bear in mind.

Firstly, these papers cast doubt on tests using PCR to detect XMRV DNA. However, they don't have anything to say about studies which have looked for antibodies against XMRV in human blood, at least not directly. There haven't been many of these, but the paper which started the whole story, Lombardi et al (2009), did look for, and found, anti-XMRV immunity, and also used various other methods to support the idea that XMRV is present in humans. So this isn't an "instant knock-out" of the XMRV theory, although it's certainly a serious blow.

Secondly, if the 'mouse theory' is true, it has serious implications for the idea that XMRV causes chronic fatigue syndrome and also for the older idea that it's linked to prostate cancer. But it still leaves a mystery: why were the samples from CFS or prostate cancer patients more likely to be contaminated with mouse DNA than the samples from healthy controls?

Robert A Smith (2010). Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses Retrovirology : 10.1186/1742-4690-7-112

XMRV - Innocent on All Counts?

A bombshell has just gone off in the continuing debate over XMRV, the virus that may or may not cause chronic fatigue syndrome. Actually, 4 bombshells.

A set of papers out today in Retrovirology (1,2,3,4) claim that many previous studies claiming to have found the virus haven't actually been detecting XMRV at all.

Here's the rub. XMRV is a retrovirus, a class of bugs that includes HIV. Retroviruses are composed of RNA, but they can insert themselves into the genetic material of host cells as DNA. This is how they reproduce: once their DNA is part of the host cell's chromosomes, that cell is ends up making more copies of the virus.

But there are lots of retroviruses out there, and there used to be yet others that are now extinct. So bits of retroviral DNA are scattered throughout the genome of animals. These are called endogenonous retro-viruses (ERVs).

XMRV is extremely similar to certain ERVs found in the DNA of mice. And mice are the most popular laboratory mammals in the world. So you can see the potential problem: laboratories all over the world are full of mice, but mouse DNA might show up as "XMRV" DNA on PCR tests.

Wary virologists take precautions against this by checking specifically for mouse DNA. But most mouse-contamination tests are targeted at mouse mitochondrial DNA (mtDNA). In theory, a test for mouse mtDNA is all you need, because mtDNA is found in all mouse cells. In theory.

Now the four papers (or are they the Four Horsemen?) argue, in a nutshell, that mouse DNA shows up as "XMRV" on most of the popular tests that have been used in the past, that mouse contamination is very common - even some of the test kits are affected! - and that tests for mouse mtDNA are not good enough to detect the problem.

• Hue et al say that "Taqman PCR primers previously described as XMRV-specific can amplify common murine ERV sequences from mouse suggesting that mouse DNA can contaminate patient samples and confound specific XMRV detection." They go on to show that some human samples previously reported as infected with XMRV, are actually infected with a hybrid of XMRV and a mouse ERV which we know can't infect humans.
• Sato et al report that PCR testing kits from Invitrogen, a leading biotech company, are contaminated with mouse genes including an ERV almost identical to XMRV, and that this shows up as a false positive using commonly used PCR primers "specific to XMRV".
• Oakes et al say that in 112 CFS patients and 36 healthy control, they detected "XMRV" in some samples but all of these samples were likely contaminated with mouse DNA because "all samples that tested positive for XMRV and/or MLV DNA were also positive for the highly abundant IAP long terminal repeat [found only in mice] and most were positive for murine mitochondrial cytochrome oxidase sequences [found only in mice]"
• Robinson et al agree with Oakes et al: they found "XMRV" in some human samples, in this case prostate cancer cells, but they then found that all of the "infected" samples were contaminated with mouse DNA. They recommend that in future, samples should be tested for mouse genes such as the IAP long terminal repeat or cytochrome oxidase, and that researchers should not rely on tests for mouse mtDNA.

They're all open-access so everyone can take a peek. For another overview see this summary published alongside them in Retrovirology.

I lack the technical knowledge to evaluate these claims, no doubt plenty of people will be rushing to do that before long. (Update: The excellent virologyblog has a more technical discussion of these studies.) But there are a couple of things to bear in mind.

Firstly, these papers cast doubt on tests using PCR to detect XMRV DNA. However, they don't have anything to say about studies which have looked for antibodies against XMRV in human blood, at least not directly. There haven't been many of these, but the paper which started the whole story, Lombardi et al (2009), did look for, and found, anti-XMRV immunity, and also used various other methods to support the idea that XMRV is present in humans. So this isn't an "instant knock-out" of the XMRV theory, although it's certainly a serious blow.

Secondly, if the 'mouse theory' is true, it has serious implications for the idea that XMRV causes chronic fatigue syndrome and also for the older idea that it's linked to prostate cancer. But it still leaves a mystery: why were the samples from CFS or prostate cancer patients more likely to be contaminated with mouse DNA than the samples from healthy controls?

Robert A Smith (2010). Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses Retrovirology : 10.1186/1742-4690-7-112

A PCR Primer

The latest episode in the nail-biting scientific drama of "Does The XMRV Virus Cause Chronic Fatigue Syndrome?" has arrived, in the form of a paper in PNAS. A team of virologists led by the renowned Harvey Alter reported finding various XMRV-like viruses, but not XMRV itself, in chronic fatigue patients.

There's been plenty of excellent coverage of this new study, but most of it has come from specialists and has assumed a certain degree of technical knowledge. So here's my attempt to provide a summary for the non-expert, writing as someone who last got his hands dirty in a molecular lab 5 years ago...

The key to the controversy is PCR, a very useful technique invented by a guy on acid (kind of). PCR means Polymerase Chain Reaction. Polymerase is an enzyme which copies DNA. If you ask it nicely, it also copies the copies, then copies the copies of the copies, and so on. Thanks to this chain reaction, you can start with a tiny bit of DNA and end up with loads.

Using PCR, you can detect certain DNA sequences, for example, the DNA sequence of XMRV. (XMRV itself has RNA, rather than DNA, but as a retrovirus, it's able to insert itself into the DNA of infected cells.)

Here's how. DNA is a chain, or strand, of simple molecules called nucleotide bases. There are four: A, C, T, and G. Most of the time, DNA molecules are double-stranded, containing two chains of bases paired up (bound) together. Whenever one strand has A, the other has C, and vice versa. T and G pair up in the same way. They can only pair up in that particular way. T can't pair with C, or G, or with another T.
PCR takes double-stranded DNA and makes more of it. It does this by taking each strand and adding a second strand which is the "opposite" (complementary) sequence of the original, with T and A swapped, and C and G swapped.

That's nothing more than a replica of the original double-stranded DNA.

However, there's a catch. Polymerase can't start a strand of DNA out of nothing, it can only make an existing strand longer. So it needs a primer which can bind to the original DNA and provide "something to work with".

No primer, no duplication. The primer has to be specific: it has to be able to pair up with the DNA. This fact allows us to use PCR to detect specific DNA sequences. Suppose you want to know whether a sample of DNA contains a certain gene, and you know that this gene starts with AAAAA, and ends with CCCCC.

You would make some corresponding primers: a forward primer AAAAA and a reverse primer GGGGG. If the gene is present, these primers will bind to the corresponding target sequences bookending the gene of interest. The PCR will work, and you'll end with loads of copies of that gene. Hooray. If not, nothing much happens. Note that the forward primer is the "opposite" of what you might expect, because it has to bind to the complementary strand. The two primers bookend the region to be amplified - see this pic for an explanation of why.

Once you've run the PCR it's relatively easy to tell whether it amplified the gene or not. But remember that PCR doesn't detect genes, it detects primer targets. The DNA in between the target regions could be anything, as long as the primers fit. In fact, you can tell the length of the amplified DNA, which does provide some information. You can also resequence the amplified DNA to see exactly what it is, but that's expensive.

On the other hand, the match has to be exact. If you're testing for a gene starting with AAAAA, and that gene is present except that it starts with AAAAC instead, you won't find it: a single base difference in the primer sequence throws the whole thing off.

So if someone "used PCR to detect dog DNA", what they mean is that they used primers which they think are specific to dog DNA. This relies on two things being true: that the primers do in fact match the DNA of all dogs (not just some breeds of dog) and that they only match dog DNA (not cats, or mice.)

There are also technical considerations. PCR is vulnerable to contamination by unwanted DNA, because it's so sensitive: even a tiny bit of contamination will cause a false positive. Rogue DNA could come from anywhere: from the researcher running the experiment, from other samples in the lab... So, every PCR experiment needs a negative control, a sample known not to contain the gene of interest. A drop of water is the simplest example. If you "detect" the gene in the negative control, you have to try again (after cleaning all your equipment and washing your hands.)

PCR also doesn't always work. It's like cooking: you have to have the right mix of ingredients, the right temperature, the right timing. If not, you'll end up with a mess. This is why every PCR experiment needs a positive control, i.e. a sample in which you know the gene of interest is present. If you fail to detect the gene in the positive control, you have to check the recipe and try again.

How does this relate to the XMRV story? That's another post...

A PCR Primer

The latest episode in the nail-biting scientific drama of "Does The XMRV Virus Cause Chronic Fatigue Syndrome?" has arrived, in the form of a paper in PNAS. A team of virologists led by the renowned Harvey Alter reported finding various XMRV-like viruses, but not XMRV itself, in chronic fatigue patients.

There's been plenty of excellent coverage of this new study, but most of it has come from specialists and has assumed a certain degree of technical knowledge. So here's my attempt to provide a summary for the non-expert, writing as someone who last got his hands dirty in a molecular lab 5 years ago...

The key to the controversy is PCR, a very useful technique invented by a guy on acid (kind of). PCR means Polymerase Chain Reaction. Polymerase is an enzyme which copies DNA. If you ask it nicely, it also copies the copies, then copies the copies of the copies, and so on. Thanks to this chain reaction, you can start with a tiny bit of DNA and end up with loads.

Using PCR, you can detect certain DNA sequences, for example, the DNA sequence of XMRV. (XMRV itself has RNA, rather than DNA, but as a retrovirus, it's able to insert itself into the DNA of infected cells.)

Here's how. DNA is a chain, or strand, of simple molecules called nucleotide bases. There are four: A, C, T, and G. Most of the time, DNA molecules are double-stranded, containing two chains of bases paired up (bound) together. Whenever one strand has A, the other has C, and vice versa. T and G pair up in the same way. They can only pair up in that particular way. T can't pair with C, or G, or with another T.
PCR takes double-stranded DNA and makes more of it. It does this by taking each strand and adding a second strand which is the "opposite" (complementary) sequence of the original, with T and A swapped, and C and G swapped.

That's nothing more than a replica of the original double-stranded DNA.

However, there's a catch. Polymerase can't start a strand of DNA out of nothing, it can only make an existing strand longer. So it needs a primer which can bind to the original DNA and provide "something to work with".

No primer, no duplication. The primer has to be specific: it has to be able to pair up with the DNA. This fact allows us to use PCR to detect specific DNA sequences. Suppose you want to know whether a sample of DNA contains a certain gene, and you know that this gene starts with AAAAA, and ends with CCCCC.

You would make some corresponding primers: a forward primer AAAAA and a reverse primer GGGGG. If the gene is present, these primers will bind to the corresponding target sequences bookending the gene of interest. The PCR will work, and you'll end with loads of copies of that gene. Hooray. If not, nothing much happens. Note that the forward primer is the "opposite" of what you might expect, because it has to bind to the complementary strand. The two primers bookend the region to be amplified - see this pic for an explanation of why.

Once you've run the PCR it's relatively easy to tell whether it amplified the gene or not. But remember that PCR doesn't detect genes, it detects primer targets. The DNA in between the target regions could be anything, as long as the primers fit. In fact, you can tell the length of the amplified DNA, which does provide some information. You can also resequence the amplified DNA to see exactly what it is, but that's expensive.

On the other hand, the match has to be exact. If you're testing for a gene starting with AAAAA, and that gene is present except that it starts with AAAAC instead, you won't find it: a single base difference in the primer sequence throws the whole thing off.

So if someone "used PCR to detect dog DNA", what they mean is that they used primers which they think are specific to dog DNA. This relies on two things being true: that the primers do in fact match the DNA of all dogs (not just some breeds of dog) and that they only match dog DNA (not cats, or mice.)

There are also technical considerations. PCR is vulnerable to contamination by unwanted DNA, because it's so sensitive: even a tiny bit of contamination will cause a false positive. Rogue DNA could come from anywhere: from the researcher running the experiment, from other samples in the lab... So, every PCR experiment needs a negative control, a sample known not to contain the gene of interest. A drop of water is the simplest example. If you "detect" the gene in the negative control, you have to try again (after cleaning all your equipment and washing your hands.)

PCR also doesn't always work. It's like cooking: you have to have the right mix of ingredients, the right temperature, the right timing. If not, you'll end up with a mess. This is why every PCR experiment needs a positive control, i.e. a sample in which you know the gene of interest is present. If you fail to detect the gene in the positive control, you have to check the recipe and try again.

How does this relate to the XMRV story? That's another post...

XMRV and Chronic Fatigue Syndrome, Continued (Again)

Yet more twists have emerged in the already serpentine tale of XMRV, the virus that may or may not be responsible for causing some cases of chronic fatigue syndrome (CFS), aka myalgic encephalomyelitis, (ME).

First off, on Saturday 2nd July, a news item in Science magazine reported that two papers on XMRV were about to be published, but that the publication of both was "on hold" because they contradicted each other. One paper, from the US federal Centers for Disease Control (CDC), supposedly found no evidence of XMRV infection while the other one, from the National Institutes of Health and Food and Drug Administration (NIH/FDA), did.

The papers were only rumored to exist at that stage, and the story behind the NIH/FDA paper was particularly complicated. A Dutch magazine called ORTHO reported (see also) that NIH virologist Harvey Alter had given a presentation in Zagreb, Croatia, in which he reportedly said that the original Lombardi et al 2009 results, which first implicated XMRV in CFS

are extremely strong and likely true, despite the controversy...We (FDA & NIH) have independently confirmed the Lombardi group findings.

This was in reference to the still unpublished NIH/FDA paper, which according to Science, has been accepted for publication but currently put "on hold" by the journal PNAS.

However, the Science news was obsolete as soon as it appeared, because the other "on hold" paper, the negative one from the CDC, turned out not to be on hold for very long, if at all. It's now available online at the journal Retrovirology: Switzer et al's Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States. It's listed as being published on the 1st July.

The CDC paper Switzer et al, as the rumors predicted, is negative. The authors tested blood plasma from 51 CFS cases and 53 healthy controls and found no evidence of anti-XMRV antibodies; they sent the same samples to a German lab and they confirmed the results. They then tested DNA extracted from blood samples in the same CFS patients and 97 controls, finding no evidence of XMRV DNA using a number of analytical methods; again, a second lab confirmed this. The paper is open access, so you can read it for more details (there are lots).

This is a big deal, because this is the first paper to attempt to replicate Lombardi et al's results in American patients. Several studies have appeared in the months following the original paper, and none of them found XMRV infection in any of their patients or controls. This is mysterious because Lombardi et al found XMRV in 67% of patients, but also in 4% of controls. However, these studies all used European people, raising the possibility that XMRV is just not found in Europe, for whatever reason.


So what exactly is going on here? Maybe only Lombardi et al used the appropriate methods which were able to detect XMRV, and everyone else has been failing to pick it up. However, in my opinion, while this was a reasonable suspicion months ago, it's very unlikely now because (by my count) 6 labs have not found XMRV in CFS patients, using lots of different approaches.

In most cases these labs showed that they were able to detect small quantities of XMRV added into a sample, as a positive control. Switzer et al, for example, say that they were able to detect 10 copies of the virus (not many) mixed into a sample of human DNA; one of the labs they used for a confirmation analysis could detect 4 copies.

There's another possibility - maybe only Lombardi et al were studying the right people. Lombardi et al used a carefully selected subgroup of CFS patients with various neurological and immunological abnormalities suggestive of a "medical" as opposed to a "psychological" disorder. However, the most popular 1994 criteria for CFS are a lot broader than this. Supporters of the XMRV-CFS link say that XMRV is probably associated only with some cases of CFS, and the various failed attempts to confirm XMRV have been looking in the wrong people.

Bearing this in mind, it's notable that the latest Switzer et al paper didn't recruit patients by approaching those who considered themselves to have CFS. Rather they identified cases through population screening: calling random numbers from the telephone directory of Wichita, Kansas, and of sites in Georgia, and asking people whether they were suffering from CFS-like symptoms such as fatigue. People who answered "yes" to enough questions were invited for a medical exam and interview and were diagnosed with CFS if they met the 1994 criteria (though in the abstract these are described as the revised 1994 criteria), as long as their symptoms weren't explained by a known, current medical or psychiatric disorder.

It's fair to say that this will have recruited a very different cross-section of patients than Lombardi et al did. However, in my opinion, while this is important, it doesn't resolve the fundamental mystery of why no-one had XMRV, not even the healthy controls, given that Lombardi et al found XMRV in 4% of healthy people. To my knowledge, this question remains unexplained. Maybe the "on hold" NIH/FDA paper will shed some light...

Finally, those interested in this topic may find my running summary of (I hope) all human XMRV research useful.

Link: virologyblog is also on the case...


Switzer, W., Jia, H., Hohn, O., Zheng, H., Tang, S., Shankar, A., Bannert, N., Simmons, G., Hendry, R., Falkenberg, V., Reeves, W., & Heneine, W. (2010). Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States Retrovirology, 7 (1) DOI: 10.1186/1742-4690-7-57

Enserink, M. (2010). Conflicting Papers on Hold as XMRV Frenzy Reaches New Heights Science, 329 (5987), 18-19 DOI: 10.1126/science.329.5987.18

XMRV and Chronic Fatigue Syndrome, Continued (Again)

Yet more twists have emerged in the already serpentine tale of XMRV, the virus that may or may not be responsible for causing some cases of chronic fatigue syndrome (CFS), aka myalgic encephalomyelitis, (ME).

First off, on Saturday 2nd July, a news item in Science magazine reported that two papers on XMRV were about to be published, but that the publication of both was "on hold" because they contradicted each other. One paper, from the US federal Centers for Disease Control (CDC), supposedly found no evidence of XMRV infection while the other one, from the National Institutes of Health and Food and Drug Administration (NIH/FDA), did.

The papers were only rumored to exist at that stage, and the story behind the NIH/FDA paper was particularly complicated. A Dutch magazine called ORTHO reported (see also) that NIH virologist Harvey Alter had given a presentation in Zagreb, Croatia, in which he reportedly said that the original Lombardi et al 2009 results, which first implicated XMRV in CFS

are extremely strong and likely true, despite the controversy...We (FDA & NIH) have independently confirmed the Lombardi group findings.

This was in reference to the still unpublished NIH/FDA paper, which according to Science, has been accepted for publication but currently put "on hold" by the journal PNAS.

However, the Science news was obsolete as soon as it appeared, because the other "on hold" paper, the negative one from the CDC, turned out not to be on hold for very long, if at all. It's now available online at the journal Retrovirology: Switzer et al's Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States. It's listed as being published on the 1st July.

The CDC paper Switzer et al, as the rumors predicted, is negative. The authors tested blood plasma from 51 CFS cases and 53 healthy controls and found no evidence of anti-XMRV antibodies; they sent the same samples to a German lab and they confirmed the results. They then tested DNA extracted from blood samples in the same CFS patients and 97 controls, finding no evidence of XMRV DNA using a number of analytical methods; again, a second lab confirmed this. The paper is open access, so you can read it for more details (there are lots).

This is a big deal, because this is the first paper to attempt to replicate Lombardi et al's results in American patients. Several studies have appeared in the months following the original paper, and none of them found XMRV infection in any of their patients or controls. This is mysterious because Lombardi et al found XMRV in 67% of patients, but also in 4% of controls. However, these studies all used European people, raising the possibility that XMRV is just not found in Europe, for whatever reason.


So what exactly is going on here? Maybe only Lombardi et al used the appropriate methods which were able to detect XMRV, and everyone else has been failing to pick it up. However, in my opinion, while this was a reasonable suspicion months ago, it's very unlikely now because (by my count) 6 labs have not found XMRV in CFS patients, using lots of different approaches.

In most cases these labs showed that they were able to detect small quantities of XMRV added into a sample, as a positive control. Switzer et al, for example, say that they were able to detect 10 copies of the virus (not many) mixed into a sample of human DNA; one of the labs they used for a confirmation analysis could detect 4 copies.

There's another possibility - maybe only Lombardi et al were studying the right people. Lombardi et al used a carefully selected subgroup of CFS patients with various neurological and immunological abnormalities suggestive of a "medical" as opposed to a "psychological" disorder. However, the most popular 1994 criteria for CFS are a lot broader than this. Supporters of the XMRV-CFS link say that XMRV is probably associated only with some cases of CFS, and the various failed attempts to confirm XMRV have been looking in the wrong people.

Bearing this in mind, it's notable that the latest Switzer et al paper didn't recruit patients by approaching those who considered themselves to have CFS. Rather they identified cases through population screening: calling random numbers from the telephone directory of Wichita, Kansas, and of sites in Georgia, and asking people whether they were suffering from CFS-like symptoms such as fatigue. People who answered "yes" to enough questions were invited for a medical exam and interview and were diagnosed with CFS if they met the 1994 criteria (though in the abstract these are described as the revised 1994 criteria), as long as their symptoms weren't explained by a known, current medical or psychiatric disorder.

It's fair to say that this will have recruited a very different cross-section of patients than Lombardi et al did. However, in my opinion, while this is important, it doesn't resolve the fundamental mystery of why no-one had XMRV, not even the healthy controls, given that Lombardi et al found XMRV in 4% of healthy people. To my knowledge, this question remains unexplained. Maybe the "on hold" NIH/FDA paper will shed some light...

Finally, those interested in this topic may find my running summary of (I hope) all human XMRV research useful.

Link: virologyblog is also on the case...


Switzer, W., Jia, H., Hohn, O., Zheng, H., Tang, S., Shankar, A., Bannert, N., Simmons, G., Hendry, R., Falkenberg, V., Reeves, W., & Heneine, W. (2010). Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States Retrovirology, 7 (1) DOI: 10.1186/1742-4690-7-57

Enserink, M. (2010). Conflicting Papers on Hold as XMRV Frenzy Reaches New Heights Science, 329 (5987), 18-19 DOI: 10.1126/science.329.5987.18