Article: Four Viruses! Alter Paper Confirms Retroviral Findings in CFS

You can view the page at http://www.forums.aboutmecfs.org/content.php?213-Four-Viruses-The-Alter-XMRV-Paper-Arrives

 

Good breakdown of the results, Cort. My reading is really slow these days. Thank you!

For how long have we people with CFS/ME been pointing out the Georgia cohort selected by several CDC researchers was invalid? The absence of evidence of any retrovirus in their "patient" population has no bearing on the other findings by researchers using samples from people who actually have the disease. There is no need to discuss the CDC findings any more. They are irrelevant.

You are probably talking about XMRV/MLVs.

But evidence that the CDC don't pick good samples are useful to dispute the findings about childhood abuse being cause (two studies), higher rate of personality disorders, current and lifetime depression, etc. On the surface, these can look like good community sample studies.

 

The gag sequence they identified, however, is not specific to XMRV - it is a marker for a range of murine leukemia retroviruses of which XMRV is one.

and the paper:

The sequences in all four variants were more closely related to the sequences of polytropic mouse endogenous retroviruses (mERVs) than to those of XMRVs

and

"The sequence alignment and the phylogenetic analysis of the MLV-related virus env gene sequences obtained from both the
CFS patient and healthy blood donor revealed that they were also more closely related to those of polytropic or modified polytropic
MLVs than to those of XMRVs" Lo et al.

nothing to do with specific.

 

Although three MLV’s were found one MLV dominated the rest, infecting 86% of the CFS patients. One of the MLV’s was found also in one healthy control.

They are talking about gag gene sequences.

What is going with XMRV itself is not as important as it was before the Alter paper

Are you kidding?

While the WPI’s overall thesis was confirmed we still have two disparate findings; the WPI found XMRV and no other MLV’s while the Lo/Alter group found no XMRV and several other MLV’s. Researchers abhor impasses like this and they must eventually be cleared up. That the virus is exceedingly tricky is clear.

you just don't get it, do you

It’s possible but hardly likely that both findings are correct. It’s more likely, I would guess, based on the ‘swarm’ thesis, that the problem lies with the WPI findings rather than Dr. Alter’s.

Wow!!!! Both findings are likely correct. Alter has completely vindicated the WPI, what are you trying to do Cort? This is way out of order.

I don't know if I can bear to read the rest of it. I wouldn suggest you don't bother ever again. You are doing a disservice to every patient with the disease by posting nonsense like this.

The FDA response did not, interestingly, suggest that they believed other problems with methodology played a role.

Yes they did, here:

"Indeed, it is possible that the PCR primers used in various studies may have different sensitivity in detecting the diverse group of MLV-related virus gag gene sequences that we found in the clinical samples. The 5′ gag leader sequence of previously described XMRVs represents the most divergent segment of the XMRV genome in comparison with the genomes of the other MLVs (4). In particular, there is evidently a unique 15-nt deletion in the 5′ gag leader region in all of the XMRVs previously identified in patients with prostate cancer and CFS (3, 4). To detect XMRVs in human samples with better sensitivity and specificity, some studies used a PCR primer spanning this unique deletion as the “XMRV-specific” primer (6). However, none of the viral gag gene sequences amplified from the blood samples of CFS patients and blood donors in our study has this particular deletion (Fig. S1). As a consequence, such primers might have been insensitive in detecting the MLV-related gag gene sequences that we have identified." Lo et al.

 

No, that's not correct.
Remember it takes a while for things to be published.
The patients were seen in 2003.
The paper on them is what started the "empiric" definition:
http://www.biomedcentral.com/1741-7015/3/19

I think you're getting confused. The CDC say that the empiric criteria are just an operationalised version of the Fukuda criteria. That's why they say the prevalence is now 2.54%. That's what they say in all the papers using the empiric criteria - they don't say they're using a different set of criteria.

That is partly my point. Although the people who were diagnosed as CFS (empiric) in http://www.biomedcentral.com/1741-7015/3/19 may never have satisfied the ordinary Fukuda definition in 1997-2000 as they also brought in ISF, CFS MDDm (i.e. hadn't been given the diagnosis of CFS because they previously had melancholic major depressive disorder). The paper at http://www.biomedcentral.com/1741-7015/3/19 doesn't make things as clear as it should.

Unless we know that the blood was taken from them between 1997 and 2000, rather than 2003 (when they did all the testing), we should assume that they all are just "empiric" criteria patients.

They had to use a group of patients to figure out the parameters of the Empirical definition; the patients they used were first identified as CFS patients under the Fukuda definition. Remember that those patients were identfied in 1997-2000 long before the Empirical definition was even a theory. Those were 'Fukuda' patients.

You can't assume that they used a definition that was published in 2005 on patients whose samples were taking in 2003. That is assuming too much.

THe CDC has always said that the ED simply operationalizes the Fukuda definition -if you agree with that then I suppose you can say they all met the Empirical definition -but that makes the difference between the two meaningless and raises the question what is all the hullaballoo about the two definitions all about. Operationalizing pf Fukudua was the goal of the ED and an international committee containing Lenny Jason signed on to that but the criteria were created by the CDC alone - and few agreed with them...The CDC's study showed that the ED bumps out some people who were classified as having CFS under the Fukuda definition and adds quite a few people who werent.

 

They also found 4 MLV's, not 3, and even that is misleading

The Alter/Lo group did not do that, citing the difficulty of having to wade through from hundreds to 1,000’s of cells in order to find the one infected with MLV’s. (Yes, it is very rare in the blood!).

That's is not accurate. I cannot find the source right now, but that makes them sound lazy. They only believed that there was no reason to delay the paper.

This study was a big breakthrough. It demonstrates that there are most likely problems with the other studies. I'm stunned that you keep saying that they were all looking at the same genetic sequence, as if that ruled out problems with geographical distribution and mutation. Never mind the fact that none of the negative studies calibrated their tests to a known human sample.

I would also like to see a reference to this?

 

Found on XMRV Global Action Facebook 5 posts down
http://www.facebook.com/pages/XMRV-Global-Action/216740433250

I've contacted Dr. Mikovits to see if any errors were made - or what Andrea was referring to when she said 'much misinformation'. I looked over it - I don't really see any problems or anything that portrayed them in a negative light but I will report back.

 

They had to use a group of patients to figure out the parameters of the Empirical definition; the patients they used were first identified as CFS patients under the Fukuda definition. Remember that those patients were identfied in 1997-2000 long before the Empirical definition was even a theory. Those were 'Fukuda' patients.

Remember that it was not just those that those that were brought in. ISF, CFS but MDDm, ISF but MDDm, controls were brought in. One can see it in: http://www.biomedcentral.com/1741-7015/3/19/

From what I recall, looking back, one is down to 46 people who previously had been diagnosed with CFS, only 6 of whom had CFS (normal Fukuda) by 2003. Very unlikely that the 43 they found satisfied the empiric criteria were from that group. They never claimed everyone who satisfied the empiric criteria had once satisfied the Fukuda criteria (when the Fukuda criteria are read as the "surveillance criteria).

You can't assume that they used a definition that was published in 2005 on patients whose samples were taking in 2003. That is assuming too much.

I'm not sure exactly what you are saying. In the empiric paper, it makes clear that the definition is derived from the patients from the Wichita 2-day study e.g.

The study was conducted from December 2002 to July 2003

http://www.biomedcentral.com/1741-7015/3/19/
and

Data came from a 2-day in-patient study of 227 people with CFS, with other chronically fatiguing illnesses, and matched non-fatigued controls identified in the general population of Wichita, Kansas.

etc.

Actually, I think something has been added to the Switzer paper since I read it. It makes clear now that the samples were from the Wichita end of 2002-2003 study (as I recall all the testing was in 2003 - they may have just started contacting people in Dec 2002). So now we know that they all were chosen using the empiric criteria. The only doubt was if they had used stored blood from 1997-2000.

Details of our two study populations have been
described previously [2,26,27]. Briefly, between 2002 and
2003 we sampled adults 18 to 59 years old from Wichita,
Kansas [26,27] and between 2008 and 2009 we sampled
adults 18 to 59 years old from metropolitan, urban, and
rural Georgia [2].

Basically it comes down to this:
all the CDC patients in the Switzer et al study are empiric criteria patients. Within any study that uses the empiric criteria, there may well be patients who satisfy the Fukuda criteria. But patients were chosen using the empiric criteria.

 

Please back off people. Yes, there were errors; there is confusion. Cort was reporting, with considerably higher fidelity than mainstream media.

The use of the 'empirical definition' and the claims about what is equivalent, are taken from the Switzer paper. I don't see any way to eliminate enormous confusion from that. We have, for example, Jason's work showing the ED is about like flipping a coin in distinguishing CFS from depression. I also feel that they could use a later definition, even if they had not said it was in use at the time the samples were drawn, by excluding those samples from patients which did not meet criteria used at time of publication. I don't expect that obscurity to be cleared up. This is all simply water under the bridge.

As for the overall significance, I don't think you can ignore Alter's statements that his results support and confirm those in the Science paper. He appears to use the labels XMRV and MLV interchangeably, when he is not being specific and careful. There were gamma retroviruses in samples from CFS/ME patients. They were very similar to XMRV. They were very similar to each other.

More shoes are about to drop concerning CDC ability to detect virus in samples. Let them try to explain what they did, and why they felt this applied to CFS in particular. They had results showing XMRV was never found in the blood of prostate cancer patients. Why wasn't that trumpeted as widely?

 

Please back off people. Yes, there were errors; there is confusion. Cort was reporting, with considerably higher fidelity than mainstream media.

My initial post was relatively gentle.
It was only when Cort said I was assuming too much etc that I justified more where I was coming from.

Other people may not be interested in the empiric criteria issue. But I think it is very important. The CDC have published lots of psych papers in the last five years and probably have more in the pipeline. It's also very relevant when challenging the Switzer findings.

 

mitochondrial infection

While a number of people, (myself included,) have mentioned viral infection of mitochondria, I want to make it clear this is not as straight-forward a question as it may seem. Most of the time you don't find a virus infecting mitochondria. Murine Leukemia Virus itself is the one exception I've heard about, in mice.

The general rule has become almost dogma in some minds. This is because most of the time it is true. As anyone with ME/CFS should know, when exceptions occur they can be very important. The medical school rule of thumb "When you hear hoofbeats, think horses, not zebras." is handy for overly imaginative students, but researchers need to notice things like donkeys, mules, zebras and even the occasional okapi.

Here's my inexpert opinion on why you don't commonly find viral infections of mitochondria:

1) Many virions are physically too large. (You likely can't park a tractor/trailer in your garage.)

2) Even if the virion will fit, the entire viral genome may be too large and complicated to fit in a plasmid mitochondria can cope with. The limit seems to be something less than 10,000 base pairs, perhaps near 8,000. There are relatively few viruses with genomes that small.

3) Even if the virion and viral genome will fit, the process of converting the information into molecules which form the virion may require more sophisticated support than is available inside a mitochondrion.

This last point sounds obscure, but it can be illustrated with a gotcha in common modern computer technology. Consider the cellular machinery which translates DNA as an operating system. For the whole cell, we have something like Windows 7 (tr), with support for all kinds of obscure things needed for compatibility with older versions. For the stripped-down machinery of mitochondrial transcription, we have something like the OS of a Palm Treo (tr). If you have tried to run a Windows (tr) application on a Palm Treo (tr), you might guess a few support libraries are missing. (I could go further and compare the complexity of a complete cell to what system programmers call "DLL Hell". This, however, takes us away from the central point here.)

The bottom line is, yes, it could be true; no, it doesn't happen often or easily.

Real researchers will have to take over from here.

 

I'm sorry but Cort is confused, he is not sticking to the facts. This needs pointing out as quikly as possible, otherwise misinformation spreads and we are again at the mercy of the the Wessely's and Reeves.

 

I'm sorry but Cort is confused, he is not sticking to the facts. This needs pointing out as quikly as possible, otherwise misinformation spreads and we are again at the mercy of the the Wessely's and Reeves.

Disagree. I would like to point out that Cort has made some objective observations that make sense. Maybe you don't agree with all of them, or they are not what you want them to be, but his analysis makes sense based on the limited knowledge we actually have.

 

While a number of people, (myself included,) have mentioned viral infection of mitochondria, I want to make it clear this is not as straight-forward a question as it may seem. Most of the time you don't find a virus infecting mitochondria. Murine Leukemia Virus itself is the one exception I've heard about, in mice.

The general rule has become almost dogma in some minds. This is because most of the time it is true. As anyone with ME/CFS should know, when exceptions occur they can be very important. The medical school rule of thumb "When you hear hoofbeats, think horses, not zebras." is handy for overly imaginative students, but researchers need to notice things like donkeys, mules, zebras and even the occasional okapi.

Here's my inexpert opinion on why you don't commonly find viral infections of mitochondria:

1) Many virions are physically too large. (You likely can't park a tractor/trailer in your garage.)

2) Even if the virion will fit, the entire viral genome may be too large and complicated to fit in a plasmid mitochondria can cope with. The limit seems to be something less than 10,000 base pairs, perhaps near 8,000. There are relatively few viruses with genomes that small.

3) Even if the virion and viral genome will fit, the process of converting the information into molecules which form the virion may require more sophisticated support than is available inside a mitochondrion.

This last point sounds obscure, but it can be illustrated with a gotcha in common modern computer technology. Consider the cellular machinery which translates DNA as an operating system. For the whole cell, we have something like Windows 7 (tr), with support for all kinds of obscure things needed for compatibility with older versions. For the stripped-down machinery of mitochondrial transcription, we have something like the OS of a Palm Treo (tr). If you have tried to run a Windows (tr) application on a Palm Treo (tr), you might guess a few support libraries are missing. (I could go further and compare the complexity of a complete cell to what system programmers call "DLL Hell". This, however, takes us away from the central point here.)

The bottom line is, yes, it could be true; no, it doesn't happen often or easily.

Real researchers will have to take over from here.

Hi, ancientdaze.

For what it's worth, in some of the lab reports on PWCs that I've seen from Dr. John McLaren Howard's neutrophil mitochondrial testing (now of AcumenLab, formerly Biolab Medical Unit) he reported finding foreign DNA in the mitochondria, which he thought to be viral.

Best regards,

Rich

 

If you are wondering why some people are not thanking Cort for this article, here are a few reasons.

His article is full of errors that anyone who just read the studies and repeated what they said would not make...unless they had an ax to grind or a spin to spin. Cort has a history of subtly spinning valid information to make it seem to say something else.

One example is his contention that FDA said it was cohort, not method, that would account for CDC not being able to find XMRV.

In fact, the FDA article specifically says that "Undefined difference in the methods of sample preparation (remember Vernon mentioned the chemical in the tubes they used for blood collection was inappropriate for viruses?) could be contributing to the discordant test results."
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm223232.htm

He once again, tries to make out that WPI didn't do what they did, or that it isn't as important as it is, while speaking out of the other side of his mouth and damning them with faint praise. Mikovits has been quoted all over the web as saying that they have been finding these other variants of MLVs, so his inference that they didn't find them is just spinmeistering and subtle slamming.

Also, his inference that there are "four viruses" is just wrong. XMRV is a variant MLV. He apparently doesn't get that, or doesn't want to stop trying to make out the XMRV variant isn't important.

He emphasizes the murk and ignores the light in this research. He continually emphasizes how hard it is to know anything about this illness. His vested interest is in keeping it mysterious and murky, even if he had to help provide the mud with which to muddy the water.

His frequent mention of contamination is another tactic of the denialists. He then goes on to say how it has been essentially disproven, but he keeps on mentioning it, bringing it back into play, thus keeping it alive. But I doubt that is why WPI will correct him. It probably has to do with his misquoting the FDA article and his inference that WPI hasn't got a clue when it comes to the MLVs that Alter/Lo/Komaroff found.

Sorry, Cort, this stuff is just too important not to say.

 

Disagree. I would like to point out that Cort has made some objective observations that make sense. Maybe you don't agree with all of them, or they are not what you want them to be, but his analysis makes sense based on the limited knowledge we actually have.

It's nothing to do with interpretation, his facts are wrong.

 

His frequent mention of contamination is another tactic of the denialists. .

Cort, a denialist?, get a life. OK this studies were hard to interpret and but this was out of line..

 

Jeeeesh people seriously...
This stuff is super difficult, especially for the brainfogged ( like me). I apreciate all the hard work that Cort does and I love reading his articles. I am sure they are not perfect and contain some assumptions or errors that is unavoidable at this stage. Great if people can point these (assumptions/mistakes) out and improve the info out there. But the personal attacks against Cort, I find them very distressing. He is not the enemy, he is human, allowed to make mistakes and allowed to have unpopular opinions if he chooses to. I can't explain it well but this all makes me so sad.

 

Sorry, but that is precisely why someone who does not understand the science should not write about it. Is all well and good to try, but not if you are misleading people. There are huge errors in the article, but they won't be spotted by most, because it is technical. People come away thinking it's only a minor thing, because they are not aware of how false the information is. He needs to pull the article down, correct the information, and then put it back up. After that he would be better getting his articles checked out first. We cannot afford to be giving the opposition a hand by making things up.

 

Jeeeesh people seriously...
This stuff is super difficult, especially for the brainfogged ( like me). I apreciate all the hard work that Cort does and I love reading his articles. I am sure they are not perfect and contain some assumptions or errors that is unavoidable at this stage. Great if people can point these (assumptions/mistakes) out and improve the info out there. But the personal attacks against Cort, I find them very distressing. He is not the enemy, he is human, allowed to make mistakes and allowed to have unpopular opinions if he chooses to. I can't explain it well but this all makes me so sad.

That would be fine leaves, but he has a certain knack for making "errors" that undermine Mikovits and the WPI

 

They also found 4 MLV's, not 3, and even that is misleading



That's is not accurate. I cannot find the source right now, but that makes them sound lazy. They only believed that there was no reason to delay the paper.

This study was a big breakthrough. It demonstrates that there are most likely problems with the other studies. I'm stunned that you keep saying that they were all looking at the same genetic sequence, as if that ruled out problems with geographical distribution and mutation. Never mind the fact that none of the negative studies calibrated their tests to a known human sample.

I would also like to see a reference to this?

I request that you reread the paper. I think I very clearly stated Dr. Mikovits assertions that the different studies are using different probes. I didn't make the statement that they are looking at the same genetic sequence - if you care to read the papers they did. It turns out that there is more to the story and I'm working on that now.

I also made a big point about different cohorts.