NIH/FDA XMRV Paper by Dr. Alter Out!

[Rrrr]

Hi, I am one who believes this is being a great week for all of us--not the end, but the second major step in the beginning of the end--it is great news.

In response to Rrrr's question about why Alter named those variants CFS 1 etc, I assume that as in astronomy the discoverer of a new object has the privilege of naming it. Alter states, as he has to, that causality has not yet been proven, only association; but clearly he believes that causality is almost certain, given the percentages. So he names them in such a way that all subsequent discussion will have to acknowledge at least the association, even if it tries to minimize it--embarrassing, to say the least. I think it was a very clever political move--and you don't get to be a top flight researcher without developing some political savvy--I worked in academia for 34 years.
Best, Chris

what i am thinking is that he named the sub-types CFS1, 2, and 3 because even tho he does not say the retrovirus causes cfs, he is basically, de facto, calling the effects of the retrovirus CFS. once these subtypes are named by him, they are named for good (for now, anyway), and anyone who wants to call them by name must use the CFS1, 2, 3, names. it is like alter is saying to all subsequent scientists who work on this MLV retrovirus, "the retrovirus IS CFS, CFS IS this retrovirus." that is what i feel from this move of his. they are not saying the retrovirus causes cfs, because they can't. technically can't. as it has not be technically proven. but they are ALMOST saying that. it's like they are coming as close as possible to saying it, without actually saying it.

 

[John Leslie]

I think the WPI was looking for other MLV viruses and only found XMRV. This is one of the somewhat disturbing results.

Regarding contamination: I am not at all familiar with the methodology of PCR and never been in such a lab. However, I will speculate. First, it sounded as though Lo/Atler really went above and beyond the usual to make sure this was not a problem. There is a second issue, which is less acceptable scientifically, but poses a strong subjective reason for not thinking contamination was a problem. Even if there was contamination, it would seem very strange that, relative to healthy controls, almost exclusively the CFS patients blood was "contaminated" in both the WPI and Lo/Alter studies. This was the case for frozen blood and blood obtained recently. What would cause CFS samples to be "contaminated" and very few controls? The odds against this seem pretty large unless someone delibrately spiked the CFS samples, which would mean unethical corruption. I doubt either in this case.

There are some strange results that still need to be clarified, and personally I am somewhat doubtful that MLVs are the cause of most CFS; however, I don't think these studies had contamination.

Even if MLVs do not cause CFS someone should try to explain WHY we have these infections and try to help us. Just saying we have compromised immune systems and that we get opportunistic infections and then once again forgetting about us totally is completely unacceptable and unethical.

Where did you get the information on what "WPI was looking for"? The WPI has repeatedly said that they were not looking just for XMRV vp62. They were looking for anything that would help the patients, and had no preconceived notions. As a result of good science, they discovered XMRV as it appears in nature in the blood, that it was transmissable, that it had variants, and they discovered other related human MLV-related viruses. They let the science lead them down this road.

 

[Anika]

Maybe an expert (which I am not) can chime in here, but my impression or recollection is that WPI did do viral chip testing (which didn't show XMRV) as part of their general research. Silverman, who discovered XMRV in prostate cancer where some type of unusual R-Nase seemed to be also associated, contacted Mikovitz at WPI because of the reported unusual R-Nase that had also been found in CFS.

A lot more obviously went on, but I think there was specific prompting for WPI to look at XMRV as discovered by Silverman - and WPI took it quite a bit further (also finding that the originally suspected association with R-Nase didn't hold up in CFS with XMRV).

What I think is most important for critics, though, is that the huge spread between positives in CFS vs controls was in fact bigger in the Lo-Alter study than in the Science study. If MRVs had been found in 30-40-50 % of controls vs 60-70% of CFS, might be a different story. (and, though we have heard that Mikovits / WPI has since found XMRV, or maybe it's MRVs, in 90% plus of CFS patients, I don't know that I've heard what the equivalent percentage is in controls with WPI's new tests.)

 

[*GG*]

Of the 41 patient samples, 29 were collected from 25 patients by one of us (A.L.K.) at the Chronic Fatigue Research Center, Brigham and Women's Hospital (Boston, MA). ... Most of the patients were from the New England Area.


Does anyone know how to maybe get an appt with a Dr at Brigham and Women's?

 

[judderwocky]

I've been thinking the same thing. The change in nomenclature could be how the paper was 'softened up' to help the CDC (and others) save face. Not that I think it would be done for the sake of the folks who did the failed studies personally, but the CDC's reputation as a government body.

i completely agree

 

[usedtobeperkytina]

what i am thinking is that he named the sub-types CFS1, 2, and 3 because even tho he does not say the retrovirus causes cfs, he is basically, de facto, calling the effects of the retrovirus CFS. once these subtypes are named by him, they are named for good (for now, anyway), and anyone who wants to call them by name must use the CFS1, 2, 3, names. it is like alter is saying to all subsequent scientists who work on this MLV retrovirus, "the retrovirus IS CFS, CFS IS this retrovirus." that is what i feel from this move of his. they are not saying the retrovirus causes cfs, because they can't. technically can't. as it has not be technically proven. but they are ALMOST saying that. it's like they are coming as close as possible to saying it, without actually saying it.

I agree. Although the results of the study itself was interesting, revealing, I think his naming the virus CFS is huge. Does childhood trauma cause viruses?

Of the other key is that the viruses mutate, like the other infectious, disease-causing retroviruses.

Tina

 

[Sean]

Even if MLVs do not cause CFS someone should try to explain WHY we have these infections and try to help us. Just saying we have compromised immune systems and that we get opportunistic infections and then once again forgetting about us totally is completely unacceptable and unethical.

Agree with that.

 

[Sean]

What this study means to us... (my personal take on the situation)...

Very well said, sir.

So, of the patients who had been 'rigorously evaluated', to confirm that they had ME/CFS, using the diagnostic criteria that the study employed, 96% tested positive.
96% is almost identical to the final WPI figure for their cohort... It's effectively a 100% result, which I think is an astonishing result.

Sure is. Highly specific associations like this, with a high level of explanatory value (ie plausibility), are extremely unlikely to be random chance, or secondary phenomena. At the very least, this family of viruses is of primary pathogenic significance, and is very close to being effectively proven the primary cause.

In response to Rrrr's question about why Alter named those variants CFS 1 etc, I assume that as in astronomy the discoverer of a new object has the privilege of naming it. Alter states, as he has to, that causality has not yet been proven, only association; but clearly he believes that causality is almost certain, given the percentages. So he names them in such a way that all subsequent discussion will have to acknowledge at least the association, even if it tries to minimize it--embarrassing, to say the least. I think it was a very clever political move--and you don't get to be a top flight researcher without developing some political savvy--

Alter knows what he is doing, how to play the game, and what is at stake.

 

[Mithriel]

There is a bacteria called Haemophilus influenzae so named because it was thought to be the cause of flu. Later they discovered that it is a virus that causes flu but the bacteria causes lung problems once you have flu which is why it was found in so many cases.

That is why they can't say that MuLVs cause ME/CFS.

The psychologisers are taking people like Alter saying there is no proof that HGRVs are causative to mean that they could just be hanging around harmlessly but that is not what is meant.

The cause of ME/CFS may turn out to be genetic or a reactivated HERV or another virus or whatever but a lot of the symptoms and suffering is bound to be being caused by HGRVs as we know from animals how much disease they induce.

Haemophilus doesn't cause flu but if you get it as well as flu you are very sick and treating it makes you much better.

Mithriel

 

[Esther12]

Given the psychologisers emphasis on triggering and maintaining aspects of CFS, even of MRVs are only an opportunistic infection, they could also be the cause of CFS.

In many way CFS seems to be an opportunistic disease. Many people came down with CFS following glandular fever. If MRVs were an opportunistic infection that took advantage of the damge done by EBV and then prevented a normal recovery, then they would have caused CFS.

 

[pictureofhealth]

I'm not sure I understand whether the CFS patients were shown to be INFECTED by these viruses, or were traces just found at this point?

I would appreciate any answers on this. Thanks.

I think either the original PNAS paper or the FDA Q&A session for the press (on the FDA website) shows either Lo or Alter specifically using the word 'infected'. Sorry too knackered to go and check the original articles/press interviews just now!

 

[SironaL]

Given the psychologisers emphasis on triggering and maintaining aspects of CFS, even of MRVs are only an opportunistic infection, they could also be the cause of CFS.

In many way CFS seems to be an opportunistic disease. Many people came down with CFS following glandular fever. If MRVs were an opportunistic infection that took advantage of the damge done by EBV and then prevented a normal recovery, then they would have caused CFS.

I thought about this too, and i think an initial environmental factor (which include infections) first has to suppress an effective Th1 immune response in the host to enable XMRV to infect that person and start to cause immune dysfunction on its own.
I have another study, which is rather complicated and technical, but very powerful. they have studied a large range of different cytokines and their expression in relation to each other. Results show that cfs patients have attenuated Th1 and Th17 immune response. Th1 is a T-cell response that is necessary to overcome/resist viral infection. Th1 cells, when activated, secrete Th1 cytokines of which IFN (interferones: alpha, bta, gamma), IL-2 and IL-12 are important members. IFNs activate antiviral responses in neighboring cells called the IFN pathway. This pathway includes RNAseL, which normally degrades viral RNA, hostcell mRNA, and induces apoptosis of the infected cell. This apoptosis prevents the virus from further replicating in that cell and causes the cell (with the virus) to be cleared by macrophages. As we know CFS has been linked to RNAseL dysfunction and to a Th1 to Th2 shift in immune response. Th2 cytokines, expressed in increased amounts in cfs, inhibit development of Th1 cells and an Th1 immune response. Th17 is another activated T-cell subset which should clear (intracellular) infection. I'm not familiar with Th17 and it is an T-cell subset in which much research still has to be done.
XMRV is sensitive to IFN partway responses, which could both explain why not everyone gets XMRV (and cfs) and why we would be sensitive to this virus. This would however imply that immune dysfunction precedes XMRV infection. although this is not impossible, i personally think that temporary immune suppression by environmental factors during first XMRV infection would be sufficient to cause chronic infection. Once XMRV is established in immune cells it can perform immune suppression on its own and maintain immune dysfunction for as long as the infection is present.

-Silverman, R. H. et al. Nat. Rev. Urol. advance online publication 1 June 2010; doi:10.1038/nrurol.2010.77
-In Vivo. 2005 Nov-Dec;19(6):1013-21.
Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome.
Nijs J, De Meirleir K.
Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium.
Abstract
This paper provides an overview of the evidence addressing the impairments of the 2'-5' oligoadenylate (2-5 A) synthetase/RNase L pathway in Chronic Fatigue Syndrome (CFS) patients. The 2-5A synthetase/RNase L pathway in CFS patients appears to be both up-regulated (i.e. increased levels of bioactive 2-5A synthetase and increased activity of the RNase L enzyme) and deregulated (elastase and calpain initiate 83 kDa RNase L proteolysis, generating two major fragments with molecular masses of 37 and 30 kDa, respectively). The deregulation of the 2-5A synthetase/RNase L pathway in CFS accompanies decreased NK-function and deregulation of apoptotic pathways. Since various components of the pathway appear to be related to performance during a graded exercise stress test, some evidence supportive of the clinical importance of the impaired pathway in CFS patients has been provided. Studies addressing the treatment of the deregulation of the 2-5A synthetase/RNase L pathway in CFS are warranted.
PMID: 16277015 [PubMed - indexed for MEDLINE]

-1. Brain Behav Immun. 2010 May 4. [Epub ahead of print]
A formal analysis of cytokine networks in Chronic Fatigue Syndrome.
Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA.
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans
for which no characteristic lesion has been identified. Instead of searching for
a deficiency in any single marker, we propose that CFS is associated with a
profound imbalance in the regulation of immune function forcing a departure from
standard pre-programmed responses. To identify these imbalances we apply network
analysis to the co-expression of 16 cytokines in CFS subjects and healthy
controls. Concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23,
IFN-gamma, lymphotoxin-alpha (LT-alpha) and TNF-alpha were measured in the plasma
of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks
were constructed from the pair-wise mutual information (MI) patterns found within
each subject group. These networks differed in topology significantly more than
expected by chance with the CFS network being more hub-like in design. Analysis
of local modularity isolated statistically distinct cytokine communities
recognizable as pre-programmed immune functional components. These showed highly
attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but
weak interaction patterns pointed to an established Th2 inflammatory milieu.
Similarly, altered associations in CFS provided indirect evidence of diminished
NK cell responsiveness to IL-12 and LT-alpha stimulus. These observations are
consistent with several processes active in latent viral infection and would not
have been uncovered by assessing marker expression alone. Furthermore this
analysis identifies key sub-networks such as IL-2:IFN-gamma:TNF-alpha that might
be targeted in restoring normal immune function.
PMID: 20447453 [PubMed - as supplied by publisher]

I think either the original PNAS paper or the FDA Q&A session for the press (on the FDA website) shows either Lo or Alter specifically using the word 'infected'. Sorry too knackered to go and check the original articles/press interviews just now!

The original Science paper too included several lines of evidence that they where not only detecting a virus that had infected CFS patients, but also that viral proteins where expressed in blood cells (which only occurs when the virus is actively replicating in the cells) and that infetious viral particles where present in the blood (they where able to infect a human cell line).

 

[usedtobeperkytina]

I think this has to be the turning point.

Option 1) these folks have retrovirus causing immune system defect.

Option 2) these folks have a pre-existing immune system defect that makes them more likely to have this virus active.

Either way, it is a disease, infectious or immune system.

I know we have had other viruses show up in higher amount, but this one is different. 7% compared to 87%. There is a clear problem there.

Tina

 

[Bob]

I think this has to be the turning point.

Option 1) these folks have retrovirus causing immune system defect.

Option 2) these folks have a pre-existing immune system defect that makes them more likely to have this virus active.

Either way, it is a disease, infectious or immune system.

I know we have had other viruses show up in higher amount, but this one is different. 7% compared to 87%. There is a clear problem there.

Tina

Yes Tina, i agree with that analysis...
Did you notice how Alter detected PMRV in 96% of the patients who had been 'rigorously' assessed as having ME? This is effectively 100%.
And Mikovits detected XMRV in 97% of her samples. (Effectively 100%)
Even if HGRV's don't actually cause ME, I expect that they would cause our symptoms.
(It might be possible that we might have a genetic defect that makes us susceptible to these viruses, so the virus isn't the actual cause of the disease, but it does cause the symptoms)...
But if the virus isn't the cause, or if it is the cause, it surely causes our symptoms, either way?!

 

[Daffodil]

personally, i think the virus is just travelling with a herpes virus for whatever reason. the person was sick with a herpes virus so they shed more XMRV in their respiratory tract and passed it along.

 

[Bob]

MLV related viruses - a simpler explanation


MLV = Mouse Leukaemia virus

MLV's are mouse retroviruses that cause cancer in certain mice.

Judy Mikovits and Harvey Alter have discovered a variety of MLV-related viruses in ME/CFS patients.

These MLV-related viruses are not MLV's (mouse viruses) but they are closely related to them.

The only difference between Alter's viruses and Mikovits' viruses are that they are related to slightly different types of MLV's.

Judy Mikovits' viruses are related to Xenotropic MLV's, and so they are 'Xenotropic MLV-related viruses'.

Whereas Alter's viruses are related to Polytropic MLV's and so they are 'Polytropic MLV-related viruses'.

So the only difference between them is the use of the terms 'Xenotropic' and 'Polytropic'.

The terms 'Xenotropic' and 'Polytropic' indicate a slightly different behaviour of a virus.


XMRV = 'Xenotropic MLV-related virus':
X = Xenotropic
M = MLV (Murine Leukaemia Virus)
R = Related
V = Virus


Alter's viruses are 'Polytropic MLV-related viruses', and so he could have named them 'PMRV' (instead of XMRV). He hasn't named them PMRV, yet. Instead, he refers to them as Polytropic MLV-related viruses, or just MLV-related viruses.

All of the viruses found so far in the two papers, are MLV-related viruses, and they are Human Gamma Retroviruses (HGRV's), which is an umbrella term.


'Xenotropic' means that a virus cannot infect, or exist as a complete, replicating virus in its original host species (i.e. mice), but it can jump to another species (i.e. humans) where it can become a whole, complete, replicating virus.

'Polytropic' means that a virus can infect both its original host species (i.e. mice) and it can jump to another species (i.e. humans).

The difference in the meaning of the two terms is why the new viruses that Alter has detected cannot be called XMRV. Alter's viruses are related to Polytropic MLV's, not Xenotropic MLV's.

It remains to be seen how all of these new viruses, or variants, will be labelled and categorised.
XMRV's (more than one variant of XMRV has now been detected by Judy Mikovits) are clearly a subset of a larger group of viruses (MLV-related viruses and Human Gamma Retroviruses).
We might end up with a new collective name for all of these MLV-related viruses.

[UPDATE: It was reported, from the 1st International XMRV Conference, that Judy Mikovits suggested the name Human-MLV-Related-Virus (HMRV) to encompass Xenotropic and Polytropic MLV-Related Viruses.]

Are Alter's viruses and Mikovits' viruses different variants of the same virus, or are they totally different viruses?
Obviously there are differences, but the similarities seem to be more significant than the differences.

Alter says that these differences are exactly what he expects to see in a retrovirus, so these observed virus mutations support the type of human retrovirus infection that Mikovits' XMRV research indicated.
Alter says that the Hep C and HIV viruses exhibit the same pattern of variants as this new type of human retrovirus that Alter and Mikovits have found in ME/CFS patients.

Indications from Alter are that all these viruses might be referred to as variants of a single disease associated virus, just the same as the multiple Hep C virus variants are often referred to as the Hep C virus (singular).

Of course, it might turn out that these retroviruses are also associated with other diseases, such as Fibromyalgia, Gulf War Syndrome, MS, Autism.


It has recently been reported that Judy Mikovits has also now found polytropic MLV-related viruses in some of the samples from her original Science study. This means that Mikovits is finding more than one virus type in individual patient samples.

But in the months since then, they have continued to study the CFS patients included in the Science paper and Mikovits says that almost all of them are positive for one or more MLV-related viruses, including X and P.
http://blogs.wsj.com/health/2010/08...is-mark-the-spot-in-chronic-fatigue-syndrome/

See here for a diagram, extracted from the Alter & Lo paper, of a 'phylogenetic tree' (i.e. a virus family tree) of MLV-related viruses... Specifically, the diagram shows the relationship of the viral gag gene sequences, taken from blood samples of CFS patients and blood donors in Alter's paper, with other MLV's:
http://www.cfids.org/mlv/phylogenetic-tree.pdf


One other interesting thing to note is that the 'commentary' in PNAS says that:

...XMRV genomes are actually hybrids between polytropic endogenous MLV sequences ... and xenotropic MLV ...
http://www.pnas.org/content/early/2010/08/16/1007944107

So I believe that whether these new viruses are related to either polytropic, or xenotropic MLV's, is not clear-cut and is not particularly significant... It's just a case of wording, and possibly an unfortunate case of using an 'X' in the naming of XMRV.

 

[Gemini]

MLV related viruses - an explanation - a simpler version

Bob,

Very nice summary: clear, concise, understandable!

Thank you!

Gemini

 

[Sean]

Bob,

Very nice summary: clear, concise, understandable!

Thank you!

Certainly is. Thanks.

 

[Mithriel]

I hope you don't mind, I've saved that to refer to again. It agrees with my reading of the papers but puts it in a very easy to understand way.

Mithriel

 

[leelaplay]

thanks Bob. Your explanation is helpful for me.