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

 

Cort, thank you for reading that study and explaining it. You had some new info.

"Will the real CFS patients, please stand up. Oh, wait, I see you can't. Well, just send me an e-mail."

I have thought, since the beginning of WPI study, that there are probably lots of undiscovered retroviruses that caused illness. It seemed to me that Mikovits was saying the virus turns on and then goes dormant. This would explain why it had not been caught. Might also explain the fluctuating nature and "Vietnam War" in the body of CFS patients. So, if they discovered one with this unique behavior, I figured there were likely others. My thought was that maybe XMRV causes variety of ailments, but the other viruses probably cause many other illnesses. Kind of like one virus can cause multiple illnesses, then another virus can cause multiple illnesses, etc.

I kind of thought that the WPI reports indicated one virus, XMRV, caused CFS. It now seems, that possibly, multiple viruses cause CFS.

So I was right about there being multiple retroviruses. And I was wrong about just one of them causing CFS.

Tina

 

aussie aussie aussie oi oi oi , go dr alter you good thing!!!!!!!!

 

So I was right about there being multiple retroviruses. And I was wrong about just one of them causing CFS.

Tina

H Tina, no you weren't 'wrong'. The Alter/Lo paper did not use the same multi methods as the Lombardi group to detect XMRV, thea authors mention this themselves in the PNAS paper on page 5 & 6. A quote from the paper now follows..........

''However, in the study of Lombardi et al. and studies reviewed subsequently by Silverman et al.the evidence for XMRV infection in humans not only involved detection of viral nucleic acids using PCR, but also reported the detection ofviral antigens, detection of anti-viral antibodies, the ability to culture the virus in a prostate cancer cell line, the detection of gamma retrovirus particles by electron microscopy, and transmission of infection to macaques. In sum, none of the four studies that have failed to confirm the PCR evidence reported by Lombardi et al., nor our own study, has attempted to fully replicate that study.''

Meaning...

The Alter/Lo paper was not a replication study, so it's inabilty to find XMRV (and simply find multiple MULV's) was not meaning XMRV wasn't also there with the MULV's. As you know XMRV is an MULV class virus, and this new study simply found the presence of MULV's again, but this time not XMRV.

You could conclude you were wrong that CFS is not caused by XMRV (on its own) when there is a replication study done on Lombardi paper. This has yet not been done. The FDA basically proved the existance of MULV's in CFS, without irrritating the CDC by proving them wrong and showing the government the WPI were correct, after all the FDA are a government agency. Alter's paper was an intelligent compromise job that didn't rock the US health departments's boat, yet simutaneously proved there is a murine retroviral link to CFS, therefore supporting the WPI.

To conclude. Two upcoming XMRV study results (not MULV's) will apparently find XMRV in CFS as the SCIENCE paper did and will NOT mention multiple MULV's. Still, the finding of MULV's has helped science, and Alter and Lo should be congratulated as it moves person's with CFS firmly into the immunology and out of the psychiatry camp. Which to put it mildly, is long over due.

Questions:

i) Do CFS patients have XMRV + multiple MULV's? (All patients) No data on this thanks to Alter/Lo not replicating Lombardi group's methods in addition to their MULV findings which they should have done.

ii) Do CFS patients have XMRV or multiple MULV's (As you are thinking Alter/Lo's paper alludes to, except it doesn't when one learns Alter/Lo didn't replicate Lombardi group's methods)

This is the big question over CFS......

Unless researchers replicate each others methods, we simply cannot know. So never rule out your original theory Tina, until the people with multiple MULV's who are negative for XMRV via Alter/Lo's methods, are re-tested via all the methods the Lombardi group used.


Then and only then could we conclude that not only XMRV causes CFS, but other MULV class viruses too.

 

Beautiful job of reporting, Cort.

 

Cort,
You should print out and frame the Forums Homepage today. Seven super informative articles of such outstanding quality overflowing with hope-filled breakthroughs and enlightening science, I was salivating reading them all! From Joey's report on Dr. Peterson, to the great news from and about WPI, to this amazingly insightful report on the Alter paper, I felt like I was reading a great issue from Time Magazine in the 1970's, when they were still cutting-edge.
Great work, Cort. Keep it up!

 

Good points Sunshine. If what you are saying is correct - that replication studies - ie those that use the same PCR process as the WPI - will find XMRV and not MLV's then I imagine all are present in ME/CFS - which would make sense. I think the Alter group is very happy to find a 'swarm' of MLV's and, of course, to include XMRV in them.

 

Cort,
You should print out and frame the Forums Homepage today. Seven super informative articles of such outstanding quality overflowing with hope-filled breakthroughs and enlightening science, I was salivating reading them all! From Joey's report on Dr. Peterson, to the great news from and about WPI, to this amazingly insightful report on the Alter paper, I felt like I was reading a great issue from Time Magazine in the 1970's, when they were still cutting-edge.
Great work, Cort. Keep it up!

Thanks Kelvin - I was looking at the Frontpage the other day and thinking that myself - Damn there's alot of good stuff on there.

 

I don't think Lo/Alter would agree that they did not essentially replicate the WPI paper in the methods used to find XMRV by PCR. It is other aspects of the study they did not replicate. That is my understanding.

 

Does it make anybody else wonder how many more there could be???

 

Good points Sunshine. If what you are saying is correct - that replication studies - ie those that use the same PCR process as the WPI - will find XMRV and not MLV's then I imagine all are present in ME/CFS - which would make sense. I think the Alter group is very happy to find a 'swarm' of MLV's and, of course, to include XMRV in them.

Thank you Cort, and also for writing the article to let us respond to it, it must have been tricky as it's very complicated to understand who is doing what from a research paper with no interviews or abilty to get answers to questions. I'm sure we'll get some answers though in the next 12 months and beyond. Hopefully they will help CFS patients know what CFS is, who has what, and if we all get entire new labels such as GRAD or stick with CFS subsets Type 1, II etc. Either way good job on the article, once again. :Retro smile:

 

I don't think Lo/Alter would agree that they did not essentially replicate the WPI paper in the methods used to find XMRV by PCR. It is other aspects of the study they did not replicate. That is my understanding.

That is my question as well. I am honestly still baffled at the WPI's ability to find XMRV in the first place. The only thing I can conclude is that very small changes in the PCR technique are enough to obscure it. It could be that the virus is so rare that you just cannot deviate from the original procedures much at all. I still do not believe that the WPI did anything 'unusual' in the PCR section of the Science paper. Dr. Racaniello stated he think there was anything unusual there.

In the revised version of their protocol on the IACFS/ME site they gave two ways to find the virus; one involved culturing and one did not. Culturing is better but is not necessary! The Alter group did not, so far as I could tell, culture the virus - they simply took the blood and scanned it for the sequences - just as the other groups did.

The WPI and every other paper, I believe, has looked for exactly the same genetic sequences in the gag gene. For some reason, the Alter group was able to pick them up while the others were not. My guess is, based on the Press Conference, is that they're not sure what they did differently.

They do however suggest that different sensitivities in different primers could explain why other groups missed the MLV's. In particular, they point out that the 'leader sequence' of the gag gene they concentrated on is different in XMRV than the MLV's.

They don't have a reason, yet, why they were unable to find XMRV...they don't seem to think, though, that that is a major issue. The important thing for them is that they found a pattern that is consistent with the WPI's results. I assume that they believe that as the studies continue they will figure out to find both XMRV and the MLV's.

To make things even crazier they report that the CDC samples they tested were negative for XMRV as well. Since the CDC sent them samples we can assume that they sent the CDC samples - what the CDC found is now the big question.

 

Excellent work Cort. This is a great deal of highly-technical information to absorb, in a very limited time. There is little comparison between the poor information provided by various talking heads to the general public, and the quality of your work. Now, if we could just get you paid on their scale.

Naturally, being the kind of person I am, there are a couple of things I'd change.

(Dr. Katz showed a slide at the CAA webinar indicating that all the participating labs, the CDC, BSRI, WPI, FDA were equally adept at detect XMRV in samples.)

True, but only if you use artificial positive samples. A fundamental finding of the Lo/Alter study is that the virus you find in infected people is different, and it keeps changing over time.

I think you mixed up the business of integrating viral genes into nuclear DNA with integration into germline DNA, something much rarer. Curiously, no one has yet mentioned the possibility this virus might infect mitochondria, possibly bypassing the nucleus.

 

Excellent work Cort. This is a great deal of highly-technical information to absorb, in a very limited time. There is little comparison between the poor information provided by various talking heads to the general public, and the quality of your work. Now, if we could just get you paid on their scale.

Naturally, being the kind of person I am, there are a couple of things I'd change.
True, but only if you use artificial positive samples. A fundamental finding of the Lo/Alter study is that the virus you find in infected people is different, and it keeps changing over time.

I think you mixed up the business of integrating viral genes into nuclear DNA with integration into germline DNA, something much rarer. Curiously, no one has yet mentioned the possibility this virus might infect mitochondria, possibly bypassing the nucleus.

I agree that we do not know if Katz was referring to 'live' or spiked samples. It could very well be that he was referring to testing the ability of the different labs to find XMRV in spiked samples. I imagine he was actually.

You're right - I did mix those up; in fact I didn't even know there was a distinction between two . I fixed it.

 

Posted by anciendaze - Curiously, no one has yet mentioned the possibility this virus might infect mitochondria, possibly bypassing the nucleus.

You know that's a great point. This is THE piece of XMRV/MULV research that when/if found will make ME & CFS patients explode in joy (hopefully not literally) and the psych's walk off red faced due to recommending exercise therapy! Infected mito's could explain why people experience brain and body exhaustion at a profound level.

If trying to 'explain' the underlying single reason for a 'state' of ME CFS, this to me makes the most sense. We know that the 1990's findings of CAV (DeFreitas) is a retrovirus and we know she found evidence of mito infection in people with ME CFS. XMRV/MULV's are retroviruses too, and are also in people with ME CFS. It certainly is a very plausible explanation and logical, even without DeFreitas's findings, especially as we know in mice, XMRV disabled CREB gene function.

I wonder who will answer the question for us? If the answer would be found in the positive, it would make ME & CFS instantly understandable for the lay person. E.g. 'I've got a retrovirus that infects my cells that make energy in my body'. How much easier would it be to say that to people, than ''ME or CFS''. Dr John McLaren Howard (Biolab) found a suggestion of this being possible by proving poor ATP/Translocator Protein function in ME/CFS Lymphocytes, the question could arise is it XMRV/MULV's causing this?

I do hope the WPI and/or other researchers are able to look for this. Finding XMRV/MULV's is a great finding and indeed it would show that we all have it and it needs to be eradicated/treated with ARV's, fine...but then we need to find the reason for the body and brain exhaustion and the process it happens by. Impaired mito function could do this.

I wonder how costly it is to 'see' infection of mito's with XMRV/MULV's, and if XMRV/MULV's testing needs to be finalised first to make sure one can see it at all?

 

I don't think there's anything new about the idea that there might be virions in the mitochondria. I think it was anciendaze who mentioned this showing up on Elaine Defreitas' electron microscope pictures, correct?

Even a non-scientist like me can develop a rough hypothesis about how this might account for the peculiar mechanisms of post-exertional malaise, particularly its delayed action, and why this symptom is unique to this disease.

 

Even a non-scientist like me can develop a rough hypothesis about how this might account for the peculiar mechanisms of post-exertional malaise, particularly its delayed action, and why this symptom is unique to this disease.

Exactly, so we need scientists to start doing something about it or at least tell us they are.

It's 'new' in the context that no one has mentioned this since October 2009 from the WPI or any known ME/CFS researcher. Klimas, Mikovits etc, none of them have said a word in their presentations. That's nearly a whole year passed. Kind of strange for something so obvious as you mentioned.

People with mitochondrial disease don't have an extreme delayed response with flu feeling days after doing something, that's the immune system part with is unique to ME CFS courtesy of those cytokines going crazy. How cytokines affect mitochondrial ATP function I don't know. If cytokines cause inflammation and immune system activation, do they therefore make cellular exhustion worse if the cells are infected with a retrovirus? From memory RNaseL Anti Viral Pathway is ramped up to compensate (as it's depleted/low molecular weight) and this also depletes ATP in ME CFS making use weaker still.

I've met someone with mitochondrial disease and he had way more energy than me (an ME CFS patient) and was able to walk and lead a life, he did have heart problems though, diabetes and vision issues.
Indeed I've met a 90yr old with more energy, as ATP is ruined in old age due to failing mitochondria that's rather disturbing to think about and why we don't seem to see many 90yr old ME CFS patients!

ME CFS is an exhaustion disease, and not a syndrome of chronic fatigue as we are told. Everything is worn out, low battery needs recharging. Eye muscles, fingers, diaphragm, face muscles everything is affected in ME CFS. It's so frustrating to not even be able to smile without one's face quivering or going into spasm after a while or even have a bowel movement without difficulty due to those weak muscles.

How ME and CFS was ignored for so long is quite incredible, the disablity was obvious yet no one ever believed us.

 

Cohort used in Lo-Alter PNAS paper

Great article, Cort!

I've been trying to keep track of the cohort used in this study, hoping to post a summary backed up by authority. Not ready for prime time yet...

But, I can note one correction that could be made in your article - where you state "The Alter study participants were provided by Dr. Komaroff from patients at his clinic. (Interestingly only half of them met the Fukuda criteria while all met the Holmes criteria.")

It would be more correct to say: "Of the 37 patients in the Alter study, 25 came from Dr. Komaroff's clinic, and the other 12 came from the practices of David Bell and Paul Cheney. (Komaroff was able to confirm that of the 25 patients from his clinic, all 25 met the 1988 Holmes criteria for CFS, and 21 of those 25 also met the 1994 Fukuda criteria. No information was provided on the criteria applicable to the other 12 patients.)"

I don't think the information about the source of the 12 non-Komaroff patients was in the PNAS paper - I think it was mentioned by McCleary in her good article, which looked back to the 1993 paper on mycoplasma fermantans that was published on these patients.

Also note - of the 25 Komaroff sample patients, 24 of 25 (96%) were positive according to the PNAS paper. This must mean that 8 of 12 of the Bell or Cheney patients (67%) were positive (implied not stated).

Lots more we still have to learn and analyze about the cohorts. But, I have seen some commentators express concern that with each "looser" case definition of CFS, there is not only an issue of bringing in people who wouldn't meet more "stringent" definitions, but there is also an issue of losing from the case definition people who meet the "stricter" criteria.

Anika

 

Self-selection etc as pre-filter prior to Holmes/Fukuda

Anika, I love your idea of the cohort summary. One thing to consider is that these were pre-filtered patients, either self-selected to some of the best biological ME/CFS practitioners in the US at the time, and/or also screened extensively by these ME/CFS physicians "in the know". So while they did indeed meet the Holmes and/or Fukuda criteria, they also undoubtedly met the unofficial "Komaroff, Cheney, and Bell Criteria".

I would submit that this would tip the scales toward these being more likely to be genuine ME patients, as compared to your run-of-the-mill Holmes patient, say, pulled from a community survey or a CBT/GET clinic.

Kind of like the Animal Farm saying, "All animals are equal, but some are more equal than others". To make an analogy, if these patients had attended say, a Wessely clinic, and were said to meet Holmes and/or Fukuda, I would suspect their pedigree would be considerably different from those studied in the Lo/Alter paper.

Bottom line, it might be important to consider what other "filters" and pre-selection biases may exist that either enhance or erode the likelihood of a given study investigating genuine ME patients - even if they all fit Holmes/Fukuda.

 

Great article, Cort. The best of what Cort Johnson does best. You not only translate the paper into plain English, you explain the implications of the findings. This is what has made me a PR fan for years.

I agree that we do not know if Katz was referring to 'live' or spiked samples. It could very well be that he was referring to testing the ability of the different labs to find XMRV in spiked samples. I imagine he was actually.

Actually the slide just before that one specified that it was whole blood spiked with XMRV positive cells, and plasma spiked with supernatent containing XMRV cells. I think it was also mentioned at the Blood Products Advisory Committee meeting.