Six strains of XMRV so far!

gracenote

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Here is why Baraniuk thinks XMRV could be significant.

The relatively recently described zenotropic murine leukemia virus-related virus (XMRV) [1] is a retrovirus that has been (XMRV) is a γ retrovirus that has been associated with associated with chronic fatigue syndrome (CFS) [2, 3] and prostate cancer [4]. This is of importance because CFS patients are commonly seen by allergists, immunologists, rhinologists, and many other physicians for their neurological nonallergic rhinitis, fatigue, pain, generalized hyperalgesia and allodynia, dyspnea without airway obstruction, drug intolerances, irritable bowel, irritable bladder, postural orthostatic tachycardia and hypotension, and other autonomic dysfunction syndromes. These are in addition to the unexplained fatigue plus at least four of the following eight conditions required for CFS case designation: 1) poor concentration or memory, 2) sleep disturbances, 3) exertional exhaustion (a small increase in activity level leads to a relapse of fatigue), 4) arthralgia, 5) myalgia, 6) sore throat, 7) sore lymph nodes, and 8) headaches [5]. Because reliable biomarkers have not been identified, this illness is often dismissed by physicians as a figment of the somatopathic patients mind.

The new finding in XMRV in CFS must make us pause and take a fresh look at these frustrated and disillusioned victims of medical neglect. . . .
I love that there are many brains looking at this; it means I don't have to think too hard, and someone (you know who you are Dr. Yes) will correct me if I've gotten it wrong!
 

gracenote

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Here is an article from WebMD Health News, Dec. 1, 2005.

Evidence for Chronic Fatigue Syndrome?
Proteins in Spinal Fluid May Be Markers of Syndrome, Early Tests Show


By Miranda Hitti

Scientists may have found biological evidence of chronic fatigue syndrome.

Chronic fatigue syndrome involves severe, unexplained tiredness that lasts for at least six months and doesn't improve with rest.

Chronic fatigue syndrome often greatly interferes with patients' lives. But it hasn't been well understood from a scientific point of view, and its cause is unknown.

The new evidence lies in patients' spinal fluid. Tests show 16 proteins in the spinal fluid of people with chronic fatigue syndrome but not in healthy people, according to a study in BMC Neurology.

Protein Proof
Of those 16 proteins, five especially stood out. "If you had one of those that was present, then you had chronic fatigue syndrome," researcher James Baraniuk, MD, tells WebMD.

Baraniuk is an associate professor of medicine at Georgetown University Medical Center.

"This ushers in a whole new era for identifying [and] recognizing the legitimacy of these disorders,' he says.

Baraniuk and colleagues compared spinal fluid from 50 people with chronic fatigue syndrome and related conditions to spinal fluid from 22 healthy people.

The researchers originally recruited people with fibromyalgia or Persian Gulf War illness and later realized that many of the patients had chronic fatigue syndrome.

"That's very important because it suggests that these are allied disorders," Baraniuk says, adding that the term "Persian Gulf War illness" is no longer used by the U.S. Army.

Test Not Ready Yet
"I don't believe there's much value in getting a spinal tap and finding somebody to measure these different proteins," Baraniuk says.

"First off, it's a research tool. ... You'd have to measure maybe 20 proteins and look at what the pattern is like. We're not there yet in terms of technology to be able to do that."

He notes that the proteins were identified in two different sets of patients. "The odds of finding these exact same proteins twice [are] astronomical," Baraniuk says.

Breaking New Ground
"People generally and many physicians generally believe chronic fatigue, fibromyalgia are not legitimate disorders," Baraniuk says.

"They sometimes treat these people extremely rudely and don't pay any attention to their symptoms," he continues. "As a result, these patients will go from doctor to doctor. The average is for them to see seven subspecialists a year and have seven different names for the problem."

"They will be told they have functional disorders, which means there's no test you can do to prove it and there's very few drugs that you can take to improve it," Baraniuk says.

"But a study like this shows that these people have something in their cerebral spinal fluid that separates them from the normal population," he says.
 

gracenote

All shall be well . . .
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how does one access the library to read this full article?

thanks!
rrrr
Rrrr,

There are two ways to access the library.

1. Reach 100 posts and become a "senior" member of Phoenix Rising. (If you need help with this, we can start you a thread and ask you questions. You only have 29 posts to go.)

2. PM a PR administrator or moderator and ask that they allow you access to the library.

Reaching 100 posts might be more fun. We'll cheer you on.

:victory:​
 

Cort

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The new finding of XMRV in CFS must make us pause and take a fresh look at these frustrated and disillusioned victims of medical neglect. At the same time, we must maintain skepticism about this viral etiology given the history of other inferred causative agents, such as Epstein-Barr virus; entero- virus; cytomegalovirus; neurotropic herpes types 6 and 8; mycoplasma; Q fever; Murray Valley encephalitis; other microbes; specific genotypes; and an array of immune deficits ranging from low CD4, CD8, and natural killer cell activities to various antinuclear antibodies to cytokine imbalances [6–8]. Baraniuk
I can certainly understand some unease at this statement but I would note that we're kind of immersed in the pro-viral side of CFS. I would hazard to guess that the research community in general is very cautious (skeptical) about the ability of EBV and HHV-6 and other factors to cause this disease.

At the Symposium on Viruses in Balt in 2008 Dr. Gallo basically said you've gotta figure out what you think HHV6 does otherwise its never going to get any credibility. Researchers are investigating too many different angles about HHV-6 - too many that he thinks it could possibly be responsible for. That field has a long way to go to attain real credibility in the research community.

I think the fact that antiviral drugs have been very effective for some patients obviously says something about those viruses and I think the evidence for viral reactivation is strong but are they causative; I would guess not causative but one part of the picture for some patients.

Both EBV and HHV6 have gained ground in CFS in recent years. At one time they were both thought to be 'it', were pretty much thrashed, and then have risen back up. That process could be what he's referring to.

Even the NIH has said, after pretty blankly stating at one point that they're not interested in pathogens, that they do have some interest in pathogens in CFS now. They did (finally) fund the WPI's big immune study.
 

Cort

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If you read the recent newsletter on him and you know that Baraniuk is very committed to a physiological interpretation of chronic fatigue syndrome. I don't know where he stands on pathogens; he's been looking in the spinal fluid for pathogens in his brain proteome study and he hasn't found anything. Its funny how little clarity there is on pathogens in the field at large; in his latest book Dr. Natelson said he always tests for pathogens because if you can find them then he can do something about them -but he says he hardly ever finds them! He's pretty conservative in his treatments but he's not stodgy with his testing. He even tests for Lyme disease now. Is he using the wrong tests? Does he have a different set of patients? Unless I missed it I don't think there's anything in the CAA's Medscape Physician education program written by Dr. Bateman and Dr. Lapp on pathogens or antivirals.....Its still a pretty fragmented field treatment wise. You have Cheney with his stem cells, Dr. Peterson and with his antivirals, Holtorf with his hormones and physicians who don't use any of those.
 

Rrrr

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thanks, gracenotes. what a funny way to access the library. i wonder if there is some way to tell folks that this is how to access the library, instead of just that notice that says you can't access the library...?

xxoo
rrrr
 

gracenote

All shall be well . . .
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thanks, gracenotes. what a funny way to access the library. i wonder if there is some way to tell folks that this is how to access the library, instead of just that notice that says you can't access the library...?

xxoo
rrrr
Good question Rrrr. I would take that up with the Cort. Now you only have 23 posts to go.
 
G

Gerwyn

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In the past there have been several viral candidates proposed as causative agents of ME/cfs

Any causative agent must be able to account for all the observed bioabnormalities in ME patients reported in studies involving correctly diagnosed patients.

In particular if a viral ageant is proposed as the causative ageant the properies of that virus must be able to account for

! post exertional malaise induced by physical or cognitive effort
2The abnormal expression of a large number of genes

The viral ageants so far do not exhibit the properties that can account for those observations and neither do Hervs..

The following attracted my attention

Infectious XMRV tends to insert into the human genome at
transcription start sites, CpG islands, DNase-hypersensitive
sites, and gene-dense regions [18].
XMRV inserts into the start "switches" of genes

XMRV was originally discovered in the start sequence of a CREB gene.

CREB/CRE proteins are involved in gene regulation in all bodily systems

Hence there is apossible mechanism whereby XMRV gan interfere with gene regulatory functions

But there are a wide range of abnormally regulated genes reported.

Rertoviruses are unique in being able to act as transposons in short they can move about the same chromosomes or different chromosomes in the same cells and or different cells

Hence XMRV has the potential to be a moblie gene regulator effecting the regulation of different genes at the same time or different times

Gammaretroviruses in general and MuLV in particular have been shown to to indirectly(Via NO production) and directly(via integration)damage mitochondria.Damage to Mitochondria (even if slight) would produce PEM.

No other class of virus has been shown to produce mitochondrial damage in this manner

Nitric oxide concentrations are elevated by the activation of IFN alpha.INFalpha is upregulated by CREB cre systems.XMRV integrates into CREB genes

Xmrv as a causative agent explains the observations in a way that no other class of virus can

The other parts of the paper that drew my attention was the following

XMRV is xenotropic because highly similar viruses exist in
the germline of mice, but their envelope (env) proteins no
longer have a receptor on murine cells [14••]. Although it
cannot reproduce in mice, the virus can bind to receptors in
other foreign (Greek xenos) species, including humans
and

It is not known when XMRV began to
infect humans, but it may have been within the last few
hundreds of generations given the 99% identity between the
six genomes that have been sequenced to date from
activated CFS leukocytes and advance
d prostate cancers

finally

XMRV proteins, RNA, and DNA were detected in plasma,
phytohemagglutin (PHA), plus interleukin-2–activated leukocytes
from CFS patients [2••, 3].
DNA sequencing
identified 736 nucleotides from XMRV Gag and 352 from
Env genes.
Now this author found the information from the science paper easily. I must ask why Mclure and Groom found it so difficult.

I must also ask why two renowned retrovirologists looking for a RNA virus did not look for viral RNA

I read the excellent article with Proff Goff.Bearing in mind that there are at least six strains of XMRV one of his sentences hit me like a club between the eyes.

He said that you only have to get your pcr primer wrong by only two neuclotides and you would not find the virus you were looking for if it was a different strain.

McClure and Groom would never have found different strain because their primer was based on a partial V62 clone
 

maryb

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Now this author found the information from the science paper easily. I must ask why Mclure and Groom found it so difficult.

I must also ask why two renowned retrovirologists looking for a RNA virus did not look for viral RNA

I read the excellent article with Proff Goff.Bearing in mind that there are at least six strains of XMRV one of his sentences hit me like a club between the eyes.

He said that you only have to get your pcr primer wrong by only two neuclotides and you would not find the virus you were looking for if it was a different strain.

McClure and Groom would never have found different strain because their primer was based on a partial V62 clone


Gerwyn now if you've worked it out lets hope others can, quickly.
 

natasa778

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The six strains of XMRV that have been sequenced have greater than 99% identity,
indicating a new human infection
Yes, whatever is causing CFS has to be VERY recent, very new, I don't think it passed "within the last 100 or so generations" or “less than 1000 years ago” as we would have seen CFS in humans sooner.

IMO only two versions are possible, either whatever is causing CFS has entered humans VERY recently, less than 100 years ago.

Or the causative agent/s have been around for longer but something new in the environment (toxins, pesticides etc) have caused IT to mutate and become pathogenic.

That is why I don’t buy the theory of “eating mice” causing xmrv to jump species – people have eaten mice throughout history, if nothing else then out of necessity throughout long periods of hunger and wars, and unfortunately there have been plenty of those in human history. Same with HIV – if it jumped from monkeys because of some odd tribal customs, or some naughty monkeys biting men, well those things would have been happening throughout history and still HIV waited to jump over until now.
 
G

Gerwyn

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Yes, whatever is causing CFS has to be VERY recent, very new, I don't think it passed "within the last 100 or so generations" or “less than 1000 years ago” as we would have seen CFS in humans sooner.

IMO only two versions are possible, either whatever is causing CFS has entered humans VERY recently, less than 100 years ago.

Or the causative agent/s have been around for longer but something new in the environment (toxins, pesticides etc) have caused IT to mutate and become pathogenic.

That is why I don’t buy the theory of “eating mice” causing xmrv to jump species – people have eaten mice throughout history, if nothing else then out of necessity throughout long periods of hunger and wars, and unfortunately there have been plenty of those in human history. Same with HIV – if it jumped from monkeys because of some odd tribal customs, or some naughty monkeys biting men, well those things would have been happening throughout history and still HIV waited to jump over until now.
no eating mice is nothing at all to do with it >I go with coffin and 60 years
 

Dr. Yes

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In the past there have been several viral candidates proposed as causative agents of ME/cfs

Any causative agent must be able to account for all the observed bioabnormalities in ME patients reported in studies involving correctly diagnosed patients.

In particular if a viral ageant is proposed as the causative ageant the properies of that virus must be able to account for

! post exertional malaise induced by physical or cognitive effort
2The abnormal expression of a large number of genes
I think you're right Gerwyn.. as long, of course, as you consider a single causative agent model. However, a virus (like XMRV) may be a prerequisite primary causative agent but not the sole one in development of some or all pathology. The model of XMRV being the primary cause but requiring co-factors (perhaps certain herpes viruses, for example) to generate ME/CFS seems to be favored by Mikovits at present. That would make causation a little more complicated to establish, though it would still be easy enough to demonstrate that XMRV infection is necessary for ME/CFS.
The viral ageants so far do not exhibit the properties that can account for those observations and neither do Hervs..
Not so far, no. But HHV-6, for one, is getting more and more interesting. HHV-6B has been shown to cause damage to and dysfunction of mitochondrial membranes and christae. HHV-6 has also been found to integrate into chromosomes as its mode of latency instead of episomally in nuclei - of course that is in telomeres only, and it does not have the transposable/ recombinant abilities of a retrovirus.

That said, XMRV definitely seems like the best candidate (by far) for the simplest explanation for the observed pathology - a single causative agent model.

The following attracted my attention

XMRV inserts into the start "switches" of genes

XMRV was originally discovered in the start sequence of a CREB gene.

CREB/CRE proteins are involved in gene regulation in all bodily systems

Hence there is apossible mechanism whereby XMRV gan interfere with gene regulatory functions

But there are a wide range of abnormally regulated genes reported.

(...) XMRV has the potential to be a moblie gene regulator effecting the regulation of different genes at the same time or different times
Kerr found 88 genes with differential expression in CFS patients. It might be interesting to look for XMRV sequences in the sequences of some of these abnormally regulated genes, or for characteristic deletions. I don't know off hand how closely Kerr looked at the genes in question.

Do you know if any of those 'great 88' were CREB/CRE genes, by the way?

I read the excellent article with Proff Goff.Bearing in mind that there are at least six strains of XMRV one of his sentences hit me like a club between the eyes.

He said that you only have to get your pcr primer wrong by only two neuclotides and you would not find the virus you were looking for if it was a different strain.

McClure and Groom would never have found different strain because their primer was based on a partial V62 clone
Yes that caught my interest too (after being reminded by this paper about the nucleotide differences in the isolates found in the Science study, that is). Does anyone know if the WPI has specifically commented on that aspect of the methodologies in the UK studies? I know they suggested the possibility of a different strain, but I don't remember if they suggested PCR didn't work because of nucleotide variance with the primers used...
 
G

Gerwyn

Guest
hi Doc
Yes to all.CREB/CRE proteins would be involved in thr regualtion of all 88 but with different cobinding proteins.only retros bind within start codons.Whatever does this must in some way be manipulative at the genomic level and be able to explain both observations. As a geek fact you only have to delete three nucleotides in mito dna to reduce output by 60%.A gamma could easily do that at very very low titre

I cant find anything on HHV6B in vivo Can you help?

cheers
 

jewel

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Ok, it took me so long to post, that in the meantime, there has been amazingly interesting, serious discussion of this article. He seems like another interesting researcher to follow. Thanks to all of you for your analysis for those of without 1) access to the primary source 2) background in the sciences. Thanks, J.
 

jewel

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It is interesting that it takes such miniscule impact to effectively reduce mitochondrial output...
 
S

strawberry

Guest
Fascinating discussion. I was wondering whether XMRV could account for Kerr's gene expression findings... thanks Gerwyn for sharing your thoughts on that.
 

justinreilly

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I agree Gracenote; I don't mind that comment in context (but I would say that 'objectivity' is the word he should have used... most doctors I run into are over-skeptical about CFS to the point of losing objectivity). What really bugs me about that passage is that he knocks a bunch of pathogens that are still being investigated as potentially causative! I also don't know why he considers findings on low natural killer cell activity insignificant or as some sort of red herring; the WPI certainly doesn't. Comments like that will make it more difficult for us if XMRV turns out NOT to be a causative agent; they just add to the pile of rubbish that buries other significant findings in ME/CFS research.
Agreed!
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