XMRV Low Copy Number

[energyoverload]

Hi Guys,

I'm sure this has been covered somewhere before, but I can't seem to find it. So apologies if I am repeating a previous post.

What I cannot seem to understand with fog brained mind, is how exactly, XMRV is hypothesized to cause such a severe disease if the copy number is so low, like the WPI emphasize how hard X is to find in the blood because of its low copy number. And the studies in the Rheus Macquaques Monkeys shows a systemic infection that is initially high, but becomes quite low if I remember correctly. This study looked at virus in the tissues.

Say if XMRV changes some of the genes in your DNA/RNA that are largely responsible for most of the biochemical changes known as Cfs/me. And the XMRV infection is a low copy number i.e. low viral load (say e.g. 10 out of every million cells are infected) How can this then induce such significant changes to protein expression?

Say if for example, this is just to illustrate my point, that XMRV downregulates ATP synthase expression in the cells that it infects.. Then this could have a significant impact on the Respiration and consequent energy production of those cells, BUT not many are affected by this change...

I've read that HIV viral load is one of the key considerations for when patients begin ARV treatment and this correlates with disease severity.

So if XMRV only actually affects very few cells then you would think that it would not be able to have any significant affect on your health?

Sorry if I have missed the point, I just really want to understand the hypothesis behind this?

 

[anciendaze]

This is one of the key problems, which too many researchers are blindly ignoring. If we were talking about cancer, then the problem would be simple. Even one cancerous cell can produce a line of cells which become a tumor. This is also one of the things which makes it hard to identify causes of particular cancers. The problem originates in extremely rare events, which are typically disregarded.

In the case of CFS, we have abundant evidence of multiple infections, but they are not consistently the same infections. This points to immune system defects. Unlike the devastation of AIDS, this is not a global attack on very common cells. It appears to hit only a tiny number of cells which retain a 'memory' of previous infections and keep virus latent after it appears. Unless you are looking for precisely the right kind of immune system cells, the virus will be hard to find.

There is a second aspect, long suspected because of analogous behavior in very similar virus in other species, it looks like XMRV picks up bits of genetic material and inserts this elsewhere. This can be a host cell sequence picked up by a common virus. This may give the virus the ability to evade detection by the immune system by using the same molecules in its outer parts the host cell uses for some vital function. If the immune system attacks that, an autoimmune problem will develop. If it ignores that, the virus will mysteriously spread inside the host body, even if it is unable to carry this infection to others.

One problem which has been the subject of considerable work, and contention, has to do with infection of mitochondria. These are organelles inside cells which perform vital functions in key chemical reactions which provide energy. In many ways mitochondria are similar to free-living bacteria. They have their own genes, though part of their genome is now integrated into the nuclear DNA of the cell. To me, it looks a great deal easier to insert genes into mitochondrial plasmids than into chromosomes. A disease caused by infection of mitochondria could spread throughout the body and result in many aspects of CFS/ME. It would have its worst effects on cells with high metabolic rates, and nerve cells are up near the top of the list.

This process could amplify extremely unlikely events into major disease. It would be hard to pin down, because there is no guarantee the same genetic change is involved in every cell, every mitochondrion, or every victim. It is simply more likely that random changes caused by XMRV would result in lower efficiency, just as random changes in a room are more likely to result in a mess.

 

[alex3619]

Hi energyoverload

We don't know what viral load means with XMRV. It is possible that most of our symptoms are from the body fighting the virus that it keeps finding and can't kill. It is also possible that the protein envolope is toxic - there are researchers working on this. Viral load is dependent on tissues - it is low in blood but that doesn't mean we have low viral load in specific tissues other than blood. HIV spams out huge numbers of virus particles. XMRV doesn't appear to. This means its strategy is different, and it may be some years before we get a good understanding of what it is doing (presuming that it is not a passenger or opportunistic virus, both of which are still possible even if they seem very unlikely). To estimate viral load you have to know what tissues are infected, then you need a sample. If we are not talking about blood, that probably means a more invasive and possibly more damaging procedure. Lymph node biopsies are one possibility - these issues have been discussed from time to time on PR in other threads. I hope that if blood is too problematic, that we can somehow use throat swabs to find XMRV. If tissue biopsies are necessary, this will be a roadblock to fast and easy testing.

This leads to a point I have made elsewhere - we may not be able to use viral load as a measure of success with XMRV. We may need other methods, such as mitochondrial function, oxidative stress, or other biochemical markers. In other words, we may have to be less concerned about the virus in measuring success, and more concerned about how we are doing and not the virus.

Bye,
Alex

 

[Sunshine]

Say if for example, this is just to illustrate my point, that XMRV downregulates ATP synthase expression in the cells that it infects

Hi. Here are two important facts to think about regarding ATP/XMRV & CFS.

* XMRV is an MULV (Murine Leukemia Virus). These are the only viruses to infect mitochondria via alteration of CREB genes in mice. Mice aren't humans, although in the case of human XMRV, XMRV is derived from a mouse. XMRV downregulates CREB genes. Do this and you harm neurons in certain brain regions, harm as in kill them. The same regions that known to be affected in CFS. Of note, CFS patients show lowered IQ on neuropsychometric scores showing real evidence of cognitive dysfunction that cannot be explained by psychiatric theories of maladjustment to society or attention seeking soothed by CBT and exercise as is the common 'treatment' for CFS.

* Lymphocyte ATP function in people with CFS is poor. This in combination with the fact folk with CFS universally suffer permanant exhaustion of brain and body (brain is always affected in mitochondrial encephalopathies) worsened by minor activity, then it seems very possible that XMRV is the direct cause of the total loss of energy in CFS patients.

Chronic Fatigue Syndrome and Mitochondrial Dysfunction
http://www.ijcem.com/files/IJCEM812001.pdf

So if XMRV only actually affects very few cells then you would think that it would not be able to have any significant affect on your health?

The problem is it only takes a few XMRV cells to infect you (XMRV is an infectious gamma retrovirus). Once inside you these XMRV cells become part of our DNA and thus, us. High XMRV copy number would mean the risk of infection from person to person transmission is far higher than if low, but even with a 1 in 1,000,000 cells being infected with XMRV it's still highly possible to infect someone. None of us know how XMRV works. If it works alone or with other viruses/bacteria, or it needs a certain gene defect.

What we also don't know is where the virus likes to hang out, the reservoir. At the moment scientists are looking in blood, but what if XMRV likes to chill out in the central nervous system and brain? That could have a devastating effect on health and as we know CFS can be a neurological disease. If ATP in the brain is impaired the exhausted brain will malfunction. Of relevance, people with CFS say that they feel stoned/drunk/exhausted/drugged often with a look of disbelief from medics. We have our blood pressure checked and then sent on our merry way.

If ATP function is shot in the brain, the brain won't work optimally resulting in impaired memory and brain metabolism defects. Brain glucose metabolism is impaired in CFS, alongside alterations in Lactate, Choline and post exertional Carbon Dioxide which would all point to a possible ATP defect. Lactate could impair brain blood flow and cause hypoperfusion, which again is found in ME (CFS) brains. If XMRV in humans is shown to cause the CREB cycle to be impaired there's our answer why.

Maybe people have high XMRV viral load in the brain or other tissue, whilst others don't. It's important to consider when considering about high/low copy numbers that XMRV probably 'migrates' to body organs in some patients and in others remains static. Once there is an agreed finalised XMRV blood test there will be more and more clues as to why some people are able to function and others are utterly incapacitated needing 24/7 care.

The current situation from the CDC saying XMRV is not found in CFS patients is not acceptable and benefits no one but powerful insurance companies and government health agencies who don't want a hybrid remix of HIV on their hands in millions of Americans who are very disabled and will be hugely costly to keep alive, never mind fix. Tragically, we are 25 years behind the times regarding research thanks to the psychiatric profession hijacking CFS and actually inventing CFS. If people with CFS had been told they had a neurological disease (ME) and billions of dollars spent on research we'd not be in this situation of the most basic scientific questions not being asked regarding XMRV, never mind answered.

Only with massive financial input will some of these questions be asked in the next 5 years. If the WPI can outsmart the world's smartest scientists in a few years of looking for XMRV, maybe the can do it again and make the next 'jump' and find the virus reservoir and go way beyond blood tests.

 

[thegodofpleasure]

Judy Mikovits and Francis Ruscetti postulate that "constant activation of CD26+ T cells against XMRV will render the adaptive immune response poorly able to respond to other pathogens, autoantigens, etc."

Hence, building on what Anciendaze and Sunshine have already said, a low viral copy number in blood isn't really the issue.

Using the above hypothesis, it would seem that any amount of XMRV located in any kind of tissue / system reservoir in the body, has the potential to cause this effect - but I guess some tissues / systems (Lymphatic, CNS ?) more so than others.

 

[acer2000]

Maybe the blood isn't a good indicator of viral load. Or maybe the ENV protein is a neurotoxin. Or maybe the immune impairment caused by XMRV leads to other smoldering infections that cause symptoms... Or maybe XMRV infects and impair mucosal immunity, causing leaky gut and immune activation/impaired liver function. There are a bunch of possible explanations. We need some research to figure out what the answer is.

 

[anciendaze]

I'm glad we're seeing this number of responses to your question. There have been far too many people telling the virus how it ought to behave, and far too few paying attention to what the illness was telling them. The bottom line is that we don't know all the links in the chain of events, and demands that we present such a theory are premature. I have tried to stay away from highly specific descriptions, which betray my ignorance, and concentrate on broad principles.

What I tried to say above, with limited success, was that this is an example of a pathological process that does not follow the 'textbook cardboard' behavior of simpler viral infections. I described how cancer amplifies very rare events until they become life-threatening. It is no accident the researchers who found XMRV, and did the research published in Science last October were experienced in tracking down causes of cancer.

The immune system normally works through a limited process of amplification of rare events. (When the limitation fails you have leukemias or lymphomas, both of which are suspected with XMRV.) In the simplest immune processes, cells which make the precise antibody needed for an immune response to a particular antigen are activated and allowed to divide repeatedly, leading to an exponential growth in the number of that cell type. This is 'clonal selection'. Other mechanisms at work in the immune system are far more complicated. It is safe to say there are many things not yet understood.

The point of this is that, like cancer, immune function also amplifies the effects of extremely rare events. The third component of the body which amplifies tiny events is the nervous system. Finding the celluar causes of something which determines a decision is extremely hard, even if the consequences of the decision are disastrous. The central nervous system is built to do this selectively in a way that will enhance survival. You only need to disrupt the process by which signals are selected within the brain by a tiny amount to cause pathological behavior. The statement that this is a behavioral problem doesn't mean we know the cause, it simply tells you that the physical basis of the problem has been 'below the radar' in the past. Improvements in technology are changing this dramatically.

The organic signs of neurological problems in CFS have been detected in human beings. They are subtle, compared to many devastating neurological diseases. The 'UBOs' on MRI scans are small and scattered. SPECT scans reveal large regions of hypoperfusion, but links to a cause have not been completed. We now have MRS scan results capable of showing enough evidence of serious abnormalities in several biochemical processes inside the living brain to provide evidence for disability claims based on neurological impairment.

The big question w.r.t. XMRV is not if these things occur, but why the pathological process is generally limited. Most of the time it does not proceed to cause full dementia, seizures, etc. The lesions remain small and scattered. Similarly, most of the time the immunological dysfunction does not reach the level in late-stage AIDS, even with a complete absence of effective treatment. This is why CFS research is important for people who do not have CFS. It illuminates processes that cause health as well as disease. Those with the illness live in the twilight zone in-between.

 

[alex3619]

Hi

You have to read this thread:http://www.forums.aboutmecfs.org/sh...ll-confirm-WPI-findings-in-a-Sept-publication

Mikovits says they have a test that tells them how XMRV is doing the damaged, and allows monitoring, and hope to publish this something like the end fo the year.

Bye
Alex

 

[guest]

Just wanted to say thanks. The question how low copy numbers can have such a strong impact on humans has been in my mind for a long time. Just to sum things up, the answer would be:

a) if the virus infects certain parts of the brain or CNS even very low copy numbers can have devastating effects since they render fundamental mechanisms dysfunctional and cause lots of downstream problems
b) we don't know if the copy numbers really are that low because we cannot look into the brain or CNS like we look into blood.

Is that correct?

 

[Daffodil]

the WPI seems very optimistic that the immune system can be corrected, even after decades of infection and immune activation. can this be true?

 

[Overstressed]

Hi Diesel,

I also want to add one more strategy the virus might use. As we look to HIV, scientist never understood why so many CD4 cells 'died', because most of them where not infected by HIV. A German scientist found out that HIV takes over the cells machinery, to make proteins(I think it is the Nef protein) that kill CD4 cells. In other words, it doesn't need to infect them in order to kill or cause damage.

OS.

XMRV might use such smart defense to damage the body...

 

[Daffodil]

long term retroviral infections can also cause lymph tissue fibrosis, as in HIV, and hinder production of immune cells.

stem cell treatments might help this.

 

[Mithriel]

ME/CFS is a disease where all the usual tests come out normal or just a little bit off. We have symptoms but they are very difficult for a doctor to see when we are examined.

A virus which has very low copy numbers fits the bill perfectly. If it was a viral load like HIV you would expect more obvious signs of it.

As people have described so well, it is a sneaky little thing that does its work by disrupting deep within the body but never in a way that overwhelms function completely.

Mithriel

 

[guest]

Overstressed: Thanks for your addition.
Mithriel: I get your point and hope that you are right.

 

[natasa778]

What I cannot seem to understand with fog brained mind, is how exactly, XMRV is hypothesized to cause such a severe disease if the copy number is so low, like the WPI emphasize how hard X is to find in the blood because of its low copy number.

as acer said, the key word here is "blood" !

low copy number is blood does not mean that there is low number in the body overall

 

[*GG*]

the WPI seems very optimistic that the immune system can be corrected, even after decades of infection and immune activation. can this be true?

I know some people have already touched upon this. I would think yes, like Overstressed mentions HIV. I believe people can carry HIV for years, not sure if they suffer any serious consequences for that, but I have heard that people that have HIV now can lead rather normal lives, like anything and everything, of course there will be some variation.

 

[Daffodil]

i dont know. i have read that 1/2 of the lymph tissue in the gut, which is A LOT, is permanntly damaged just days after HIV infection. can you imagine all the irreversible damage after decades? i am hoping XMRV is very different.....