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Does anyone have a good hypothesis of how XMRV could account for the 24hr delay?

Discussion in 'XMRV Research and Replication Studies' started by Jill, Jun 6, 2010.

  1. Jill

    Jill Senior Member

    Auckland, NZ
    Just wondering out loud here to see if anyone else has thought on this , or heard any researchers talk about this.
    As I am in a post exertional flare up right now it seems pertinent.
    What could be the mechanism, whereby a person can feel relatively well, go out and do a few seemingly minor activitys with friends, then almost exactly to the hour, 24hrs later come on with all the flu like symptoms and end up prostate in bed ? How could a virus do this?
    This delay in symptoms is soooooo striking when I'm in a slightly better phase.
    Does the virus somehow get 'stimulated' into action by activity (stress) and it takes 24 hours for the body to react by sending out a cytokine response to quell the virus? This is how I've come to think of it, but have no idea whether this could be correct. It then takes me 3 days to get back to my "normal". Essentially the time frame of every other virus.
    Please note I have not always had this 'pattern'. When bedridden for 2 years, there seemed no pattern at all.
    How do others, more knowledgeable in virology/immunolgy "see" xmrv as causing the peculiar symptoms of this illness.
  2. V99


    I'm no scientists, but the gist of it seems to be, that if XMRV can mess with cells, say the mitochondrion, then that cell starts to function differently, and low and behold you have energy problems.

    Some other bright spark will make this clearer, but I don't think I'm too far off the mark.
  3. Mark

    Mark Former CEO

    Sofa, UK
    There is this thing about "running a marathon in your sleep". When you exercise muscles, lactase(?) etc are released as part of the healing cycle. That's the part that hurts. When we fail to sleep and regulate properly, during the night the post-exercise processes carry on. We sleep in a shallow way and our misregulated bodies work through the night. We wake up after a 10-14 hour dreamless sleep feeling absolutely shattered.

    That's one common pattern, maybe there's an equivalent with flu symptoms, or are these different aspects of the same pattern?

    The 24 hour aspect does sound potentially related to biological rhythms. A first thought based on that would be: assuming a relatively regular pattern of waking/sleeping, the levels of various regulators in the body (cytokines, hormones etc etc) would likely be at similar levels at similar times of day. That could trigger a response. Maybe the peak levels provide the greatest "risk period" and you are at your most vulnerable then to a proliferation of symptoms - especially if you have overstressed your body's parameters in those respects the previous day?

    I'm paraphrasing the mitochondrial theory somewhat, but it's something like: when we're "running hot" and our "reserves" of "depleted resources" are overstretched, we are vulnerable - when cytokines, cortisol and hormones are just right (wrong) - to a collapse or 'storm' of some kind. XMRV proliferates with cytokines, cortisol and hormone levels so one of the most exciting things about these early findings re XMRV proliferation was that they married up so well with clinical experience and with these details of the 'mitochondiral' and other theories: XMRV actively replicating would be the "some kind" of storm we are vulnerable to when levels are just wrong, and XMRV could also be the DNA-disruptor that stops specific aspects of our digestive system (which is missing specific enzymes) and/or immune systems from functioning properly - resulting in highly specific vitamin deficiencies and 'missing ingredients' that define the limit to which we can stretch our bodies without hitting the walls of these fundamental "missing pieces" in our bodies' defences.

    George, is all this OK or just me spouting rubbish again? Could someone who knows stuff turn the above into sense? Thanks.:D
  4. jimbob

    jimbob ME/CFS84-XMRV+

    myrtle beach, s.c.
    Im actually just going to dumb it down a bit. It's like having the flu and near the end of it you have a day where you're not over it, however you don't feel like laying in bed all day, so you get up and naturally do more than you should. You end up back in bed the next day adding an extra day to your recovery! We don't get many of these so called good days, so we kind of abuse them, but why not enjoy it, even knowing the consequences, whats the alternative, laying in bed worrying if you should take a chance? I've had many of these days over the last 26 yrs and I always take advantage of them!
  5. vdt33


    I think it has to do with dysautonomia and the brain's regulation of the genes, proteins, enzymes, etc. -- that is, the maintenance of homeostasis. There tends to be swings in hormones, neurotransmitters, immune system components, energy (ATP), etc. When we use up too much ATP with activity, there is not enough ATP for other bodily processes. The methylation cycle gets diverted away from making glutathione, for example.

    It is possible that XMRV is involved in this loss of ability to maintain homeostasis because XMRV likes to insert itself in the regulation portion of the CREB and NFAT genes in our DNA. These genes are involved in regulation of bodily functions, especially those involving the brain and homeostasis. Read some of Gerwyn's posts about CREB and NFAT.

    XMRV also inserts itself in the DNA of the mitochondria and could therefore disrupt production of energy (ATP).

    Don't quote me on any of this. It is just my understanding of XMRV so far. :D

    Gerwyn on XMRV DNA Target Sites:

    Our automatic body processes are controlled by the autonomic nervous system. If this becomes dysfunctional then we are left with the neuroendocrine symptoms of ME/CFS --

    Sensitivity to lights
    Sensitivity to sound
    High resting heartrate
    Postural Orthostatic Tachychardia Syndrome (POTS)
    Poor temperature control and so on.

    The organic thermostat that controls all these functions is the hypothalamus in the brain. When any function such as heart rate strays outside the normal range, this is detected by the hypothalamus and brought back into normal ranges by the action of the pituitaty gland and the Adrenal cortex (and medulla).

    If this control system breaks down, our autonomic functions go haywire.

    The "molecular thermostat" of the immune system is the NFAT genes (amoung others). The retrovirus XMRV inserts itself into the part of our DNA that contains these genes, the retrovirus XMRV can act as a "molecular dimmer switch" for this gene and affect the levels of its activity and in turn the levels of various chemical components of the immune system.

    One example would be that if one of the NFAT genes was upregulated by the "dimmer switch" being turned up, then the level of circulating cytokines would be high. There would be chronic levels of inflammation in multiple body systems.

    This leads to a number of consequences:

    Raised levels of abdominal fat

    Impaired Glucose tolerance and increased insulin resistance

    Alzheimers type symptoms

    Cardiovascular abnormalities

    Increased risk of stroke

    Postural Orthostatic Tachychardia or Hypotension

    Impaired blood flow to the brain.

    These increased cytokine levels (interferon and interleukins) can lead to Metabolic Syndrome.

    Raised interferon levels lead to hyper stimulation of the Tumor Necrosis Factor (TNF) alpha gene. This can lead to high levels of Nitric oxide which in turn depletes glutathione directly and indirectly, damaging mitochondria and creating a partial block in the methylation cycle.

    Raised TNF alpha leads to muscle fatigue and pain.

    This also reduces BDFN gene expression (also caused by blocking CREB genes) reducing fat oxidation and further compounding problems with fatigue, cognitive problems like memory, dyscalculia, dyslexia and so on

    CREB and NFAT co regulate each other just to make life really interesting!!!!

  6. alex3619

    alex3619 Senior Member

    Logan, Queensland, Australia
    PEM and XMRV, taking a step back

    Hi Jill

    Maybe we can back up a step and enquire about what is the immediate cause of post exertional malaise, what do we already know?

    We know the mitochondria aren't functioning properly. This means that when we push ourselves we are actually burning up mitochondrial chemicals (primarily ADP), an emergency reserve if you will, that are needed to keep the mitochondria functioning. This was pointed out in the mitochondrial study done at Oxford University and publised January last year - the name of the study eludes me at the moment. This damage takes several days to repair, during which we are very vulnerable to further overexertion.

    Second, we know that fatigue and pain sensor expression increases rapidly after exercise. We know that this will make us feel more fatigue even if we aren't, but if we are genuinely fatigued this will mutiply fatigue perception to way above normal.

    We know that the body is supposed to produce chemicals to induce muscle repair and recovery, but we don't produce enough of the right kind. This means we don't recover as fast nor adapt to enable more activity in the future - we can't easily get fit.

    We know that we produce lots of cytokines that will make us feel sicker if we exert ourselves. I do not understand cytokines, this is a highly specialized area that changes rapidly. We would need a cytokine expert to explain it to us in order to get a good grasp of this.

    I think I recall reading that gene expression changes post exercise. I could be wrong about that, but many of these issues required altered gene expression so it is probably true regardless of whether or not we know it for a fact.

    We know that exercise induces oxidative stress, which we already have too much of, and so depletes antioxidant reserves, which we already have too little of.

    We know that blood supply to the brain decreases, possibly resulting in more neurological symptoms from oxygen and nutrient deficiency.

    I have probably missed a few, if anyone can think of some please add to this list.

    XMRV has stress sensors. If our stress levels are higher, then XMRV could replicate as a result of exercise. This will take time. I can't see it as a direct cause however, except maybe in a very small way. XMRV also produces a protein envelope that is claimed to be a toxin. I do not know what it is doing to us at the molecular level.

    The most likely cause of PEM is directly related to the mitochondrial damage, both through substrate depletion and oxidative stress. This probably induces all sorts of emergency responses that make us feel sicker, to try to force us to slow down. Too much mitochonrial damage could be lethal, the body takes this seriously. It wants us to slow down, and if we don't it will make us slow down by making us so sick that we have no other option.

    The heart is very vulnerable to such mitochondrial damage, and if the heart is impacted we will also see a decline in cardiac function until the heart recovers. The brain is the first place we are likely to see a negative response to decreased cardiac function.

    Now, it is an entirely different question as to whether or not XMRV is causing the mitochondrial damage. I think it could be, but that is for a different post. The door is certainly open to XMRV interacting with EBV and other pathogens as well, or a large number of other things. I really think that if we want to understand this, we first need to break the problem down into smaller pieces, and try to undersand those pieces.

  7. usedtobeperkytina

    usedtobeperkytina Senior Member

    Clay, Alabama
    Well, I see many good theories here. And I wonder if maybe there are many. The fatigue we feel is more extreme than so many other fatiguing causes. Maybe ours is so strong because it is one, two and three punch. Three things that lead to fatigue.

    The Light study showed gene reaction changes immediately in correlation to PEM. This might be XMRV disrupting normal gene behavior, as the "puppet master" some have referred to.

    But I can't help but wonder if the fatigue is connected the delayed effects in the immune system. We all know that we have high cytokines. And we all know the cytokines contribute to our "flu-like" symptoms. We all know that if you get a flu virus, it takes three days before you feel the symptoms of the immune system.

    So, if XMRV replication is turned on by the activity, as was said earlier, then it becomes numerous in the body. Then it infects new immune system cells. This causes dysfunction in those cells. This allows latent infections to become active again. This causes a cytokine response to try to fight those infections. And that causes symptoms. With so many steps between XMRV and cytokines, you can see why this would take a day or two. In my case, I think my symptoms are worse on day two after activity.

  8. V99


    I remember reading something a while back about mitochondria and ATP. I had a look and Dr. Myhill has a similar description on her website.

  9. V99


    David Bell has an article here

    These are a few excerpts.
  10. kurt

    kurt Senior Member

    I don't think there is a good explanation for PEM from XMRV, at least not directly. What known viruses or retroviruses produce PEM? None that I can find. And I believe the idea that the adrenal hormones stimulate viral replication does not work, as XMRV replicates only when the cell replicates and adrenal hormones do not stimulate cell reproduction.

    As for the idea that the virus is causing direct cellular regulation problems in the brain, the monkey study showed that XMRV likes the lymphatic system, not the brain. Here is the abstract from that study:

    There was no XMRV found in the blood of those monkeys, by the way. So the idea that the infection would just eventually get everywhere and therefore eventually will be in the brain is not supported by that study. In that study the injected virus was obviously cleared from the bood but lodged in lymphatic tissues.

    My own hypothesis is that we have a detox delay that induces a type of dysautonomia for the exertion response. In other words, PEM is due to a delayed processing of some endotoxin caused by exertion. Here is why, we know that CFS patients are pathological detoxifiers. And many of us have multiple drug sensitivities and chemical detox problems. For example, something that takes an ordinary person an hour or two to detoxify might take a CFS patient 24 hours to detoxify. Therefore, if some chemical from exertion must be detoxified before post-exercise fatigue can set in, and CFS patients process that chemical very slowly, then our post-exercise fatigue will simply be delayed. In essence a delayed-detox dysautonomia. What that would mean is that the delay is independent of the ATP/ADP problems we also have. The ATP depletion of course will worsen the eventual malaise once it finally hits.

    Another reason this hypothetical explanation makes sense to me is that post-exercise fatigue is clearly designed to allow the body to rebuild and heal, and probably the toxins from exercise must be first processed and detoxified before the rebuilding and healing can work. In a healthy person that detox probably happens very quickly, an hour or two, then they get tired and must rest a little from the exercise. And their resting is restorative, which of course ours is not, which compounds the situation. In a CFS patient with slow detox we can probably count on a consistent delayed response to exertion depending on our personal level of detox pathology, combined with the level of exertion and amount of endotoxins released.

    If this hypothesis for PEM is correct, and XMRV could explain why we are pathological detoxifiers, then maybe there would be a connection to PEM. Or maybe if XMRV in the lymphatic system could explain some of the endotoxin and neurotoxin overload we appear to experience. But there are already several good explanations for the detox issues including poor methylation genetics, herpes activations that deplete glutathione, infections in the cells, co-infection toxin loads, etc.
  11. omerbasket

    omerbasket Senior Member

    If they couldn't find XMRV in the blood of these monkeys, using the methods that do find it in blood of human beings, doesn't that suggest that perhaps XMRV works different in monkeys than it does in human? I think there might be a number of explanations (perhaps the virus didn't reach there yet, and would have reached there had the test was being done in a later stage? But then it might have reached other places, like the brain, too), but if it says that there is no XMRV in the blood of these monkeys - than XMRV works differently on monkeys in comparison to humans.
  12. natasa778

    natasa778 Senior Member

    I disagree with the use of the word "support" above.

    The fact that they did not find the virus in the blood could very easily (and very likely) be rephrased that the virus was not present in the blood at that given time.

    The absence of the virus in the blood at that given time does not mean that the virus does not spread through the blood when reactivated.

    When reactivated it could then travel to/get to target tissue, and then again 'quietly' reside there until the next reactivation event.

    The fact that it was not found in the blood does not "unsupport" that it spreads to the brain or elsewhere at another time, or through other routes btw.
  13. richvank

    richvank Senior Member

    XMRV and PEM/PEF in CFS within the GD-MCB hypothesis

    Hi, Jill

    It will be up to you to decide whether the following is a "good" hypothesis, which you asked for!

    In the GD-MCB hypothesis, the problems in the mitochondria in CFS result from glutathione depletion as well as from the partial block in the methylation cycle which it produces in genetically predisposed people.

    The glutathione depletion allows the oxidative stress, which is well-documented in CFS. This leads to partial blocks in the Krebs cycle and respiratory chain within the mitochondria, which are supported by observed urine organic acids analyses. It also leads to oxidative damage to the mitochondrial membrane, also observed (by Dr. John McLaren Howard in the UK). It also allows buildup of toxins and pathogens which interfere with the DNA and enzymes in the mitochondria (again, observed by Dr. Howard).

    The partial block in the methyation cycle decreases the production of carnitine and coenzyme Q-10, which are needed by the mitochondria, and which have also been observed to be deficient in CFS.
    The partial block in the methylation cycle also decreases the production of creatine, which is needed as an energy storage and transport molecule for buffering ATP in the muscles and in the neurons.
    There is some evidence of creatinine deficit in CFS from urine creatinine measurements. The magnetic resonance spectroscopy measurement studies have mostly assumed that creatine was at a normal level in the brain, but good absolute measurements there have not yet been reported, and I expect that they will also show low creatine.

    The PEM/PEF or "crashes" in CFS, according to this hypothesis, are caused by two things: the first is that increased exercise demands ATP in the skeletal muscles and the heart muscle at higher rates. Because the mitochondria are dysfunctional, they are unable to phosphorylate ADP to form ATP at sufficient rates. Therefore, some of the ADP is broken down to AMP and is eventually lost from the cells as adenosine. In addition, when the activity of the mitochondria is raised in the attempt to produce ATP faster, this necessarily means that the levels of the oxidative free radicals will rise, also. The most vulnerable molecules in the cells to these reactive free radicals are the unsaturated fatty acids in the membranes, especially the mitochondrial membranes.

    The results of these processes are that ADP becomes depleted in the mitochondria, and the mitochondrial membranes sustain more damage during exercise. Time is required to respond to both these changes. D-ribose supplementation may help the first of these, because the synthesis of ribose is a slow step in the pathway for making new ADP. Supplementation with essential fatty acids and antioxidants to protect them may help with the second. Or one might go further and supplement with ready-made phospholipids, as in Patricia Kane's intravenous treatment or as in the use of NT Factor, which uses liposomes.

    Now, how does XMRV come into this picture? We don't know yet what its role is in the pathogenesis of CFS. However, it could be involved in several ways. One way would be its direct effects on gene expression because it is incorporated right into human nuclear DNA molecules. It could be impacting the ability to supply glutathione, or it could be impacting other aspects of the GD--MCB pathogenesis mechanism, such as at the level of B12, folate, or enzymes of the methylation cycle.

    Second, the immune system's response to XMRV infection could be helping to deplete glutathione, since the cell-mediated immune response has a high demand for glutathione.

    Third, XMRV might be a "passenger" in the process, in that after the GD--MCB mechanism has taken place in response to other stressors, the immune system is dysfunctional, and XMRV can then activate and cause additional demands on the immune system and on glutathione.

    Until more is learned about XMRV, I don't think we can narrow down the possibilities.

    If anyone is interested in more details about the GD--MCB hypothesis, they can be found at

    Best regards,

  14. gracenote

    gracenote All shall be well . . .

    Santa Rosa, CA
    My question about the monkeys is how long did they have XMRV infection? I don't think we can draw any hard and fast conclusions yet.
  15. lansbergen

    lansbergen Senior Member

    There was a transient viremia, peaked at day 7.

    Virus in brainstem at day 289 in the female monkey
  16. Jill

    Jill Senior Member

    Auckland, NZ
    I've got alot of reading here! Thanks for all the input. The other thing i find so curious to explain is that why the hell aren't we deconditioned couch potatoes. When I'm good - I'm pretty sort of "fit". Not what you'd expect at all. Muscles don't ache in the 'usual' way - its the immune/flu symptoms(incl flu-like muscle pain) that knocks me out. I guess it'll take time to sort it all out. Alex - like you its day 2 that is worst for me. Today infact. Just out of interest - since we seem similar, my regime is : Neurontin 600mg night, LDN night, 1 mg clonazepam night, 20mg nortrip, night. LDN helps me in the morning (that morning panic) - except when I'm in relapse (when nothing but rest helps). I also need b12. I need to relook at Richs protocol. I have the pills here but got ill when I tried it, then had a 3 year divorce to get thru, now I could give it another bash. Please note - despite the above meds I can't work . Reading even will bring on a relapse, in the same way activity does.
  17. usedtobeperkytina

    usedtobeperkytina Senior Member

    Clay, Alabama
    Kurt, are you saying Mikovits is incorrect when she said androgens and cortisol (stress hormone) do not effect XMRV replication?

    She said:

    "It responds to hormones, and it responds to inflammatory cytokines (it's called the nfb element). Cortisol, the stress hormone, it turns on the virus very rapidly and continues to have it expressed. So do inflammatory events, as is caused by other pathogens... and so do hormones, like androgens and progestens, which makes sense as to prostate cancer, inflammatory prostate cancer and the disease being more common on women."

    Well, maybe it is me that misunderstood. She actually didn't say replication. She said "turns on" and "expressed."

  18. Wonko

    Wonko Senior Member

    The other side.
    28-36hrs for PEM onset for me - in fact the day after "exertion" that causes the PEM I usually have LESS background symptoms than normal - until the onset
  19. judderwocky

    judderwocky Senior Member

    IMHO most of the problems can be traced back to Interferon. Viral infections cause the release of interferon which can actually account for most of the problems people have listed on here. Interferon (which also stimulates RNASe L and fun stuff like that) alters the expression of cytokines... many of these are cascade reactions... that involve oxidative stress on the virus... and as a side effect our cells. Viral proteins are attacked through a chemical strategy that makes the cellular body more hostile to viral rna and dna... unfortuantely this has deleterious effects on normal cell functioning. Remember one of the body's most simple defense systems is to simply increase the oxidation state of the cell.... this has a whole bunch of effects though, which could go on for pages and pages. Interferon increases the crazy things like tumor necrosis factor, interleukins and other inflammatories. Some molecules are simply amp's (anti microbial peptide seuqences).... etc....others are molecules that increase the oxidation state of the cell.. the body will literally dump these molecules around like bleach trying to mop up all the crap. This of course wears the cell out.... Mitchonidra... as some have mentioned have difficulty functioning. IN part this is bacause of what is called electron leakage... as the oxidative state goes up to hi, the mitochondria can not maintain chemical balance, and the energy (charged electron on the outer membrane) becomes entangled in the oxidative leakage. ...

    the problems however.... are exponentially magnified... to produce many of these chemicals the body needs lysine and methinonine... which it also needs to produce things like carnitine... without carnitine... your mitochonddria is even less effective.... a double "whammy"....

    the hits keep coming... interferon changes the metabolism of tryptophan from serotonin into kyneurine (sp?) and the body subsequently cannot maintain neurotrasmitter levels of serotonin, and implicitly melatonin (sleep, mood etcc) are effected.

    Additionally the virus also seems to knockout a section of our intracellular defense in the same way that HIV does... even more so, when these viruses get in tthe cell they are dependent on existing chemical pathways and stimulators to reproduce.... they take these sections of our dna over so that they can reproduce when our cells are stimulated into higher states of production of certain molecules...

    there are bunch of things that are shown to affect retroviral replicatoin rates... hormones, cell proximity to other cells, ... pretty much a bunch of the things that are involved in cell signalling. Progesterone is one of the reasons that it is associated with a higher prevalence in women... the testosterone in prostate cells as well could explain the links to prostate cancer.... hormones... cortisol.... all that stuff is increasing viral load... which causes your body to produce more cleanup molecules and inflammatories, and therefore to have more self inflicted oxidative damage.

    AS a result the increase in activity often times cuases a spike in the viral load... so the activity jars your body into acidentally producing more of the virus at the same time its trying to clean itself up. Glutathione is essential for HIV patients, it increases the longevity of their already weak cells because it increases the threshold they can tolerate of oxidative chemicals.

    The symptoms of CFS can be replicated in ANY healthy individual by giving them massive dosages of Interferon therapy. EVEN THE CDC recognized this back in 2006 and proposed using this as a clinical approximation of the disease....

    The onset of the fatigue is most likely related the time it takes for your body to begin resonding to the increased levels. Think about it... when you get sick from the flue they always tell you "you're contagious 1-2 days before the onset of symptoms"....

    Its like pushing a rock down a hill... it might take a second to get going but once it does... they only thing you can do is to get out of the way, and hope that you can avoid as much of the cascade reaction as possible.

    I take kefir and vitamin d which reduce inflammatory profiles, and increase certain antimicrobial defense pathways like cathelecedin ( one of the most prominent AMP's known to exist in our body can ONLY be stiumalated by vitamin d... ever heard of vit d/ sunlight therapy for TB or for other infections ? turns out we have a special primate gene that allows us to use vit d to increase our production of this wonderful chemical),,,... and i use tons of antioxidants to clean up all the crud my cells are cleaning with .... NAC , Acetyl l Carnitine, Alpha Lipoic Acid (which can regenerate other antioxidants).... fruit juices, vitamin c, elderberry juice, red tea (rooibos tea has very high levels of an antioxidant your body already produces called superoxide dimutase or SOD).....

    those are my thoughts.... jumbled as they are right now lul

    keep your immune system strong... the body balances its oxidative and inflammatory responses with other pathways.... if you can give it a little rest and help with some of the
  20. judderwocky

    judderwocky Senior Member

    one of the reasons they give vitamin c and anti oxidants to people with the flu is because it allows the cells to survive the oxidative wash without going through apoptosis... exploding... as a result the cells can weather the storm and return to normal functioning after they no longer detect the viral RNA ...

    the real key in my opinion to managing this disease... or at least what i have found useful for whats its worth... its just tweaking your body systems... reducing inflamation, reducing stress and hormone levels, reducing anything which might cause a viral spike, and then anticpating those viral spikes iwth lots of antioxidants.....

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