XMRV: Necessary but not sufficient?

[richvank]

Hi, all.

It seems to me that the information currently available on XMRV suggests that it is necessary, but not sufficient, for a person to be infected with XMRV in order to develop ME/CFS.

I say "necessary" because nearly all the people who had ME/CFS were found to have this infection.

I say "not sufficient" because a significant percentage of the healthy controls from the general population were also infected, but had not developed ME/CFS (at least not yet!).

I think that the only way we can interpret this combination of observations is to say that XMRV is "necessary but not sufficient."

If XMRV infection is not sufficient alone to produce a case if ME/CFS, what else would be needed? I don't think that's known yet. It could be that other infections are needed, or it could be that the immune system must be compromised.

As far as I can tell, the latter would be compatible with the GD-MCB hypothesis, which proposes that a variety of stressors (physical, chemical, biological and/or psychological/emotional) raise cortisol and epinephrine and place demands on glutathione, tending to lower it, before the onset of ME/CFS.

Lowering glutathione produces oxidative stress, and the virus apparently needs oxidizing conditions to form disulfide bonds in its protein coat.

Raising cortisol and depleting glutathione both tend to suppress the cell-mediated immune response, which is needed to combat viral infections.

There also seems to be information suggesting that raising cortisol stimulates the virus.

So it would seem that all of this would fit together well, and it would also agree with the histories of many PWCs, who report that they experienced severe stress of one kind or another before the onset of their illness. There has to be a way to bring together these various histories with the common factor of the presence of XMRV infection, and I think this model does that.

Rich

 

[acer2000]

CFS onset and progression sounds an awful lot like Feline Leukemia Virus and the diseases it can cause in a percentage of cats.

http://en.wikipedia.org/wiki/Feline_Leukemia_Virus

"About twenty percent are able to put the virus into a latent stage, in which the virus will remain until the cat becomes stressed causing the FeLV to re-emerge."

I am not going to paste the whole article as its quite lengthy, but the paragraph under the section entitled "progression" is very interesting. Its certainly worth a read. They mention how a percentage of cats fight it off, some induce latency, some get sick, some die. But then they say that of some that induce latency, "stress" triggers it back into activity at which point it can cause illness.

Oh and the good news is there is a vaccine for this FLV, although it appears to have had some problems.

 

[anne_likes_red]

Good to see your thoughts on this Rich!

I've been following your research with great interest since I went looking for more information about sulfation and methylation years and years ago

I have congenital toxoplasmosis which flared up in adolescence - typical of that type of toxo - and after treatment for that in hospital I found myself with CFS (that was 24 years ago). A few years later I was told I had a "leukaemia profile"...had bone marrow tested, but it lead nowhere useful.

I'm interested to see what part XMRV plays in all this. "Necessary but not sufficient" resonates well with me.

I'll look forward to more of your thoughts on this puzzle in due course!

Much respect,
Anne. (New Zealand)

 

[richvank]

To azus389 and anne likes red

Hi, azus389.

Thanks for posting the information on feline leukemia virus. There do seem to be similarities between how animals and humans interact with these viruses. When the defenses are lowered, these guys go after us again, and when the defenses are able to come up, they "run away, to fight again another day."

Hi, anne likes red.

Thank you for the encouragement. Sorry about the toxoplasmosis. Doesn't sound like fun. Has it flared up again since your teenage years, or was it knocked out by the treatment, so that your illness is more like other cases of CFS now?

Rich

 

[anne_likes_red]

Toxoplasmosis.

Hi Rich,

As far as I can tell I've had no trouble from the congnital toxo for more than a decade now.
It affected my eyesight (scarred the retinas) prior to my being born, then the major flare during adolescence, then every year or two for a further nine years.
Unable to tolerate any sulfur drugs I was eventually treated with pyremethamine which I believe is most often used in AIDS patients. I also had a type of HBOT which seemed very effective and it was that which led me to look further into "methylation" and to your work.
My toxo doesn't ever seem to have affected me in the way more classically aquired (from cats usually) toxoplasmosis does, with flu like symptoms.

I'd have to say I have pretty classic CFS amd FM. No more, no less

I feel really hopeful things are moving nicely in the right direction towards some effective treatment!

Best, Anne.

 

[jenbooks]

I didn't have severe stress before getting sick, just a tickbite on a lovely June day, with something very virulent in it. I'd like to know if XMRV can be transmitted by ticks. A few of us have speculated it may be the reason for chronic abx refractory lyme.

 

[Eric Johnson from I&I]

> Lowering glutathione produces oxidative stress, and the virus apparently needs oxidizing conditions to form disulfide bonds in its protein coat.

True, the redox conditions they need are certainly oxidizing compared to /something/. But one has to wonder whether the human body could ever in fact be reducing enough to inactivate a significant fraction of the virions via a non-catalyzed redox reaction. After all, while I'm sure different disulfide bonds vary in their proclivity for being reduced, depending on context (the amount of bond strain, etc)... the human body has many of them, and many "kinds" of them (that is, has em in many different contexts). A priori, why should we imagine that XMRV's disulfides are any more easily reduced than the thousands of "kinds" of disulfide bonds whose stability we depend on?

I have to wonder the same thing about claims that N-acetyl cysteine can damage a significant number of chlamydial elementary bodies.


> If XMRV infection is not sufficient alone to produce a case if ME/CFS, what else would be needed? I don't think that's known yet.

Surely its not sufficient in those whose condition was precipitated by EBV mononucleosis, or the like. But of course it also cant be sufficient in others either, for the reasons you give.

We know CFS has a certain heritability, and genetics is a well-known determinant of infectious diseases, notably TB and leprosy. Genetic variance in susceptibility (be it susceptibility to being infected at all, or to having disease) could even be due to a singe allelic locus, as has been claimed for schistosomiasis.

But I'm not sure how serious to be about the heritability estimates in CFS. There are certain possible artifacts in all methods of estimation.

Virulence differences between strains might also explain a lot and could be pretty likely in most instances of this type of question. But they are not very plausible here, given the very low sequence diversity of XMRV.

 

[Eric Johnson from I&I]

> stressors [in the broad sense that would generally include toxic substances -- anything]

I'm sure youre familiar with it, but for the benefit of others, the key objection to this is that all or almost all evidence for it depends on subjective or quasi-subjective retrospection.

Subjective retrospective evidence can be suspect in light of the intense drive to discover the cause of a misfortune, which can perhaps be seen in the example of witchcraft accusations, which I think are a human universal. Just look at the number of people who state "certainty" about some supposed cause of their disease which is obviously not well-evidenced, or in some cases even plausible.

One can also see how suggestible and errant people are by looking at responses to placebos. Fake sleeping pills make quite a high number of people report sleepiness, without causing other side effects -- the same pills are found to be relaxant without causing sleepiness when they are claimed to be relaxants.

 

[Mark]

Another possible explanation for 'not sufficient'

Sorry folks, here comes another of my monster posts...somebody please slap me if they're messing up your nice neat threads.

I think "Necessary but not sufficient" is a wonderful summary of what we can conclude from the WPI study. We've been stumbling towards that understanding on a number of threads, and I think it's a very good summary of what we can be pretty sure of. The "not sufficient" part is then the next focus, and of course we can't answer that without further research which is probably many months away. I think Dr Peterson stated "there have to be co-factors" at the CFSAC meeting, which is another way of saying "not sufficient".

The main theories that have been put forward for the co-factors are of course the fairly obvious ones of genetic factors, other immune system vulnerabilities, and co-infections. I'd like to suggest another possibility which I've been considering recently and which makes a fair degree of sense to me now, unless somebody can explain to me why it's nonsense!

My starting point is the preliminary finding of XMRV in 40% of a small group of people with autism. This is the same test, the exact same XMRV, with completely different effects. How can this be? And presumably if there had been parallel tests on loads of other conditions like Alzheimer's, AIDS, allergies and food sensitivities, etc etc - well if there had been, surely we'd have heard about the percentages for those, whether they were high or low - all that info would be useful. So it's quite possible that XMRV is implicated in loads of other conditions as well, and the best place to start looking would be those conditions that have been rising rapidly since the 80s, like autism has. (I just checked wiki to see when they date the autism epidemic to, and sure enough, it started in the 80s. And I never bought the idea that the rise in autism is 'because we are diagnosing it better nowadays'...)

The other thing that's fed into my thinking is some of the details of which cells XMRV can infect. Several snippets about this in the CFSAC presentations and elsewhere. My recollection is: XMRV can and does infect various kinds of cells; in some but not all of the XMRV+ CFS patients it's found in B and T immune cells; the german prostate study may have been weak because it was only looking for XMRV in the prostate tumour cells not in the blood; XMRV can/could infect the heart and brain as well. I get the impression it could theoretically infect almost any cell.

SO: preamble over, here's the theory. What kind of condition you get after XMRV infection depends on which particular cells XMRV happens to infect. If it manages to infect B and T cells, that's going to mean that (a) anything that activates those cells gives XMRV a chance to replicate, and (b) the functioning of those B and T cells is going to be impaired. Whereas if it infects the brain, the effects are going to be completely different. And if it infects something else less fundamental, maybe you get subclinical effects (explaining the 3.7% infection rate in healthy controls). In each case it shows up in the blood tests, but the core cells infected are different, so therefore the consequences are different too.

Perhaps someone with a proper scientific training can react on whether what I've just suggested makes any sense at all? The other theories of co-infections and genetic vulnerabilities make good sense to me, but this is just something else to throw into the mix.

One more strand to this: even if what I've just suggested is nonsense, it seems to me that the first question researchers should be asking is: what are the rates of XMRV infection in other conditions, specifically those conditions that are either on the rise in the last 20 years or are medical mysteries. And by the way, it's not necessary for these early studies to be rigorous or large or published, I don't see why someone couldn't get samples from 10 people with each of a number of those conditions, send them off to the lab with anonymised coding, and see what comes back. And I don't see why that needs to take more than a few weeks. You would learn SO much about where to focus resources in the next steps, and you'd also get an improved picture about the general level of infection (currently estimated 3.75%) in the general population. In fact, I rather suspect the CDC and/or others have already done this, and I simply don't understand the ethics of not immediately releasing all your scientific findings, however preliminary, in such crucial matters. I understand the economics and the reputation/ego-related reasons, but not the ethics...the WPI had to do it in order to get the credibility breakthrough, but they're an exception to the rule because of the prejudice they were up against.

It does seem odd to me that if the WPI study was ready for publication in May as I've read, there hasn't been time to answer these crucial questions already. It also seems that using up the limited and stressed lab capacity for public tests is a bit of a waste of that resource, given that at this stage the test results aren't of much practical use. I don't mean to denigrate those who have ordered these tests, I well understand the reasons why and I'd be tempted myself if I was in the US and had the money to do it, but quick preliminary studies like I've suggested would be so much more worthwhile.

One more suggestion to any researchers reading this. In computing, we mitigate risk by implementing 'vertical slices' and 'horizontal slices'. We also sometimes start big projects by doing a rough and ready approximation of things first (prototypes) to get an idea of the landscape, and then do the more rigorous work later. Both these techniques help us reduce the overall development time by pointing us in the right direction sooner rather than later. The analogy to science would be: given that right now we seem to know almost nothing about XMRV, we don't need rigorous studies at this stage to prove things, we need quick rough-and-ready experiments, intelligently and strategically targeted, to point us in the right directions, and we can follow those up with rigorous studies later when it's time to prove it.

I don't get the impression that medical science is terribly smart about pursuing that efficiency of knowledge exploration in the way I've suggested, because the political structures make it difficult, and because there's an over-emphasis on everything you do having to be super-rigorous in order to gain acceptance. There's a place for doing things quickly sometimes as well. I just wish the science could move a bit more quickly and efficiently sometimes, because the clock is still ticking for so many of us and we'd like to get our lives back before our 70s if possible please!

Not to have a go at researchers though, just a suggestion. Big up to the WPI and anyone else working on this, you are changing the world, you have already changed our world, and we can never thank you enough!

 

[Mark]

I didn't have severe stress before getting sick, just a tickbite on a lovely June day, with something very virulent in it. I'd like to know if XMRV can be transmitted by ticks. A few of us have speculated it may be the reason for chronic abx refractory lyme.

I'd guess: almost certainly yes, jenbooks, it's possible because XMRV could be in their blood. They could have picked it up from a mouse perhaps? Lots of anecdotal accounts out there from people with cats who had flea bites just before they got sick. Including, that would figure with the 3 people in my family (inc myself) who all got sick at roughly the same time.

 

[shiso]

"Necessary but not sufficient" sounds plausible to me, at least in the majority of sudden viral onset CFS cases, assuming a causal role for XMRV (which is still a big assumption). In response to a question from the CFSAC panel Dr. Peterson also said "you need co-factors" or something to that effect.

I find it hard to believe that it's a mere coincidence that so many people experienced some kind of severe viral infection, often accompanied by other physical and/or psychological stress leading up to their onset. I know I fit this onset pattern to a T.

And yes, subjective retrospection is exactly that, but I've always had a high level of self-awareness and I know what I experienced during that month went beyond my normal thresholds for physical and emotional "stress", which were pretty high (or so I thought).

The question I have been pondering is, IF XRMV is necessary (if not sufficient), when and how on earth did I acquire it? I have zero history of neuro-immune disease or unusual cancers in my very large extended family on both sides and have had very few sexual partners, none of whom have had any kind of disease to this day. When and how I contracted a retrovirus, if I have it, will always remain a mystery to me. So many questions...

 

[Eric Johnson from I&I]

> My starting point is the preliminary finding of XMRV in 40% of a small group of people with autism. This is the same test, the exact same XMRV, with completely different effects. How can this be?

Its likely to be pretty similar, but we dont know it will be the exact same until we sequence several from each disease, and compare.

The bog-standard explanation for autism, assuming both it and some oddly dissimilar disease are caused by identical XMRV, would probably be that XMRV acts as a teratogen. That is, disrupts the development of a fetus prior to birth: directly so, by invasion of the fetus, or indirectly, via immune molecules of the infected mother. It might also act perinataly, infecting the baby not long after birth.

Believe it or not, schizophrenia is often considered quite likely to be a result of influences during gestation of the fetus that will one day become schizophrenic -- I forget what the evidence and arguments for that are. The reason that this is amazing is that schiz almost always becomes detectable only at age 15-30... or something like that. Long after birth. The leading etiologic candidate, though very far indeed from being proven, and formerly considered to be pretty well disproven, is influenza in the mother of the yet-unborn and yet-unschizophrenic individual. Theres supposed to be some evidence from a mouse model or something, which suggests this could happen via a maternal cytokine.

Some believe the schizophrenic brain is probably screwed up from the beginning, in a way that is unveiled only when it attempts to undergo further development typical of adolescence or the peri-adolescent period.

Several other teratogenic infections are known, such as syphilis and rubella. The latter can cause retardation if I'm not mistaken; I know for sure theres at least one now-banished infection that can.

 

[gracenote]

Why not?

In computing, we mitigate risk by implementing 'vertical slices' and 'horizontal slices'. We also sometimes start big projects by doing a rough and ready approximation of things first (prototypes) to get an idea of the landscape, and then do the more rigorous work later. Both these techniques help us reduce the overall development time by pointing us in the right direction sooner rather than later. The analogy to science would be: given that right now we seem to know almost nothing about XMRV, we don't need rigorous studies at this stage to prove things, we need quick rough-and-ready experiments, intelligently and strategically targeted, to point us in the right directions, and we can follow those up with rigorous studies later when it's time to prove it.

I don't see why someone couldn't get samples from 10 people with each of a number of those conditions, send them off to the lab with anonymised coding, and see what comes back. And I don't see why that needs to take more than a few weeks. You would learn SO much about where to focus resources in the next steps, and you'd also get an improved picture about the general level of infection (currently estimated 3.75%) in the general population.

Why couldn't that someone be one of us one of us with the functional, organizing, energetic ability, that is (and I wish it were me, but it's most definitely not) who could contact patient groups with these various conditions and find people who would be willing to pay for their own VIP tests. Then tabulate the results. Then send these to scientists, anyone we can think of anywhere, to pursue further.

With the brilliance I've seen on this forum, might there be somebody able to get this going? It would definitely take more than "a few weeks," but wouldn't it be worth a try?

 

[Andrew]

Hi, all.

It seems to me that the information currently available on XMRV suggests that it is necessary, but not sufficient, for a person to be infected with XMRV in order to develop ME/CFS.

It looks that way to me now, except I don't know how many subgroups of CFS they tested. So far all I have seen is tests on the worst cases in the "fluish" cohort.

 

[Andrew]

Hi, all.

It seems to me that the information currently available on XMRV suggests that it is necessary, but not sufficient, for a person to be infected with XMRV in order to develop ME/CFS.

It looks that way to me now, except I don't know how many subgroups of CFS they tested. So far all I have seen is tests on the worst cases in the "fluish" cohort.

BTW, I think this article by Cort gives some excellent context for understanding this more.

 

[Aftermath]

1980s: AIDS, Autism, ME/CFS

So it's quite possible that XMRV is implicated in loads of other conditions as well, and the best place to start looking would be those conditions that have been rising rapidly since the 80s, like autism has.

I'm glad that I'm not the only one who can't stop dwelling the time period thing. It's just too coincidental.

 

[usedtobeperkytina]

possible

Well, cortisol, progesterone and viruses turn on the virus, according to Mikovitz. She also theorized that a vaccine might turn it on too.

So the 3.5% might have it dormant.

Also, possibly, the not so severely ill among us might have gotten the virus back into dormant stage but the symptom abnormalities, the damage, is still there because they are interdependent. So we are sick, just not as severely as we once were. So depending on the test, these might show negative for XMRV activity. Although, they have the virus living in their cell.

These are just some theories.

Oh, and I suspect that maybe breast cancer may be related to XMRV. I have nothing but gut instinct on this.

Tina

 

[Eric Johnson from I&I]

The first recorded CFS epidemic was in LA in the thirties, though its a nondescript syndrome that might not always have the same cause. There were other epidemics before Tahoe, though more of them were after. Fifty or so total.

It also seems fairly likely to me that non-epidemic cases existed in the past, for example the entity "neurasthenia." One reason it might not have been taken seriously in the past, and so written about, is that there were so many more highly impressive diseases in the past, and things were not as easy to diagnose. TB and syphilis put on quite a show until 1950, for example. Syphilis is truly a spectacular terror in many cases; you can be covered in huge scabs, your entire nose can be destroyed by necrosis, you can be paralyzed, and of course you can go stark raving insane.

Fibromyalgia was supposedly described by Hippocrates (or was it Galen), according to some. I have not located that passage. It would be fun to search for other descriptions in Avicenna or Maimonides, or Roman doctors if any wrote.

For a great example of probable "neurasthenia", check out Proust's description of his aunt, here, on pages 65-77. Just put "65" in the search blank and you will get there. Youll be allowed to turn a few pages, and when the allowance runs out just "search" for the next page number.

http://www.amazon.com/Swanns-Way-Modern-Library-Classics/dp/0812972090

I dont think a definitive diagnosis of Aunt Proust is possible, but it is very striking to read. MS and lupus are both pretty unlikely for various reasons, but not totally excludable. I dont know if she was described more later in the book, I got pretty fed up with it and didnt read past page 100 or so.

 

[Eric Johnson from I&I]

> the damage, is still there because they are interdependent

While some people could be permanently damaged, there is reason to be optimistic; damage seems semi-unlikely, because for every symptom there are people who have recovered from a severe instance of it. In the beginning I had spectacular, evil neurological symptoms, but they are all gone or essentially gone.

 

[anne_likes_red]

Modern epidemic illness...and links.

I've always felt the rise of Autistic Spectrum Disorders, and perhaps many other modern epiemic illnesses, is due in part to an increasing "burden" of toxicity passed on from mothers to their infants. For example heavy metals accumulate and can pass via the placenta. I'm not sure what else....some medications maybe? Organophosphates? A whole host of things that in isolation may not cause great harm, but as part of a cumulative burden may do so.
I've long suspected a link between many of the modern epidemic illnesses and figured that somewhere in the mid-eighties when they did in fact become epidemic it was, in simple terms, because for many the cumulative level of toxic burden began to overtake our detoxification capacity.
It's been easy for me to think and feel this way because when I first became very unwell I personally felt 'poisoned' rather than virus-struck.

However.....this whole new XMRV discovery....

Exciting times

PS Mark I loved your epic post!