XMRV: exogenous and/or endogenous?

[SeaShel]

Thanks for posting this fresh eyes.

I'm currently in an HERV K18 study Dr. Huber is doing.

I don't know anything about scientific method and studies, but when the XMRV news broke I wondered if they would test the study participants "on the side" for XMRV.

Your explaining the exo and endo helped me have the correct words for what I was thinking.

Since she was quoted in this article, I'm even more curious to know what might be going on behind the scenes. I haven't had a definitive answer from the research aide as to whether will be given any info on our specific samples.

Shelley

 

[leelaplay]

I agree this line of enquiry looks very likely to be important. If there is a bigger picture that's set to emerge and replace the core conclusions from the WPI study with a more nuanced picture, this is a very good candidate.

I was looking into multiple sclerosis on wiki the other day (following up the XMRV association with atypical MS), and I was quite startled by what I read because although the clinical symptoms and other stuff at the top of the page don't look too familiar, the rest of the explanations look uncannily similar to the XMRV theory. The impression I got was that the best theory on how MS works (and it's another ideopathic condition) seemed to sound like an endogenous retrovirus version of XMRV, even down to details like B and T cell abnormalities. Not to mention the unexplained rise in MS since the 80s.

The 8% of the genome made up of ancient retroviruses is also a really suggestive factor. To me it suggests that the process of XMRV crossing species is an ancient process, and that exogenous viruses become endogenous in this way all the time, such that XMRV and AIDS could merely be the 20th century's most successful retroviruses rather than being something new.

So even if as individuals some of us don't have XMRV, it's quite likely that the general model of retroviruses creating neuro-immune disorders will still hold good for other as-yet-undiscovered retroviruses and will turn out to be a breakthrough in understanding not just a range of ideopathic conditions, but the origins of many other established conditions too.

When you think of it, it seems more likely than not that there are further retroviruses out there waiting to be discovered.

How interesting Mark. Is this Mark, ex- angry old man and now x? ?

It's tough for me to follow the science. Would this be a fair extrapolation - if the human race has manged to turn exogenous retroviruses into endogenous, then there should be antibodies or whatever mechanisms that work with retroviruses in our cells as well that will re-turn off the old endogenous retroviruses? So this would be an avenue for research for a cure?

Could one use an analogy that the 8% of the genome that are old endogenous retroviruses are like a vaccine. It's how the body immunizes itself against them. Somehow xmrv is activating the "vaccine" (viruses that the body has kept to prevent being vulnerable to them) so that the vaccine is causing disease rather than preventing it.

Thanks to all who help me try to follow this!

islandfinn

 

[Mark]

How interesting Mark. Is this Mark, ex- angry old man and now x? ?

That's me. Further changes of identity would not be out of character...

It's tough for me to follow the science. Would this be a fair extrapolation - if the human race has manged to turn exogenous retroviruses into endogenous, then there should be antibodies or whatever mechanisms that work with retroviruses in our cells as well that will re-turn off the old endogenous retroviruses?...Could one use an analogy that the 8% of the genome that are old endogenous retroviruses are like a vaccine. It's how the body immunizes itself against them. Somehow xmrv is activating the "vaccine" (viruses that the body has kept to prevent being vulnerable to them) so that the vaccine is causing disease rather than preventing it.

I immediately suspected something similar when I read about the 8% of the genome that's ancient retroviruses. The other thread relevant, I think, posed the question as to whether retroviruses are what drive evolution, which also raises fascinating questions.

As a computer programmer, I instinctively thought of the 8% as effectively functioning as a kind of memory bank of old infections. On the one hand, the story is that retroviruses inflitrate the immune system and eventually survive as endogenous DNA code, and I then imagine that evolutionary pressure, and some other mechanism, eventually combine to 'switch off' any harmful endogenous code in the human genome. But on the other hand, it's interesting that the deactivated code remains in the genome: is it put to any use?

Of course one can easily imagine why the body might have no mechanism for getting rid of such bits of code in its DNA, but I would tend to suspect that in evolution, nothing is wasted, and this bank of information could feasibly be very useful to the immune system. As an idea of the type of thing: is it possible that the immune system consults this bank of ancient retroviruses when it encounters a new molecule for the first time and has to decide whether to create antibodies for it or not? Something along those lines.

I suspect it would be a bad idea to describe the bank of information as a "natural vaccine" though, and I don't think any of this theory we're speculating over is necessary to explain why infections and/or vaccines can trigger a response from XMRV. The explanation that part of the immune system is corrupt because XMRV has overwritten some of its code and co-opted some of the immune mechanisms, seems quite sufficient to explain the effects we're considering, without needing to bring re-activation of endogenous retroviruses into play.

The whole question is more likely to have deep implications for the understanding of older diseases rather than for new ideopathic conditions. I've suspected for ages that when they eventually crack our condition they will unlock whole new areas of medical science in the process, and all this new science I'm reading about sounds as if it has the potential to do exactly that.

 

[_Kim_]

But on the other hand, it's interesting that the deactivated code remains in the genome: is it put to any use?

Good use as it turns out. They made be necessary for reproduction. Endogenous retroviruses regulate periimplantation placental growth and differentiation

 

[leelaplay]

That's me. Further changes of identity would not be out of character...

what fun!

As a computer programmer, I instinctively thought of the 8% as effectively functioning as a kind of memory bank of old infections. On the one hand, the story is that retroviruses inflitrate the immune system and eventually survive as endogenous DNA code, and I then imagine that evolutionary pressure, and some other mechanism, eventually combine to 'switch off' any harmful endogenous code in the human genome. But on the other hand, it's interesting that the deactivated code remains in the genome: is it put to any use?

Of course one can easily imagine why the body might have no mechanism for getting rid of such bits of code in its DNA, but I would tend to suspect that in evolution, nothing is wasted, and this bank of information could feasibly be very useful to the immune system. As an idea of the type of thing: is it possible that the immune system consults this bank of ancient retroviruses when it encounters a new molecule for the first time and has to decide whether to create antibodies for it or not? Something along those lines.

Or maybe it's like quarrantine with computer virus checks? Aren't those saved but locked away. Being a computer-guy, you would better know if the anaology works.

I suspect it would be a bad idea to describe the bank of information as a "natural vaccine" though

I agree. I had a niggly feeling as I wrote that. I think 'vaccine' is one of those trigger words now that people bring a history to that might obsfucate the meaning here. Wrong choice of words.

if

 

[Mark]

Mark, could you post a link to that MS info? Very interesting - but there's so much in the wikipedia entry, I couldn't find it.[/quote

At the risk of distracting the thread from the endogenous/exogenous theme, here's the stuff on MS. In my defence, the reason for making the connection is the sense that MS may be caused by an endogenous equivalent of XMRV.

I got the prevalence data somewhere else and I can't seem to find it now, but I think it said rates of MS have been increasing since the 1980s. Selected quotes that I found suggestive below...the general gist I would highlight is that it is all unexplained, they basically know very little about it, it's also a neuro-immune disease, and some kind of mystery virus is one of the leading theories. Based on all this, I'm guessing it's caused by a not-quite-endogenous retrovirus. If I had MS, I would want studies looking for XMRV rates in MS patients, and I'd also want 80% of the research focus to be spent on looking for an unknown retrovirus.

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


"ideopathic disease of suspected autoimmune cause"

"onset usually occurs in young adults, and it is more common in females"

"Although much is known about the mechanisms involved in the disease process, the cause remains unknown. Theories include genetics or infections. Different environmental risk factors have also been found"

"Almost any neurological symptom can appear with the disease, and often progresses to physical and cognitive disability and neuropsychiatric disorder"

"There is no known cure for MS...MS medications can have adverse effects or be poorly tolerated, and many patients pursue alternative treatments, despite the lack of supporting scientific study."

"Life expectancy of patients is nearly the same as that of the unaffected population"

"Cases with non-standard behavior have also been described...There is debate whether these are atypical variants of MS or different diseases"

"The person with MS can suffer almost any neurological symptom or sign, including changes in sensation (hypoesthesia and paraesthesia), muscle weakness, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia), fatigue, acute or chronic pain, and bladder and bowel difficulties. Cognitive impairment of varying degrees and emotional symptoms of depression or unstable mood are also common"

"Apart from familial studies, specific genes have been linked with MS. Differences in the human leukocyte antigen (HLA) systema group of genes in chromosome 6 that serves as the major histocompatibility complex in humansincrease the probability of suffering MS. Two other genes have been shown to be linked to MS. These are the IL2RA and the IL7RA, subunits of the receptor for interleukin 2 and interleukin 7 respectively. The HLA complex is involved in antigen presentation, which is crucial to the functioning of the immune system."

Under Environmental factors: Infectious cause:
"Genetic susceptibility can explain some of the geographic and epidemiological variations in MS incidence, like the high appearance of the disease among some families or the risk decline with genetic distance, but does not account for other phenomena, such as the changes in risk that occur with migration at an early age. An explanation for this epidemiology finding could be that some kind of infection, produced by a widespread microbe rather than a rare pathogen, is the origin of the disease"

"The prevalence hypothesis proposes that the disease is due to a pathogen more common in regions of high MS prevalence. This pathogen is very common, causing in most individuals an asymptomatic persistent infection. Only in a few cases, and after many years since the original infection, does it bring demyelination."

(I'm casting the more prevalent "hygiene hypothesis" in the bin along with "we just detect things better nowadays", "maybe it's all in their mind" and all the other unprovable junk science whose only purpose seems to be to attempt to deny reality).

""Human herpes viruses are a candidate group of viruses linked to MS Varicella zoster virus has been found at high levels in the cerebrospinal fluid of MS patients, but the most reproduced finding is the reduced risk of having the disease in those who have never been infected by the Epstein-Barr virus""

Non-infectious Environmental Risk Factors are also interesting, including weak evidence for an association with severe stress, etc.

"Blood-Brain Barrier Breakdown:
The bloodbrain barrier is a capillary system that should prevent entrance of T cells into the nervous system. The bloodbrain barrier is normally not permeable to these types of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junctions forming the barrier. When the bloodbrain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped inside the brain."

(is this similar to the barrier that has to be lowered due to infection in order for XMRV to infect?).

"MS is currently believed to be an immune-mediated disorder with an initial trigger, which may have a viral etiology, http://en.wikipedia.org/wiki/Multiple_sclerosis#cite_note-pmid11955556-0although this concept has been debated for years and some still oppose it. Damage is believed to be caused by the patient's own immune system. The immune system attacks the nervous system, possibly as a result of exposure to a molecule with a similar structure to one of its own"
"As with many autoimmune disorders, the disease is more common in women, and the trend may be increasing. In children, the sex ratio may reach three females for each male. In people over fifty, MS affects males and females almost equally."

(This looks like a massive clue!)

"There is a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the southern hemisphere, with MS being much less common in people living near the equator. Climate, sunlight and intake of vitamin D have been investigated as possible causes of the disease that could explain this latitude gradient"

(Googled around this a bit further. None of the theories mentioned was able to explain the geographic variation. Unfortunately there is no mention anywhere of the single most obvious explanation to me: these are environments where molds can thrive. Yes, I'm still big on the whole fungus theory...)

 

[Mark]

Or maybe it's like quarrantine with computer virus checks? Aren't those saved but locked away. Being a computer-guy, you would better know if the anaology works.

Yes, that was it! That's a much better expression of how I saw it: Quarantine. If an ancient retrovirus comes back round again, it's filed in the genome under "harmful: deactivated" - that surely must be useable information, at least to identify retroviral patterns when they are encountered.

 

[fresh_eyes]

I've suspected for ages that when they eventually crack our condition they will unlock whole new areas of medical science in the process, and all this new science I'm reading about sounds as if it has the potential to do exactly that.

I agree, Mark x. Years ago I heard a doctor say the same thing, and it's always stuck with me. Amazing that it seems it might be happening now.

ps Thanks so much for posting the MS info - I'll read it when the brain fog clears.

 

[fresh_eyes]

Thanks for posting this fresh eyes.

I'm currently in an HERV K18 study Dr. Huber is doing.

I don't know anything about scientific method and studies, but when the XMRV news broke I wondered if they would test the study participants "on the side" for XMRV.

Your explaining the exo and endo helped me have the correct words for what I was thinking.

Since she was quoted in this article, I'm even more curious to know what might be going on behind the scenes. I haven't had a definitive answer from the research aide as to whether will be given any info on our specific samples.

Shelley

This is so interesting, SeaShel. So, you don't know your test results re HERV K18? How did you get in the study? Is it all people with ME/CFS?

 

[SeaShel]

fresh eyes, I'm glad you asked! I had typed out 3 paragraphs of an answer and decided to dig up the study paperwork I received originally to more completely answer you, and found out the the answer to a question I had only guessed at. (was that clear as mud?)

I honestly don't remember where/how I heard about the study, but have to think it was from the ProHealth board. I've been sick so long that I had gone for quite some time without keeping up on much and only visiting that board very infrequently, as it was just too discouraging not having a good doc and not much new to go on.

The study is "HERV K18 as a Risk Factor for CFIDS" and the docs are Renee Taylor of U of Illinois at Chicago, Brigitte Huber of Tufts, Ben Katz of Children's Memorial Hospital in Chicago, Andrew Lloyd of U of New South Wales. It's supported by the NIH.

Anyway, I will just quote from my paperwork for you:

"Previous studies have found a conection between having mono or an HHV-6 (roseola or sixth disease) infection and CFS. There may be a genetic link that explains this connection. The purpose of this study is to test whether some people with CFS carry a gene that would make them more likely to have CFS after having mono or an HHV-6 infection."

Further on it says:

....if you meet certain conditions, you will be invited to participate in Phase II of the study. Eligibility to participate in Phase II will be based on 2 criteria:.....you are not in remission and your symptoms are active and severe; and if the results from the first blood draw indicate that you have the specific genetic makeup for the CFS that we are studying (variation in the HERV K18 gene), then we will invite you to participate in the second phase of the study.

I've had 2 draws and at the 2nd interview it was said I'd be continuing on, but I'm not taking that as cast in stone till I get something official.

It sure wouldn't break my heart to have them test for XMRV also, and share their findings.

I wonder if this will shift anything with the study, or is that a total no-no?

Let me know if there's anything else you'd like to know.

 

[fresh_eyes]

Wow, SeaShel, that is so interesting. I had not been keeping up with CFS research until XMRV (like you, I found the whole topic kind of discouraging) and I had never thought that "genetic predisposition to CFS" could mean something to do with endogenous retroviruses. I guess that sheds some light on the question asked earlier re: do we all have the exact same ones - there are clearly some differences.

I wonder if this will shift anything with the study, or is that a total no-no?

I'm pretty sure that's a total no-no, but I'm sure it is influencing what they want to do next - maybe they'll design a followup XMRV study using the same samples. I do hope you'll keep us posted.

 

[SeaShel]

Absolutely, I will keep you posted. It's probably yet another situation of 'hurry up and wait'. I don't expect to hear anything about the next round till March or April.

With my inherent lack of patience and nosy nature, if I was a researcher on this study you can bet I'd be running the samples for XMRV as soon as I could though.

Shelley

 

[Advocate]

On the endogenous/exogenous question, here's something that was posted yesterday on the National Cancer Institute website, in a Q and A:

"When retroviruses infect germ cells (sperm or egg), endogenous viruses, can develop. The integrated viral DNA, or provirus, is passed from parent to offspring. There is no evidence suggesting that XMRV can do this in humans.

http://www.cancer.gov/newscenter/pressreleases/XMRV_QandA

 

[fresh_eyes]

Also on the endo/exo question, I re-watched Coffin's CFSAC testimony today, and he said that the MLV that is the very close relative of XMRV (what the M stands for) is eNDogenous. In mice. I don't know if anybody else missed that the first time, but I did.

 

[George]

XMRV can only be Exogenous = from without

If I understand what you concerned about it's the transmission of the virus. I wanted to make sure that people don't use the word incorrectly especially with the doctors who can be pains about the smallest things. (big grin) You may have noted on the interview with Dr. Kilamas that she pointed out this virus is most likely handed down from parents to children. That doesn't make it Endogenous though. In order for a virus to be classed as Endogenous it has to be part of the total genome. Not just part of the DNA in a couple of thousand cells.

Endogenous substances are those that originate from within an organism, tissue, or cell [1]. Endogenous retrovirus are caused by ancient infections of germ cells in humans, mammals and other vertebrates. Their proviruses remain in the genome and are passed on to the next generation.

Endogenous processes include circadian rhythms.

What is being passed down from parent to child is live virus. Eventually virus passed from mother to child in the womb will begin to create immunities and after around a 100 generations or so the immunity will be integrated into our total DNA.

The test is does it cause problems in the host it's infecting. If it does then it's still Exogenous. XMRV causes problems in humans, therefore it is exogenous or from without. Even if it is passed down five generations, which is about right with XMRV.

It will only become endogenous when it becomes a part of the human genome rather than just infecting the DNA of a specific cell. As a part of the human genome it would mean that it would no longer cause problems, we would have integrated it into our DNA. Kind of like Neiman pic. It's part of our gene structure but in general it doesn't cause problems unless there is a genetic defect at conception.

SIV jumped species to become HIV. SIV in monkeys is not a problem for the monkey but HIV reinserted into a monkey causes problems. And of course to humans as well because they have no immunity to the HIV virus. MLV doesn't bother mice it's part of their make up. Except when humans take it out of their genetic structure, change it (into say MLV-6) and put it back into the mice. Then it wreaks havoc because the mice have no Endogenous immunity to the changed virus RNA.

Every few thousand years Humans get hit with something like this. Over the course of 50,000 years we have weathered a lot of virus that have jumped species. That's why a portion (about 8%) is incorporated into our DNA. We get hit, we have people who build immunity, we incorporate it so that it become Endogenous, then the virus in question isn't a problem any more.

Happily in our lifetimes we have drugs!

 

[Alice Band]

Prevalence of Chronic Fatigue Syndrome and Chronic Fatigue Within Families
of CFS Patients

Journal: Journal of Chronic Fatigue Syndrome (ISSN: 1057-3321), Volume: 13
Issue: 1 Page Range: 3-13 [2006]

Authors: Rosemary A. Underhill MB, BS, MRCOG, FRCSE, Ruth L. O'Gorman

The prevalence of CFS (Chronic Fatigue Syndrome) and chronic fatigue were
investigated in family members of CFS patients using a questionnaire-based
study.

Significant differences were seen between the prevalence of CFS in all
groups of family members relative to the published community prevalence
of 0.422%, (spouses/partners: 3.2%, p < 0.001; offspring: 5.1%,
p < .001; parents and siblings: 1.1%, p < 0.02; second and third degree
blood relatives 0.8%, p < 0.02.)

The prevalence of CFS was higher in genetically unrelated household
contacts and in nonresident genetic relatives than in the community,
indicating that both household contact and genetic relationship are risk
factors for CFS.

 

[Marylib]

You guys are smart

I am waiting for the "dummies" version of this

 

[fresh_eyes]

The test is does it cause problems in the host it's infecting. If it does then it's still Exogenous.

Hi George. Thanks for your very lucid explanation about endo vs. exo. That fits with understanding as well, though I suspect there may be more yet undiscovered in that field. One question, though - how does your explanation fit with the quote from the top of the thread:

"This new retrovirus [XMRV] may be able, through infecting human cells, [to] induce a transcription of an endogenous virus," says Huber, who has been studying the presence of an ancient retrovirus (HERV-K18) dormant in most people but active in patients with CFS and multiple sclerosis. "We've already shown that Epstein-Barr virus can do exactly this."

(The complete article goes into it more: http://www.scientificamerican.com/article.cfm?id=chronic-fatigue-syndrome-retrovirus)

My understanding of this was that EBV has been shown to re-activate the endogenous "ancient retrovirus HERV K-18", and they wonder if that reactivated retrovirus then begins to "cause problems" again, at least in combination with the EBV (or maybe XMRV). Or no? I thought that was the point of that research.

 

[Mark]

Wow this simple question is proving to be a tough one to pin down!

What George said makes sense, but how does it square with the quote Advocate picked out from the NCI Q&A?

""When retroviruses infect germ cells (sperm or egg), endogenous viruses, can develop. The integrated viral DNA, or provirus, is passed from parent to offspring. There is no evidence suggesting that XMRV can do this in humans."

I read that as saying that if XMRV were to infect a germ cell, that could put it in the DNA of offspring and result in an endogenous virus. The only way I can square that with George's post is if, when they say "can develop" they mean "can develop 100 generations later", but that seems a bit of a stretch.

 

[fresh_eyes]

Good point, Mark. It has turned out to be a very complex question, hasn't it?

George, what would be happening in the mean time, between that first germ-cell infection and fully defunct endogenous status generations later? Wouldn't it be getting passed down in some people's germ cells (& perhaps causing disease) for some time before that immunity you describe developed? Wouldn't it be "endogenous" in some people during that time - or is it only endogenous when the entire human race has it in their genome? Do we all have all the same endogenous retroviruses?

My questions have only increased since hearing Klimas' statement that they think XMRV is likely passed down mother>child or father>child. Obviously, unless we're talking about the germ cell (sperm) being infected, father>child wouldn't really come into play - it would just be father>mother>child, which is totally different.

And thanks for sharing your knowledge, George - do you have a background in this kind of thing?