XMRV: exogenous and/or endogenous?

[fresh_eyes]

Hey all you science types out there: is there any chance that XMRV is endogenous? Is that just impossible?

My thoughts have gone in this direction because my dad was diagnosed with lymphoma as a young man, but then it just went away spontaneously and they thought maybe they'd made a mistake (I remember in particular him talking about having hugely swollen lymph nodes); since then he has lots of health ups & downs, food intolerances, needs to nap a lot, etc. Since I've learned about the CFS/lymphoma connection this has been much on my mind. I suppose another possible scenario would be him passing it to my mom and she to me, but that would make her an asymptomatic carrier I think, overall she's been in good health.

Any thoughts appreciated.

 

[jenbooks]

There's a possibility. They need to ascertain this by seeing if everybody who has it has it on the same place in their genome in which case it would be endogenous, whereas if exogenous it would integrate at various places in individuals' genomes. Make sense?

 

[fresh_eyes]

Good info, jenbooks - that does make sense. Thank you. I'll be interested to know if that's among the research happening now.

 

[Mark]

Hmm...not too sure about this, here's my understanding. The retrovirus would become "endogenous" in humans once we've all got it and have it as a standard part of our DNA. For now it's an "exogenous" retrovirus because it came from mice in which it is endogenous (all species of mice have it except for John Coffin's 'moose mouse'). The probability that XMRV did not come from the mouse retrovirus (MRV? MLV?) is infinitesimally small because they're genetically almost identical.

I don't understand your response Jenbooks because, surely, it isn't in the human genome at all, just in certain cells (and not all cells) in about 4% of the population? But perhaps I misunderstand, I'm pretty new to this science and maybe you have an interesting new theory here that's along very different lines to what everyone's assuming.

Perhaps you're asking the different question: is it possible I inherited it from my Dad, in which case from what you've described I'd say: yes because it sounds like he has CFS and therefore XMRV could potentially be in any cell in his body, but since we don't know how it's transmitted there's plenty of other ways he could feasibly have transmitted it to you; even saliva isn't ruled out at the moment. The 3.75% of healthy controls who have XMRV appear to be asymptomatic so it's perfectly possible your mum has XMRV too (but not XAND).

Another guess is that somebody who got XMRV from their Dad's DNA would thus have XMRV in every cell in their body, which would be pretty radical and one might expect a pretty extreme and unusual pattern of symptoms in this case.

I'm sure we all feel the need to speculate about our families, I know I do, but as my Dad reminded me earlier today, this speculation isn't of any practical use right now so we should regard all this stuff as purely 'entertainment' really, we think about it out of curiosity and for mental stimulation but it serves no other purpose I can think of. If there's any degree of emotional stress associated with this speculation it's perhaps best to try not to think about it. That's not going to stop me speculating though - I love it!

 

[fresh_eyes]

Hi Mark,

Thanks for your thoughts. I'm pretty into speculating on XMRV these days - after the first announcement I refrained, but as evidence seems to be building, I get more and more excited & can't resist - your dad's probably right, but since when do we listen to our parents' good advice, right?

I think my question wasn't all that clear. My understanding of exogenous v. endogenous is that eXogenous = acquired (by an individual - not to be confused with Xenotropic = acquired by one species from another), and eNDogenous = passed down in the genes. So my question was basically the bit about could this have been passed to me from my dad's DNA.

Reading about the Neimann Pick kids (the "childhood alzheimers" mentioned by Peterson at CFSAC as testing XMRV+), it said that it's a genetic disorder but that *everybody* has the Neimann Pick gene. I don't know any more than that, but I do have the sense that, as the understanding of genetics grows, they're realizing it's not all about just having certain genes, it's also about "expression" - like the genes get turned on. So I've wondered if a person might have XMRV in their cells from birth (from conception, actually), and it just gets "turned on" by whatever other factors at some point in their life (EBV infection, say) to create CFS. This would also shed some light on how babies become autistic after a vaccine, that it might turn on an endogenous retrovirus.

Another fascinating fact I learned recently was that, when they first mapped the human genome a few years ago, they found that 8% of the genome consists of old, apparently defunct retroviruses. Imagine! BUT, are these the same for everybody, or do they vary from person to person? I'm going to do more research on this.

OK, I think that's it on wild speculation for now. I can't wait to make everybody in my family get tested for XMRV! Have to wait for the price to come down, though...

EDIT: ps Just read about your family situation on the cholesterol thread - wow! More fuel for my speculation!

 

[jenbooks]

Hi Mark it originated in mice but we don't know when it jumped species. And I'm not sure (haven't reviewed all the literature) whether they have determined for sure it's exogenous. It's easy enough to see if it's now endogenous or exogenous per my first post. I am pretty sure they think the latter but don't know if it has been ruled out and certainly should be.

 

[Daisymay]

XMRV is definitely not endogenous, it's exogenous

Hi,

From the original paper finding XMRV in prostate tumours by Silverman in 2006 it clearly staes that it is not edogenous but exogenous.

http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.0020025

Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant

Discussion

"The XMRV sequence is not found in human genomic DNA, and none of the human endogenous retroviruses, including the only known gammaretrovirus-like human endogenous sequences (hERVs E and T) [70], bare any significant similarity to the XMRV genome. This indicates that XMRV must have been acquired exogenously by infection in positive subjects. From what reservoir and by what route such infections were acquired is unknown. It seems unlikely that direct contact with feral mice could explain the observed distribution of infection in our cohort, since there is no reason to believe that rodent exposure would vary according to RNASEL genotype. It is possible that infection is more widespread than indicated by the present studies, especially if, as seems likely, individuals with the wild-type RNase L clear infection more promptly than those with the QQ genotype. But if so, a cross-species transfer model of XMRV infection would require improbably high levels of rodent exposure for a developed society like our own. Thus, although the viral sequence suggests that the ultimate reservoir of XMRV is probably the rodent, the proximate source of the infection seems unlikely to be mice or rats. Provisionally, we favor the notion that the XMRV infections we have documented were acquired from other humans, i.e., that XMRV may have been resident in the human population for some time. This speculation will, however, require direct epidemiologic validation."

 

[fresh_eyes]

Wonderful, Daisymay! Thanks for finding that. That's one question down, one million more to go.

 

[winsomme]

more sensitive testing

i have a side question on this.

The original incidence of XMRV was found to be 67% in CFS patients and 4% in the controls.

After the testing was refined and made more sensitive, the incidence in CFS patients went up to 95%....what did the control go to? Did the control figure stay at 4% even with the more sensitive testing?

 

[acer2000]

After the testing was refined and made more sensitive, the incidence in CFS patients went up to 95%....what did the control go to? Did the control figure stay at 4% even with the more sensitive testing?

As far as I know, they didn't say. I would really like to know the answer to that question as well.

 

[George]

After the testing was refined and made more sensitive, the incidence in CFS patients went up to 95%....what did the control go to? Did the control figure stay at 4% even with the more sensitive testing?

We next investigated whether XMRV stimulates an immune response in CFS patients. For this purpose, we developed a flow cytometry assay
that allowed us to detect Abs=antibody to XMRV Env by exploiting its close homology to SFFV Env (16). Plasma from 9 out of 18 CFS patients infected with XMRV reacted with a mouse B cell line expressing recombinant SFFV Env (BaF3ER-SFFV-Env) but not to SFFV Env negative control cells (BaF3ER), analogous to the binding of the SFFV Env mAb to these cells (Fig. 4D and S6A). In contrast, plasma from seven healthy donors did not react (Fig. 4D and fig. S6A). Furthermore, all nine positive plasma samples from CFS patients but none of the plasma samples from healthy donors blocked the binding of the SFFV Env mAb to SFFV Env on the cell surface (fig. S6B). These results are consistent with the hypothesis that CFS patients mount a specific immune response to XMRV.

I would like to point out that in the supplement they state that they used healthy controls who did not test positive for XMRV in the original 67 %

 

[fresh_eyes]

Found some more info on the endogenous v. exogenous question - it looks like they suspect XMRV might activate previously latent ENDOGENOUS retroviruses in the genome:

"We think that the problem is that CFS is a collection of many, many different diseases even though it has similar symptoms," says Brigitte Huber, a professor of pathology at Tufts University's Sackler School of Graduate Biomedical Sciences in Boston. She and others suspect that the retrovirus may be unleashing other underlying conditions and viruses in the body.

"This new retrovirus 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."

Even in their testing for the XMRV retrovirus, Mikovits says, "We could see a human endogenous virus at the same time" as XMRV. "There are a number of old diseases that seem to be rising at an infectious rate," she says. Although this background noise of various viruses may be difficult to sort though, it brings clues to help researchers find the root cause of CFS. "It's possible, downstream, that this will all feed into the same mechanism," Huber says.

That's from Scientific American, here http://www.scientificamerican.com/article.cfm?id=chronic-fatigue-syndrome-retrovirus

This seems like it could be a very big deal, considering the human genome is apparently 8% old retroviruses thought to be defunct.

 

[leelaplay]

wow fresh eyes

I'm reminded of someone's comment a few weeks ago - something like:

"How bad is it that I want to find out that I have a retrovirus?!"

I haven't been able to read the article you linked to, and I'm (obviously) not one of our science-brains, but if I've understood what you just wrote,

ETA Have to remind myself: if it turns out that everyone who has ME/CFS has xmrv

xmrv is exogenous - , we got it from somewhere, probably through blood, body fluids?, saliva? or mother's breast milk

a retrovirus is something that once you get it, it stays. It rewrites our DNA so that it becomes and stays part of our DNA

?? once the xmrv has rewritten our DNA, if we have children, do we pass the rewritten DNA that includes xmrv down to them? Does it then become endogenous?

??if our children inherit xmrv as part of their DNA, will they get ME/CFS or will they be like the 4% of the healthy controls in the 1st WPI study?

our DNA is 8% old retroviruses that are inactive. These are endogenous, inherited through our parents' DNA

?? does this mean our bodies have developed an immunity to them?

??does the study you quoted give the info on the human genome being 8% old retroviruses (sorry to have to ask)?

??does everyone have the exact same old retroviruses?

xmrv may awaken these old retroviruses and make them active again


islandfinn

 

[Martlet]

Wow Finn, you have asked some really, really good questions and I now hope someone has answers.

 

[George]

wow fresh eyes

I'm reminded of someone's comment a few weeks ago - something like:

"How bad is it that I want to find out that I have a retrovirus?!"

Great find Fresh Eyes! I swear I read that article and went right past that!

I haven't been able to read the article you linked to, and I'm (obviously) not one of our science-brains, but if I've understood what you just wrote,

xmrv is exogenous - we got it from somewhere, probably though blood, body fluids, saliva or mother's breast milk

a retrovirus is something that once you get it, it stays. It rewrites our DNA so that it becomes and stays part of our DNA

?? once the xmrv has rewritten our DNA, if we have children, do we pass the rewritten DNA that includes xmrv down to them? Does it then become endogenous?

A retrovirus is not endogenous until it no long causes problems for the species it is part of. So for the next couple of centuries HIV, HTLV and XMRV will be Exogenous for the human species.

??if our children inherit xmrv as part of their DNA, will they get ME/CFS or will they be like the 4% of the healthy controls in the 1st WPI study?

You are adding 1+1 and getting two which looks correct. Problem is there is no plus sign yet. The plus sign would be when the virus become Endogenous. Right now we have XMRV in the blood. That's what we pass on to others and to children.

our DNA is 8% old retroviruses that are inactive. These are endogenous, inherited through our parents' DNA

?? does this mean our bodies have developed an immunity to them?

Separate from that we have XMRV RNA in our cells making baby XMRV. The article is suggesting that the XMRV that gets into some of our cells and starts making babies is activating old retrovirus that we incorporated into our DNA 5,000, 10,000, 15,000 years ago. Those old retrovirus don't bother us. They are Endogenous. But if they get woke up and become active then they could be causing a rise in illness that may seem new to us but humans may have suffered from thousands of years ago.

??does the study you quoted give the info on the human genome being 8% old retroviruses (sorry to have to ask)?

??does everyone have the exact same old retroviruses?xmrv may awaken these old retroviruses and make them active again

The article is just theory based on an observation. It's being put forth based on what virologist know about viruses in general. The actual science hasn't been done yet to decide if its fact or fiction.

I hope that helps. I kind of over simplified I hope not to much.

 

[fresh_eyes]

XMRV endogenous AND exogenous??

Hi all. Already posted this elsewhere but folks requested that it get its own thread. Very interesting article in Scientific American 10/8 that I had missed somehow. It addresses the question of whether XMRV is exogenous (acquired) v. endogenous (passed down in the genes), and it looks like they suspect it might be a combination, with eXogenous XMRV possibly activating previously latent eNDogenous retroviruses in the genome:

"We think that the problem is that CFS is a collection of many, many different diseases even though it has similar symptoms," says Brigitte Huber, a professor of pathology at Tufts University's Sackler School of Graduate Biomedical Sciences in Boston. She and others suspect that the retrovirus may be unleashing other underlying conditions and viruses in the body.

"This new retrovirus 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."

Even in their testing for the XMRV retrovirus, Mikovits says, "We could see a human endogenous virus at the same time" as XMRV. "There are a number of old diseases that seem to be rising at an infectious rate," she says. Although this background noise of various viruses may be difficult to sort though, it brings clues to help researchers find the root cause of CFS. "It's possible, downstream, that this will all feed into the same mechanism," Huber says.

The full article is here http://www.scientificamerican.com/article.cfm?id=chronic-fatigue-syndrome-retrovirus

This seems like it could be a very big deal, considering that the human genome is apparently 8% old retroviruses thought to be defunct (per wikipedia: http://en.wikipedia.org/wiki/Endogenous_retrovirus).

 

[fresh_eyes]

Hi everybody, new thread started on this: "XMRV endogenous AND exogenous??" (thanks islandfinn for the title suggestion!) Come on over there if you like and let's discuss.

 

[Mark]

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.

 

[fresh_eyes]

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.

 

[leelaplay]

here's my response from the other thread AND George's kind, not too over-simplified for me, response to it

wow fresh eyes

I'm reminded of someone's comment a few weeks ago - something like:

"How bad is it that I want to find out that I have a retrovirus?!"

I haven't been able to read the article you linked to, and I'm (obviously) not one of our science-brains, but if I've understood what you just wrote,

(I have to remind myself this only applies if it turns out that everyone who has ME/CFS has xmrv)

xmrv is exogenous - , we got it from somewhere, probably through blood, body fluids?, saliva? or mother's breast milk

a retrovirus is something that once you get it, it stays. It rewrites our DNA so that it becomes and stays part of our DNA

?? once the xmrv has rewritten our DNA, if we have children, do we pass the rewritten DNA that includes xmrv down to them? Does it then become endogenous?

??if our children inherit xmrv as part of their DNA, will they get ME/CFS or will they be like the 4% of the healthy controls in the 1st WPI study?

our DNA is 8% old retroviruses that are inactive. These are endogenous, inherited through our parents' DNA

?? does this mean our bodies have developed an immunity to them?

??does the study you quoted give the info on the human genome being 8% old retroviruses (sorry to have to ask)?

??does everyone have the exact same old retroviruses?

xmrv may awaken these old retroviruses and make them active again

islandfinn


Last edited by islandfinn; Today at 11:13 AM. Reason: to remember all is speculative til know that all with ME/CFS have xmrv

Great find Fresh Eyes! I swear I read that article and went right past that!

I haven't been able to read the article you linked to, and I'm (obviously) not one of our science-brains, but if I've understood what you just wrote,

xmrv is exogenous - we got it from somewhere, probably though blood, body fluids, saliva or mother's breast milk

a retrovirus is something that once you get it, it stays. It rewrites our DNA so that it becomes and stays part of our DNA

?? once the xmrv has rewritten our DNA, if we have children, do we pass the rewritten DNA that includes xmrv down to them? Does it then become endogenous?

A retrovirus is not endogenous until it no long causes problems for the species it is part of. So for the next couple of centuries HIV, HTLV and XMRV will be Exogenous for the human species.

??if our children inherit xmrv as part of their DNA, will they get ME/CFS or will they be like the 4% of the healthy controls in the 1st WPI study?

You are adding 1+1 and getting two which looks correct. Problem is there is no plus sign yet. The plus sign would be when the virus become Endogenous. Right now we have XMRV in the blood. That's what we pass on to others and to children.

our DNA is 8% old retroviruses that are inactive. These are endogenous, inherited through our parents' DNA

?? does this mean our bodies have developed an immunity to them?

Separate from that we have XMRV RNA in our cells making baby XMRV. The article is suggesting that the XMRV that gets into some of our cells and starts making babies is activating old retrovirus that we incorporated into our DNA 5,000, 10,000, 15,000 years ago. Those old retrovirus don't bother us. They are Endogenous. But if they get woke up and become active then they could be causing a rise in illness that may seem new to us but humans may have suffered from thousands of years ago.

??does the study you quoted give the info on the human genome being 8% old retroviruses (sorry to have to ask)?

??does everyone have the exact same old retroviruses?xmrv may awaken these old retroviruses and make them active again

The article is just theory based on an observation. It's being put forth based on what virologist know about viruses in general. The actual science hasn't been done yet to decide if its fact or fiction.

I hope that helps. I kind of over simplified I hope not to much.