CROI 2010: CDC Finding A Different Strain of XMRV

[Mark]

I haven't seen this news mentioned on the forum and I haven't found it on a forum search either, so maybe, just maybe, I found something significant...

The oral abstracts from the XMRV presentations at CROI 2010 (Conference on Retroviruses and Opportunistic Infections) are now online:

http://www.retroconference.org/2010/data/files/webcast_2010.htm

(click 'Friday'- the plenary session(summary of XMRV) by Goff is at the top of the list and the oral abstracts are near the middle).

I seem to remember excitement about this conference a while back, and then disappointment when the proceedings appeared to be unavailable to the public. It looks like they are now, anyway. This is where the info on monkey studies came from, I think? So maybe our scientists have already pored over all this stuff, but the bit that grabbed me was:

Walid Heneine of the CDC said they could not detect antibodies in the two positives(out of a hundred something prostate cancer(PC) patients) they found. Also the phylogenic tree of the positives showed they were somewhat different than the other XMRV's from the CFS and PC patients. From the summary- "The finding of distinct XMRV suggests that multiple strains may be circulating and shows a broader XMRV diversity than currently known."

btw I found this quote by googling my way to ERV's site by mistake... :Retro smile:
http://scienceblogs.com/erv/2010/02/xmrv_im_not_so_positive_youre.php
The above quote is from Post 15 by John.

The reason this seems significant to me is related to the other main point I've been wanting to make in relation to the current confused state of XMRV/CFS research: it's not just the XMRV/CFS studies that are reporting wildly conflicting results, the prostate cancer studies have exactly the same problem.

The German XMRV/prostate cancer study found no XMRV at all in over 500 samples studied. This was well before the Imperial College study etc (maybe that's where they got the idea of failing to find anything ), and in a research community without all the political issues we have. What this says to me is that the discrepancies between results point to something rather strange and confusing in the retrovirology, and that there's therefore no need to invoke the political influences and conspiracy theories to explain why some researchers find XMRV and others don't. Clearly this failure to find XMRV is happening elsewhere as well, and the most obvious conclusion is that there's something about these retroviruses, and the means used to test them, that isn't yet understood. There must be something you have to do in order to get positive results that is not yet widely understood.

The CDC rumour quoted above points towards the beginnings of an explanation of this conundrum: in their tests on prostate cancer, the XMRV they found was all a different type of XMRV. Implied in this is that they didn't find any sign of the same strain of XMRV that the PC and CFS researchers found, but in their samples, they found a different strain. It appears that every lab that has found XMRV has found a specific strain, and not found the others. How could one explain such a pattern? I can only think of two explanations off the top of my head...

1. Maybe each different population really does have a different strain of XMRV, and each group of researchers are studying a different population: the different strains they find reflect the differences in their biases in the collection of - say - prostate cancer samples. The CDC samples, for example, are only from one particular type of prostate cancer, and something in the way they gather those samples biases them towards a different PC population to the earlier studies.

2. Speculating wildly, and as a non-scientist, is it perhaps possible that somewhere during the culturing and testing process, all these tests are actually creating a particular type of XMRV through a combination of something retrovirus-like in their patient populations in combination with their primers. That's probably a hopelessly unscientific speculation (probably not even a hypothesis Gerwyn :Retro smile but it would seem to make sense to me that if something along those lines were happening, you would get a different, but very specific and consistent strain with every different testing methodology. You could even get a different strain by using the exact same tests and primers, if background contamination was involved in the combination: the type of XMRV you got would depend on what other DNA happened to be in your test tubes.

The other mystery one has to explain is how come WPI found so much XMRV? (ie how come they found it consistently in such a high proportion of patients, if XMRV has more varied strains than we thought). We have assumed up till now that the XMRV we're talking about is remarkably consistent, just as the WPI reported in Science. But that consistency is based on two and a half sequenced instances of the viruses, so it's entirely possible that the rest of the WPI's positives came from other strains of XMRV. So one possible explanation seems to be that the WPI testing methods are managing to pick up various strains of XMRV, whereas other researchers' tests are looking for a specific strain (based on their control samples) and failing to find the others.

I've waffled and speculated quite a bit there, and I'm not going to apologise for that, I love it!

But the main issue is fairly simple: the CDC are saying that all the XMRV they are finding in prostate cancer is different to the XMRV everyone else has been finding so far - and that surely has to be significant in beginning to explain all the discrepancies.

So over to the real amateur scientists: Was this report of the CDC findings known about here already or can I claim my first spotters badge? What might the findings mean? And is there anything else new to be mined from the CROI abstracts? I've checked out Goff's presentation (Goff is a colleague of John Coffin): "Mouse to Man? XMRV and Human Disease", but I haven't got to the rest of the oral abstracts on XMRV (halfway down the 'Friday' page) yet...maybe there's fuel for some more juicy speculation to be found in there...

 

[Mark]

OK so, with impeccable timing, I just found the thread on CROI 2010. It was 'HOT!' back in February!

http://www.forums.aboutmecfs.org/showthread.php?3241

Thought this might be the same thing, but I couldn't seem to find the thread before.

So the only part that might just be news is the statement that the CDC are finding a different type of XMRV in their PC samples. Haven't seen much made of that point in the recent discussions, so I'm still hoping that snippet might be significant. Please don't tell me that's old news too...

 

[gracenote]

OK so, with impeccable timing, I just found the thread on CROI 2010. It was 'HOT!' back in February!

http://www.forums.aboutmecfs.org/showthread.php?3241

Thought this might be the same thing, but I couldn't seem to find the thread before.

So the only part that might just be news is the statement that the CDC are finding a different type of XMRV in their PC samples. Haven't seen much made of that point in the recent discussions, so I'm still hoping that snippet might be significant. Please don't tell me that's old news too...

Mark, I don't know if this is old news or not, but keep trying. It's good to have you posting again.

I'll give you cheer either way.

gracenote

:victory:​

 

[George]

Hey Mark it's a good find. Don't forget that Dr. Mikovitz mentioned a different strain found in China. She's speculated that there could be different strains as well as an XMRV-2 even. So you're in good company.

 

[Elliot]

This is fantastic news in the sense of research.
Would explain why the laboratories (the negative cfs-correlation studies) haven't found a single strain of xmrv in their cohorts.
Obviously there might not be a correlation with cfs and xmrv. But does seem to be another avenue to look down, by looking for multiple xmrv strains in cfs patients.

 

[parvofighter]

Don't worry - be happy

Hey Mark, don't go losing any sleep over those German prostate cancer researchers either - they're in good hands. You may have missed it (from one of the Dr Mikovits webcasts) that Dr Singh and Mikovits are re-testing Dr Bannert's patients from that 500-strong German study.

The German XMRV/prostate cancer study found no XMRV at all in over 500 samples studied. This was well before the Imperial College study etc (maybe that's where they got the idea of failing to find anything )

Isn't it great that scientists care enough about truth to re-test their potentially flawed samples!

​

 

[usedtobeperkytina]

How does this relate to Coffin's comments that there is very little variation in the CFS XMRV and the PC XMRV?

He talked like it was so similar that antiretrovirals might not be effective since it doesn't replicate often, he theorized, based on the similarities. He contrasted that to HIV which is vastly different even in the same person two weeks after infection.

How does his comments make sense with Mark's news?

{And I love to theorize also.}

Tina

 

[ldhunter]

Yes, very interesting. Maybe it will help to make sense of the different degrees of illness that those who are XMRV positive have. Thanks for sharing.

 

[Mark]

Hi Elliot, it's always nice to see your face, never fails to bring a smile to mine! :Retro smile:

Would explain why the laboratories (the negative cfs-correlation studies) haven't found a single strain of xmrv in their cohorts.

I'm hoping the scientists will tell us that's correct, but I suspect it may not be enough on its own to explain that failure to find XMRV. As I understand it, the PCR tests look for specific sub-sequences in the XMRV genome, and they look for sequences that ought to be specific for XMRV. So various different strains might well all have those same sub-sequences in their genetic code, in which case the PCR tests should pick up all the different strains.

However, if some of the different strains lacked the sequences the tests looked for, that could explain a lot, because if there are several different active strains it seems pretty likely that they would tend to appear in different geographical locations. UK XMRV might then be mostly from a different strain, and I'd expect samples collected at different times to show different strains too.

I think that as far as PCR testing is concerned, at least, it would all depend on the details of those sequences. It's entirely possible, as far as I can see, that the sequence the WPI looked for is universal for all XMRV whereas the sequences the other studies looked for is only present in some of the strains. That would indeed have the potential to explain all the discrepancies, at least in the PCR testing.

My guess is that this is not correct though, because one would expect that the sequences they choose to look for would be sequences that are unlikely to change: things that are characteristic of XMRV yet also essential to its function and located in areas that are unlikely to successfully mutate. But I do wonder whether that's really feasible: there are only 8000 or so base pairs, as I recall, so if some of them differ in a different strain, how could you be sure the difference didn't lie in the sequence you were looking for?

I'm really looking forward to hearing what our scientists have to say about this point...

 

[Jerry S]

Mark, I don't know if this is old news or not, but keep trying. It's good to have you posting again.

I'll give you cheer either way.

gracenote

:victory:​

Three cheers for Muster Mark!

:victory: :victory: :victory:​

 

[Mark]

How does this relate to Coffin's comments that there is very little variation in the CFS XMRV and the PC XMRV?

He talked like it was so similar that antiretrovirals might not be effective since it doesn't replicate often, he theorized, based on the similarities. He contrasted that to HIV which is vastly different even in the same person two weeks after infection.

This is the other key question I'd love to hear the scientists speculating / hypothesising about. Coffin did indeed say that it's notable - and a little puzzling - that XMRV appears to have replicated very few times because it hasn't changed much. He also suggested that this implies that XMRV crossed from mice to humans relatively recently because it hasn't had time to mutate much.

What we don't know is the percentage difference in the new strain the CDC are finding, and whether that changes the picture on its apparent lack of variation. Perhaps the CFS XMRV and the PC XMRV are indeed very similar, but there are lots of other strains that are quite different. Maybe that would then suggest that the CFS XMRV and the PC XMRV are showing up in very similar forms because those particular strains are the most powerful and resilient ones, or the most pathogenic, but there are lots of other strains and lots of replication going on - the only strains you tend to see are the most successful ones.

As a non-scientist, it does seem to me that an alternative explanation for the lack of variation is that this retrovirus is actually very old rather than very new, and these unvarying forms are merely the forms that are by far the strongest - the perfected forms of the retrovirus. That would make some sense to me because whatever is making us ill, it isn't killing us like AIDS does, it's keeping its hosts (us) alive, more like a parasite that has established a symbiotic relationship with us. Such a parasitic or symbiotic relationship would presumably take a fairly long time to perfect.

I guess it's all a question of evolutionary biology, and I have no idea what the theory would say about it all. It seems to me that the tiny size of the XMRV genome (about 8000 base pairs) could be relevant, and also that our intuitions about the timescales involved in evolution could be misleading in this context. Surely evolution in an organism with a tiny genome can happen much more rapidly than in an organism with an enormous genome? Plus, the succeeding generations of a virus would happen very quickly because (I'm guessing) it can replicate again and again in a matter of seconds, so the timescales are completely different. And retroviruses infect by the 'hack' of reverse transcription (RNA to DNA), and they can recombine with ERVs, so the error/mutation process could work very differently.

I do wonder what the small genome implies. We get all kinds of information from comparing sequences of 'junk' DNA in the human genome and working out things like: statistically, this must mean that these two individuals have a common ancestor 33 generations back. But how much room is there for variation and 'junk' in an organism defined by only 8000 base pairs? Sounds like a pretty tight and efficient structure to me. Yes, HIV mutates and changes to an enormous extent, but that's a big part of its power, that's one of the things HIV is all about. We know next to nothing about the realities of other types of infectious retroviruses, in humans at least, so perhaps our assumptions about them could be misleading.

But these are all just my completely informed guesses - just a bit of fun - I can't wait to hear the reactions of somebody who actually knows what they're talking about!

 

[cfs since 1998]

What we don't know is the percentage difference in the new strain the CDC are finding, and whether that changes the picture on its apparent lack of variation. Perhaps the CFS XMRV and the PC XMRV are indeed very similar, but there are lots of other strains that are quite different. Maybe that would then suggest that the CFS XMRV and the PC XMRV are showing up in very similar forms because those particular strains are the most powerful and resilient ones, or the most pathogenic, but there are lots of other strains and lots of replication going on - the only strains you tend to see are the most successful ones.

As a non-scientist, it does seem to me that an alternative explanation for the lack of variation is that this retrovirus is actually very old rather than very new, and these unvarying forms are merely the forms that are by far the strongest - the perfected forms of the retrovirus. That would make some sense to me because whatever is making us ill, it isn't killing us like AIDS does, it's keeping its hosts (us) alive, more like a parasite that has established a symbiotic relationship with us. Such a parasitic or symbiotic relationship would presumably take a fairly long time to perfect.

I was thinking along the same lines. My thought was that, considering XMRV is a simple retrovirus, the very first human simple retrovirus in fact, maybe it's just not robust enough to survive mutations. So it might very well be replicating, but a small number of mutations could result in the virus being rendered noninfectious or otherwise disadvantaged some way. It would be a form of viral Darwinism--all the isolates are similar because that is the "best" strain, and any deviation would be "worse" and would die out. If this is what's happening then we also wouldn't be able to say how old or new XMRV is either based on lack of mutations, it could be relatively new or old or very old.

 

[Mark]

More snippets from the CDC's prostate cancer study, from Walid Heneine's presentation. The incidence they found was much lower than the other studies, they found XMRV in only 2 out of 162 prostate cancer samples. They did two PCR tests on each sample: one for POL and one for GAG. One of the samples was positive on both, the other was positive only on the POL - but they ran that test twice and it was only positive once. In both cases they also did a further PCR comparing with murine DNA and thereby ruled out mouse contamination in those positives. They then did a further PCR test for XMRV ENV on both the positive samples and both were positive on that test as well.

The divergence of the XMRV genetic code they found was 4-6%, which is quite a bit more variance than previously found.

In both positive samples, they found no antibodies to XMRV, suggesting latent, sequestered, or even cleared infections in those samples.

They noted that the differences from previous results may reflect the use of different assays or different patient populations.

My conclusions from all that are that XMRV detection is a lot more complicated than was expected, that all the results so far (not just the CFS results) are inconsistent and confusing, that different assays are giving very different results and nobody understands why that is, that in all the positive studies there's no real dispute that they are finding genuine infectious XMRV, and that XMRV is more varied than previously thought. The fact that in one case they ran the same test twice and got one positive and one negative also speaks volumes about how unreliable the current testing is, and in that case at least it's pretty clear that the negative was a false negative, rather than the positive being a false positive.

I think that's all good news for the validity of the WPI findings, and suggests to me that the 3 negative XMRV/CFS studies really do mean absolutely nothing as far as the XMRV/CFS correlation goes.

 

[Mithriel]

I don't feel up to finding the references, sorry, but some papers have come out which show that XMRV grows well in a prostate cell line but not in the others which were used in some of the papers which found low numbers.

Until a test is validated finding a virus or bacteria reliably is not simple even if it is present. let's face it, they want to grow in bodies and living systems not test tubes. It is like trying to work out the life cycle of animals by putting them in a zoo without knowing what they eat or how they live.

I think it was the flu virus which only grew in the foot pads of armadillos :Retro smile:

Mithriel

 

[HowToEscape?]

Is there any reason to think that the WPI study got false positives?
Without a biology, much less virology background I have trouble interpreting the various studies. Sure, I can dismiss the Wessely example, but there appear to be others without such issues.

Did WPI find a uniquely effective way of finding XMRV, or did they shine the flashlight so intensively that some random noise got amplified into data? Did their methods find something which reacts such that it reads positive for XMRV but is actually something else? Or is there no way to answer these yet?

??

 

[bullybeef]

What I would like to know is why are the CDC so quiet of all things XMRV etc. Has the truth shocked them into silence?

 

[gracenote]

What I would like to know is why are the CDC so quiet of all things XMRV etc. Has the truth shocked them into silence?

bullybeef,

Are you aware of what the CDC has on their website regarding XMRV? (Last update was Feb. 18, 2010.)

http://www.cdc.gov/ncidod/dhqp/bp_xmrv.html

 

[George]

Yes, wasn't it kind of the CDC to finaly put up information about a new retrovirus ( which they didn't find) on their web site, since they are the world leaders in infectious disease and all. And only 4 days after that nice Dr. Reeves got transfered. ( big grins)

 

[Eric Johnson from I&I]

> I think it was the flu virus which only grew in the foot pads of armadillos

I think that's leprosy your thinking of

 

[Mithriel]

I stand corrected - unless I was an armadillo. ouch! ouch! ouch! :Retro smile:

Mithriel