NEW - FDA Website Q&A on XMRV, MLV's & Alter/Lo PNAS Study outcomes

[pictureofhealth]

Here is a link to the FDA website Q&A session following the PNAS publication of the Alter/Lo Study, the XMRV v MLV findings in CFS and what needs to happen next:

http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm223232.htm

 

[Cort]

The big news is that the Alter group tested the CDC samples and could not find XMRV in them, which suggests that those people are very different from the patients in the Komaroff group and the WPI group. I thought they were very different - but no that different!

Check this sentence out

Additionally, the CDC laboratory provided 82 samples from their published negative study to FDA, who tested the samples blindly. Initial analysis shows that the FDA test results are generally consistent with CDC, with no XMRV-positive results in the CFS samples CDC provided (34 samples were tested, 31 were negative, 3 were indeterminate).

It would seem odd to me if the Alter group did not return the favor and provide the CDC group with THEIR samples..........which they must be testing.

 

[Rrrr]

the fact that neither group found any xmrv in those CDC samples indicates to me that there was something wrong with the samples, not the corhort.

 

[SDP]

the fact that neither group found any xmrv in those CDC samples indicates to me that there was something wrong with the samples, not the corhort.

True, but sample selection cannot account for the different results in healthy controls.

Perhaps this can be explained by the small sample size. But still, given the prevalence reported in the positive studies, the odds would be against the CDC selecting 100+ people (patients and controls) who are not infected.

 

[RustyJ]

True, but sample selection cannot account for the different results in healthy controls.

Surely it could, if samples and control came from different sources.

 

[pictureofhealth]

Surely it could, if samples and control came from different sources.

Just posted this on the Name Change thread for some reason, (in response to another comment I think), but makes more sense here.
I've reworded it slightly -

The Alter/Lo paper looks as if it might clarify at least one of the big questions which has come up recently - namely why those severely ill XMRV -ve patients night have tested negative for XMRV.

They may simply have another/different (but related) MuLV which is not detectable if you are looking specifically and only for XMRV.

It still doesn't explain though why Alter/Lo can detect all these other MuLV's but why not XMRV - which they were looking for.

Perhaps i) regional variations in MLV's really do make all the difference and also

ii) mutations must be important - perhaps in as little time as one month to the next.

iii) Or, if we want to take it further and go with the vaccination contamination theory - the differences cropping up are due to different strains of lab mice used for vaccinations in different regions and countries! (ooops).

Whichever way you look at it, there sure are a lot of unexplained MLV's about the place contaminating the human race - but the fact is, they are there and they are coming from somewhere!

I dunno - I think we're missing a huge trick here somewhere. Maybe it is co-infections.

We're really still at the beginning here.

Looking forward to what amazing gems will come out of the September XMRV Conference, especially the interim findings from the WPI's UK blood testing.

 

[pictureofhealth]

Does XMRV exist any more or has it mutated already?

Looking at the comments from the Tuesday teleconference, another big question comes to mind -

Does XMRV itself exist any more or has it mutated already?

The viral mutations in the patient after infection could explain all the variations (as per Alter and Los comments below).

What really jumped out at me was the following question from News, at Tuesdays (23 Aug) FDA/NIH/ CDC Teleconference (taken from the very helpful transcript prepared by Parvofighter and XMRV Global Action and posted on Facebook at this link:
http://www.facebook.com/note.php?note_id=432527206796


Michelle Cortez, Bloomberg News: "If we have low levels of virus in the blood and yet we are seeing many variations on the sequence, can you speculate as far as what is going on. Is it some kind of.. is it mutating inside the patient? Or are we seeing there is quite a variety of virus out there and different people are being exposed to different kinds."

Dr Lo. "Indeed for this type of virus this is quite characteristic. Once you infect in this case earlier questions finding the virus gene sequence in the blood that means this is an infection. This is a cell associated virus so of course if we truly find it in the patient blood we think that's an infection going on. Although a virus titre or virus gene copy is very low. But finding when we sequence them and we finding a variation in the sequence and this is again like earlier description, this is very characteristic for retrovirus infection and we do anticipate that. In a way it was a little bit surprise when the WPI's first publication in Science and they show it as a single kind of kind of a sequence. That is unusual for retrovirus, but now they are also stating they do see the variation of the sequence and also appear to be more closely related to polytropic related MLV's.
"
Michelle Cortez: "Would that be from mutations that are happening after the person is infected?"

Dr Lo: "Yes, that can be. Retroviruses use the RT, the reverse transcriptase and that is an enzyme that the fidelity is not very good so each time when they replicate they very easily introduce a different kind of a mutation. So after the infection certainly they can also start to accumulate this kind of mutation or changes."

Dr Alter: "To demonstrate that further we in our paper, we recalled 8 patients from Dr Komaroff. 15 years later 7 of the 8 still had the virus but the virus had changed within the patient over that time. These are minor variations, very characteristic of the mutation in the patient. And again suggest that this is a real phenomenon in the patient and not a laboratory contamination."

.............

Also, would mutations explain symptom variation between patients and/or symptoms changing in each patient throughout the course of the illness?

 

[RustyJ]

Michelle Cortez: "Would that be from mutations that are happening after the person is infected?"

Dr Lo: "Yes, that can be. Retroviruses use the RT, the reverse transcriptase and that is an enzyme that the fidelity is not very good so each time when they replicate they very easily introduce a different kind of a mutation. So after the infection certainly they can also start to accumulate this kind of mutation or changes."

Aaaahhh! It is starting to make sense, even to me.

Dr Alter: "To demonstrate that further we in our paper, we recalled 8 patients from Dr Komaroff. 15 years later 7 of the 8 still had the virus but the virus had changed within the patient over that time. These are minor variations, very characteristic of the mutation in the patient. And again suggest that this is a real phenomenon in the patient and not a laboratory contamination."

.............

Pictureofhealth: Also, would mutations explain symptom variation between patients and/or symptoms changing in each patient throughout the course of the illness?

I seem to remember Komaroff discounting this suggestion, saying there was little symptom differentiation - all were very sick - within his own patients (provided, of course, there were multiple variants in his group).

Perhaps it is misleading to dwell too much on the variations. It has been pointed out that HIV varies just as much, yet all variations come under HIV I or II. Ultimately the talk will come back to a single entity, perhaps still called XMRV. Also there is the suggestion that researchers are persisting with the variations discussion to distance themselves from WPI.

I have yet to hear someone say how different the MLVs are from XMRV. If they are not very different, then it is still XMRV.

 

[alex3619]

Hi, I think the simplest and most probable explanation for not finding xmrv is that APOBEC3 confuses the PCR test, and you only have unmodified xmrv for testing if you culture it first. Recently grown xmrv would not be modified, so it is detectable. Bye, Alex

ps I am sick of capping xmrv, too much work as I type it too much

PPS I also wonder if the primary co-infection for XMRV might not be other MLVs: having one MLV weaken our immune system will be more likely to allow others to infect and multiply.

 

[taniaaust1]

the fact that neither group found any xmrv in those CDC samples indicates to me that there was something wrong with the samples, not the corhort.

Maybe the CDC had put them in a microwave or something . They did not wantt to find the virus and had declared they wouldnt find it. Is is possible something got done to samples?? so it wouldnt be found?

 

[Wonko]

RustyJ - pretty sure I saw a figure of 96.6% identical somewhere last night - how close this actually is in retroviral terms I dont know but afaik in people terms it's more variation than there is between us and most primates

 

[taniaaust1]

Dr Alter: "To demonstrate that further we in our paper, we recalled 8 patients from Dr Komaroff. 15 years later 7 of the 8 still had the virus but the virus had changed within the patient over that time.

umm now that brings some confusion to my mind.. did all 8 of those Komaroff patients have the virus at the start??? I assumed he was talking about 8 with the virus being retested years later.
If so, this means one of them was "cured" of the virus!! Or did he mean that the virus didnt mutate in one of the 8 but stayed the same???

 

[RustyJ]

umm now that brings some confusion to my mind.. did all 8 of those Komaroff patients have the virus at the start??? I assumed he was talking about 8 with the virus being retested years later.
If so, this means one of them was "cured" of the virus!! Or did he mean that the virus didnt mutate in one of the 8 but stayed the same???

I interpreted it to mean that maybe there was a false negative.

 

[jace]

RustyJ - pretty sure I saw a figure of 96.6% identical somewhere last night - how close this actually is in retroviral terms I dont know but afaik in people terms it's more variation than there is between us and most primates

But viruses and retroviruses are far simpler organisms than humans and primates, so the analogy is not direct. One would have to look at the percentage of difference, to make a direct comparison.

 

[Countrygirl]

=taniaaust1;115701]umm now that brings some confusion to my mind.. did all 8 of those Komaroff patients have the virus at the start??? I assumed he was talking about 8 with the virus being retested years later.
If so, this means one of them was "cured" of the virus!! Or did he mean that the virus didnt mutate in one of the 8 but stayed the same??

As I remember it, all eight had the virus at the start, but the one who was negative the second time was still ill and not recovered. I feel this is quite important because a retrovirus is for life, and as the patient was still ill, it does suggest that a negative result is not reliable yet.

 

[Wonko]

erm...96.6%

I agree which is why I said I didnt know in retrovirus terms - the differences could be primarily located in the method used to enter cells and not the payloads - how big the retrovirus's essential machinery is relative to it's size would be important in determining it's effective similarity to XMRV - ie it's probably possible you could have a retrovirus with sigificantly more differences than this but be functionally identical - but my field didnt used to be biology - it was computers - so I dont know

 

[bullybeef]

Could this mean that XMRV and it's variants are potentially infecting many more people? Starting to seem that way to me. If the 7% is what they can find now, could it be that others are still hiding away.

 

[Ash]

remember this study had bugger all patients & controls so any percentages will have a much higher margin of error - they used an established banked cohort for speed (just like the negative studies)

 

[Otis]

Maybe the CDC had put them in a microwave or something . They did not wantt to find the virus and had declared they wouldnt find it. Is is possible something got done to samples?? so it wouldnt be found?

Remember Dr. Vernon's criticism that the CDC didn't use sodium heprin (think that's right) tubes to draw/store the blood thereby eliminating (I think she worded it this strongly) any chance of finding viruses. Sorry, too ill to find the reference right now.

So you don't need a microwave to zap viruses.

 

[Otis]

As I remember it, all eight had the virus at the start, but the one who was negative the second time was still ill and not recovered. I feel this is quite important because a retrovirus is for life, and as the patient was still ill, it does suggest that a negative result is not reliable yet.

Dr. Lo at one point said that one day a test could be negative and the next day positive, presumably due to the low copy numbers. As I recall the WPI did multiple PCR runs on patients to find the virus on some cases. It's very likely likely a MLV was in this patient, just not detected with PCR that day.