Endogenous Murine Leukemia Viruses: Relationship to XMRV and MLVs in Human DNA

More content from Coffin.

Endogenous Murine Leukemia Viruses: Relationship to XMRV and MLVs Detected in Human DNA Samples
J. M. Coffin and Oya Cingz
Received 15 June 2011; Accepted 7 July 2011

Academic Editor: Arifa S. Khan

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Xenotropic murine leukemia virus related virus (XMRV) was the first gammaretrovirus to be reported in humans. The sequence similarity between XMRV and murine leukemia viruses (MLVs) was consistent with an origin of XMRV from one or more MLVs present as endogenous proviruses in mouse genomes. Here we review the relationship of the human and mouse virus isolates, and discuss the potential complications associated with the detection of MLV-like sequences from clinical samples.

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http://www.hindawi.com/journals/av/aip/940210/

Read this paper and I don't think it contains a lot of new information, but correct me if I am wrong.
What does seem new is that a paper with Coffin's name on it is now also questioning the Lo/Alter study?

Jemal said:

...
What does seem new is that a paper with Coffin's name on it is now also questioning the Lo/Alter study?

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That's how I read it as well, Jemal. Here's the relevant quote:

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A final problem with the sequences reported by Lo et al. is that they do not exhibit the sort of evolution expected for long-term infection. Although these authors reported that sequences that appeared to show evolutionary changes were obtained from some of the same patients ~15 years after the initial sampling [14], examination of the sequences made available in the GenBank database reveals that the evolved sequences are in fact very similar to other endogenous MLVs. (Figure 6, right panel) [27]. Rather than evolving as would be expected of a true infecting virus, these sequences therefore seem to be simply moving up and down the MLV phylogenetic tree. The conclusion that they represent MLV sequences amplified from trace mouse DNA contamination is inescapable.
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Not every scientist agrees with Coffin though on evolution

(start)
Once a virus is endogenised, it is forced to follow the evolutionary rate of the host. Since XMRV is integrated in cell-lines the virus evolution is restricted to the host's pace of evolution, and viral descendants have none or minimum sequence diversity. Thus, if a contaminated product, previously cultured in cell-lines, is administered to people then the infections would provide the evolutionary patterns reported by Hue and colleagues.4 If the immunological data reported by Lombardi and colleagues5 are correct, then we need to trace the common source for these infections to prevent possible public health concerns. Products from cell-lines should be the first candidates.

by Gkikas Magiokinis
Uni of Oxford, UK
http://evolve.zoo.ox.ac.uk/Evolve/Gkikas_Magiorkinis.html


The Lancet Infectious Diseases, Volume 11, Issue 4, Page 264, April 2011

yeah basically, if you infect millions of people with some batches of contaminated vaccine or similar, there won't be as much difference between the organisms as you would have if were a NORMAL infectious event, with a spread from person to person over time which allow more time for change and interaction with other genetic material.

like if you dropped smallpox from a bomb on a city, all those infected would have the exact same strain with no variation.

vaccines, my fellow canaries-in-the-coal-mine!

SilverbladeTE said:

(...)

like if you dropped smallpox from a bomb on a city, all those infected would have the exact same strain with no variation.

vaccines, my fellow canaries-in-the-coal-mine!

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This is a possibility I wish were being investigated by at least one person who had resources, commitment and knew what the heck they were doing.

I've seen several stories of people who, usually in the health care field, become ill after a getting a shot for this or that. And their coworkers become ill... Often events like this people offer the possibilities that: either the shot was just a "trigger" or rather even just something memorable that happened around the same time frame and therefore is singled out.

An alternate possibility is that it is involved more closely then just as a "trigger." We don't know... Why these outbreaks have never been rigorously investigated I'll never understand...

I mentioned this as a possibility to explain the seemingly "strange" phylogeny's of MLLV's found in humans, by the people that are finding them but even though the person I mentioned it to seemed to agree with this possibility they sounded like they weren't keen to investigate it.

I think in Osler's Web it is mentioned Cheney did a chart showing there was almost no M.E. in the 60s, very little till the late 70s and a huge spike in the mid-80s so any hypothesis would have to account for that.

A lot is being made by of the fact that XMRV and relations would be killed straight off by the human immune system, but *most* pathogens are "losers" and only cause disease under a set of circumstances favorable to them. Even the more virulent pathogens are often like this.

Doesn't Chia hypothesize something like this but with Enteroviruses? That is: that the viruses can not spread efficiently but that our immune systems are unable to clear the double-stranded RNA form? (don't remember exactly).

In any case all of us carry many many micro-organisms many of which are losers and which would only become dangerous to us under what could be considered "unlikely circumstances."

Hi KnightofZERO, one of the issues with the Cheney data is the difficulty of getting a good diagnosis. While some might argue he can't be sure and is over-estimating, many would argue he is under-estimating. One of the issues he had to face, iirc, is that the curve always seemed to be tapering off - no matter the year you took data from. People who became ill didn't show up till years later, it always looks like the spread is tapering off. If we had rapid diagnosis and a central reporting agency, I suspect we would see a serious pandemic growth curve in the early stages. The mere suspicion of this should be enough to warrant close attention but this is still being ignored so far as I know.

The CDC has spread the definition so wide its useless. One effect of this is that if a subgroup is growing rapidly, people with the core biological ME or CFS, then it would be lost in mass data, shown as a small increase at best. The problem with epidemic growth curves though is they start off small and then when they reach a critical population penetration they take off. I don't want to see this happen for ME or CFS.

The delay in diagnosis might also be putting a stop to the reporting of epidemics. Wait six months for a diagnosis and the epidemic is over. Besides, who wants to report mass hysteria - even the docs have been treated so badly they might be wary of reporting things. Of course, there might be other reasons why we rarely see epidemics. I can think of several which I have discussed elsewhere.

I have heard assurances repeatedly that ME or CFS are not increasing in prevalence. After all the numbers at major ME and CFS clinics are not going up much if at all. First, such clinics are rare, and are difficult to get into - and second they are often expensive. So they do not adequately survey the population. Such is the disrepute of an ME or CFS diagnosis that I suspect many are simply not even diagnosed - a decrease in diagnostic rates might well cover up an increase in prevalence.

One thing that suggests to me that prevalence has to be rising is the apparent disparity between recovery and new cases. More and more new cases, very few recover - where is it going to go but up? Sure we can die young from this, but it takes decades in most cases, and wont really make a dent in numbers.

Several common sources do indeed look suspect. My guess is that if vaccines are a source of contamination only some will have the causative agent, others will be safe. This might even be the case for a single batch of vaccine. Hence some get sick but most don't, and so it might be easy to dismiss as coincidence i.e. it can't be the vaccine because only some got sick. This is also the case if it requires some other factor, like a co-infection or genetics - only some will get sick so the vaccine is "safe".

These are complex issues begging for attention. I think I recall Anthony Komarof has been asking for funds for such studies since the 80s. Such funding has never been available, the only programs were for the CDC surveillance, and they used increasingly irrelevant definitions.

I actually have a lot of time for Fukuda himself. He did insist that his definition was only a beginning, that subtyping was necessary.

Bye
Alex

Knight of Zero,

Have you read Osler's Web? It's a great introduction to the history of CFS and the 80's outbreaks. Very hard to respond to you on such a long topic.

ME has been around in recorded outbreaks since 1938. These outbreaks were taken serious, investigated and reported on. You'll find reports and papers on them still on the internet. They used the technology that they had then.

Historically what happened is that the 1950's outbreak in the Royal Free Hospital in London was "discredited" as being a psychiatric event and parts of the medical profession began to consider ME and then CFS are psych illnesses. Many of them still do, they have powerful backers and powerful supporters.

Yes, we would all love the outbreaks to be investigated properly. You would need to read Osler's Web to get the full picture of how the CDC didn't properly investigate one outbreak and how they continued to not investigate it properly since.

There are lots of theories on ME and CFS. Is it one trigger or many. What part do vaccines play, what part the terrain, why does it affect certain groups more. The simplest epidemiology has not been done.

Patients have a very good idea if what needs to be done and not done. For examples the CDC's terrible Empiric definition and how to define the disease. We said loudly and clear what would happen when CFS was invented and every step since then.

Yes, we would all like the funds made available and the investigations to start in earnest. Patients have been asking for this for decades. We talk to doctors, elected representatives, start petitions, talk to the media, do protests, talk to charities, groups that fund research. We just go on and on trying to get things done. Few listen to us and few care.

twenty five years at square one

alex3619 said:

One thing that suggests to me that prevalence has to be rising is the apparent disparity between recovery and new cases. More and more new cases, very few recover - where is it going to go but up? Sure we can die young from this, but it takes decades in most cases, and wont really make a dent in numbers.

Several common sources do indeed look suspect. My guess is that if vaccines are a source of contamination only some will have the causative agent, others will be safe. This might even be the case for a single batch of vaccine. Hence some get sick but most don't, and so it might be easy to dismiss as coincidence i.e. it can't be the vaccine because only some got sick. This is also the case if it requires some other factor, like a co-infection or genetics - only some will get sick so the vaccine is "safe".

These are complex issues begging for attention. I think I recall Anthony Komaroff has been asking for funds for such studies since the 80s. Such funding has never been available, the only programs were for the CDC surveillance, and they used increasingly irrelevant definitions.

I actually have a lot of time for Fukuda himself. He did insist that his definition was only a beginning, that subtyping was necessary.

Bye
Alex

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Totally agree with your statements Alex. Also understand the tapering issue. In any case, his presentation would seem to show there was a dramatic increase around the time of the late 70s to mid 80s which may or may not have still been ongoing. There needs to be a central reporting agency. If the CDC won't do it, or won't do it well, then we need it done through some other agency.

Yes, we would all like the funds made available and the investigations to start in earnest. Patients have been asking for this for decades. We talk to doctors, elected representatives, start petitions, talk to the media, do protests, talk to charities, groups that fund research. We just go on and on trying to get things done. Few listen to us and few care.

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Hi thanks! I totally share this sense of frustration. It's like this people think such a major public health problem is going to go away by not looking into it?! How ridiculous of them... Some of the groups that claim to represent us are so "conservative" they would make Barry Goldwater blush!

Inaction is not going to make the problem go away! It is only going to condemn future generations...

Also, I have read Osler's Web--that's where I got the report of Cheney's presentation from originally.

I agree there were outbreaks before the 60s like Royal Free, but if Cheney's presentation was correct then there was a major increase in the incidence of M.E. in the late 70s and early-mid 80s.

I agree with the comments re: basic epidemiology has been often left undone or when it was done it was years ago (that is, before the CDC got involved) like in the very early M.E. outbreaks.

This is one of the things that is so frustrating. So many basic "Checklist Items" were never done or done in a slipshod manner.

It's my opinion if we only had had over the last decade, a team of about 30-40 clinicians and researchers at the top of their game investigating things like these common outbreak clusters whilst sharing information and with access to new technology and funding and resources we would probably know nearly all of the pathology, and the pathological changes from onset to chronicity, and probably know the cause as well.

good wishes to you all!

Thank you for such a brilliant email KnightofZero

Exactly right. If we would have had a well funded, motivated and openminded team who took the 70's/80's outbreaks seriously (and especially learned the lessons from HIV) then we would not be in this mess today.

ukxmrv said:

Not every scientist agrees with Coffin though on evolution

(start)
Once a virus is endogenised, it is forced to follow the evolutionary rate of the host. Since XMRV is integrated in cell-lines the virus evolution is restricted to the host's pace of evolution, and viral descendants have none or minimum sequence diversity. Thus, if a contaminated product, previously cultured in cell-lines, is administered to people then the infections would provide the evolutionary patterns reported by Hue and colleagues.4 If the immunological data reported by Lombardi and colleagues5 are correct, then we need to trace the common source for these infections to prevent possible public health concerns. Products from cell-lines should be the first candidates.

by Gkikas Magiokinis
Uni of Oxford, UK
http://evolve.zoo.ox.ac.uk/Evolve/Gkikas_Magiorkinis.html


The Lancet Infectious Diseases, Volume 11, Issue 4, Page 264, April 2011

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They're saying pretty much exactly the same thing! Coffin is saying that the sequence diversity of the submitted XMRV is too low to be from an actively replicating virus and that they show more similarity to what we see in endogenous retroviruses ie retroviruses that are permanently incorporated into the host genome and replicated by the host replication machinery (which is far less error prone than the the viral reverse transcriptase)

Have you looked at HTLV sequence diversity Redruth?, as Dr Mikovits thinks that this may be a better model to compare to. Dr Mikovits talked at the IiME conference of HTLV samples from the same patient being very similar over 40 years. XMRV is going to behave like XMRV not like HIV. She's working with Dr Rusetti.

Also about the above - have a read of the entire response by Gikkas above and he talks about a possible explanation being contaminated product being administered to people (i.e. not contamination of patients samples).

He suggests the possibility that actual infected patients with low diversity because they were infected from one source. Coffin doesn't think that CFS patients are infected with XMRV and is using low diversity as part of this thinking as "proof".

These two points may help you on the other thread as well. Good luck and thanks for sticking with us. I hope that this helps your sister.

RedRuth said:

They're saying pretty much exactly the same thing! Coffin is saying that the sequence diversity of the submitted XMRV is too low to be from an actively replicating virus and that they show more similarity to what we see in endogenous retroviruses ie retroviruses that are permanently incorporated into the host genome and replicated by the host replication machinery (which is far less error prone than the the viral reverse transcriptase)

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There is indeed some similarity, but also a major difference in interpretation of the implications of the low sequence diversity: they are considering a very different possible implication. Whereas Coffin et al have flatly stated that the research question is now closed and the XMRV results should be viewed as proven contamination, Magiokinis says "we need to trace the common source for these infections to prevent possible public health concerns" - and rather than talking about contaminated experiments, he talks about the possibilities of what might happen "if a contaminated product, previously cultured in cell-lines, is administered to people".

It seems to me that they are looking at the same data and reaching some broadly similar conclusions, but then considering very different potential implications of these findings. Somewhat between the lines, it seems quite clear to me that Magiokinisis highlights the possibility that a vaccine-mediated 'contamination' of humans would lead to the very results that Coffin et al reported - a possibility that Coffin appears to be ignoring, for quite understandable reasons...

Quite, Mark.

I have been reading "Frequent detection of XMLV in human cultures established from mouse xenografts" Zhang et al., and that is a real possibility. This contamination has been widespread since the seventies and spreads rapidly in the lab.
The problem was disregarded. Even though it was initially recognised it was swept under the carpet because research work would be invalidated if you admitted that the cell line you worked on was subsequently found to be contaminated with another virus.
Add to that the increasing pressure on all research to come up with a product, the squeeze on funding, and caution and foresight are lost in the scramble to get ahead.

I used not to be very convinced by the "contamination by contamination" theory.

Listen to this..."our studies demonstrated that several MLV strains were present in over one fourth of xenograft cell lines....contamination was widespread...confirming the highly infectious nature of MLV viruses...horizontal spread may occur rapidly. ( a few days)

There is another paper which suggests that contamination could get into people - it is in the Dong/Silverman paper.. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003144

quote...."the possibility to encounter XMRV in the cultures of human cells....due to lab. contamination..a pool of MLV based constructs ...may spread to other cells, especially in co-culture experiments. In addition ...live attenuated vaccines could.become contaminated with XMRV..." quote.

ukxmrv said:

Have you looked at HTLV sequence diversity Redruth?, as Dr Mikovits thinks that this may be a better model to compare to. Dr Mikovits talked at the IiME conference of HTLV samples from the same patient being very similar over 40 years. XMRV is going to behave like XMRV not like HIV. She's working with Dr Rusetti.

Also about the above - have a read of the entire response by Gikkas above and he talks about a possible explanation being contaminated product being administered to people (i.e. not contamination of patients samples).

He suggests the possibility that actual infected patients with low diversity because they were infected from one source. Coffin doesn't think that CFS patients are infected with XMRV and is using low diversity as part of this thinking as "proof".

These two points may help you on the other thread as well. Good luck and thanks for sticking with us. I hope that this helps your sister.

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Yes, I understand these points but Coffin isn't disagreeing with Magiokinis about the evolution of ERVs! They're putting forward reasons why the XMRV sequences don't show the kind of sequence variation that infections replicating retroviruses usually show.

ps thanks for your comment about my sister.

RedRuth said:

Yes, I understand these points but Coffin isn't disagreeing with Magiokinis about the evolution of ERVs! They're putting forward reasons why the XMRV sequences don't show the kind of sequence variation that infections replicating retroviruses usually show.

ps thanks for your comment about my sister.

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But the central point is that Dr Coffin uses this data to argue that there IS NO PROBLEM.

This is what we are disputing.

I was just trying to understand his/her comment : Not every scientist agrees with Coffin though on evolution In fact the comment should be: Not every scientist agrees with Coffin on why the MLV like sequence's haven't evolved.

The paper the OP refers to uses phylogenetics to show that the sequences from the Lo study don't conform to a nested hierarchy that you would expect from either a replicating retrovirus or an endogenous retrovirus. In other words the amount of variation or evolution is irrelevant, it's how the changes/mutations in the sequences line up that's important. Figure 6 of the paper refers to a phylogenetic analysis of contaminating Mouse DNA and how similar it is to the phylogenetic tree of the lo data. The implication being that the MLV sequences are contamination.

currer said:

But they could be putting that contamination into us....!

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True, I suppose that's one explanation. My personal opinion is that the autism/vaccination furore that turned out to be based on faked data has made it difficult to question the safety of vaccines which I think is a bad thing. It's like the ID/creationists making scientists wary of criticising evolutionary theory. There could be viral contamination of cells used to make vaccines in fact I'm pretty sure there was a problem with SV40 and some vaccines. There should be absolute vigilance in vaccine production and no complacency. Having said that I don't want to get into a vaccine/conspiracy theory debate.

To resolve this debate, the WPI have said they are concentrating in future on the antibody data.
JM's patients have antibodies to MLVs

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Probably a good idea

Have you considered the implications of the Zhang paper?

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I haven't read it all (I assume you mean the one on finding MLVs in multiple cell lines?) I suppose it has implications for the contamination issue and health issues of lab workers .................................... like me.

Does your lab work with xenograft derived human cell cultures?

Because 26% of the cultures tested were positive for XMLVs some to more than one strain.

Perhaps you had better show that paper to your lab chief. This problem was known about in the seventies, then it stopped being reported on. But it hadn't gone away. The Zhang paper says that most scientists nowadays had become ignorant of this contamination problem. So they cannot protect themselves against it.

The Zhang paper advises monitoring lab personnel for viral antigens or antibodies to MLVs.

RedRuth said:

I haven't read it all (I assume you mean the one on finding MLVs in multiple cell lines?) I suppose it has implications for the contamination issue and health issues of lab workers .................................... like me.

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Just curious, is this your blog RedRuth?

http://scienceblogs.com/erv/

Thanks
Mark