Discussion in 'XMRV Research and Replication Studies' started by VillageLife, Jan 4, 2012.
New paper by dr Ruscetti
The important thing from this study is the possibility that a primary mode of infection is through the lungs. In an infected mammal the lung tissue is likely to produce virus, and any virus coming through the nose (and mouth in humans) has a path to the lungs. Furthermore, XMLV is likely to be contaminating many more labs. Any cell line passed through mice might contain the virus - I don't have any idea how many cell lines this is, but it could be a lot. They only tested the standard cell lines available to them. One in five passaged through mice was contaminated, which fits with other studies.
If anyone can recall the discussion, the hospital with one of the earliest outbreaks of what seems very much to be ME was involved in early mouse and primate research into viruses, in California (the 1932, 1934 outbreak). I wish I had more information about this but it keeps dead ending on me. Not much from that time has made it onto the internet. This is not to say that MLVs have anything to do with ME, but the question still has not been definitively answered. We still need Lipkin et. al.
Even if MLVs have nothing to do with ME, there is a clear risk that these cell cultures may infect people in the future. Face masks should be manditory for any lab using these cultures, in my opinion. The argument that our blood can rapidly neutralize XMRV for example is much weaker if tissues can be infected in the lungs without even going through the blood. Presumably this also applies to MLVs.
I believe the outbreak you are referring to is that of Los Angeles County in 1934.
In 1938, the US government published Public Health Bulletin No.240 titled as follows:
Epidemiological Study on an Epidemic, Diagnosed as Poliomyelitis, Occurring among the Personnel of Los Angeles County General Hospital during the summer of 1934. Gilliam, AG (1938).
There were 198 employees of the hospital that were diagnosed with Poliomyelitis, which was shortly thereafter called Atypical Poliomyelitis and later ME. Many people who are aware of this outbreak are under the impression that only 198 people were affected. That is not the case, as the outbreak was much larger. The 198 number was just the patients involved in the epidemiological study that were hospital employees. The total number of patients diagnosed with Poliomyelitis at the Los Angeles County General Hospital during the outbreak of 1934 was 2499. This number of diagnosed cases that I quote comes from the epidemiological study. I suppose the total number could be even larger still, as this was just one hospital.
You reference a lot of mouse and primate research done at that time. It is also my understanding that a lot of that early research was tested on the hospital staff as the initial human trial. It seemed as if it was part of the job description in those days.
Thanks for this interesting thread - my own Doc considered both Polio and MS from all the symptoms. Seems a very important piece of research from Ruscetti here though.
HI Dan_USAAZ, this is indeed the 1934 outbreak, but there were two cases in the same location in 1932. Bye, Alex
No, that is anything but clear. Not wanting to poo-poo viral contamination of cell lines used for medical research, but there was one study that tested the response of human white blood cells to XMRV, with special regards to APOBEC3G. That is protein that works against all kinds of retroviruses a kind of build in retroviral defense in all humans. This protein brings up the mutation rate of XMRV way way into the non-functional area by messing with the reverse transcriptase of the retroviruses, the few viral particles that are produces contain genetic code that does not work anymore. Only HIV has a way around APOBEC3G (and other human proteins that do the same yes, there are more!).
The environment is stock full of viruses, we get them all time from animals we are killing, butchering and eating and we have eaten animal for over a million years, probably much longer. We injured and have been injured by other animals for a very long time and had lots of chances of exchanging viruses. If mouse viruses got into humans, it has already happened 10.000 years ago. The main threat are pathogens from close relatives (SIV->HIV).
Besides, with retroviruses the cancer rate goes up, way up. Very very noticeable up. Nothing we see in ME/CFS.
Yes, it would be troublesome if half a percent of the people would have a unrecognized retrovirus, but there is simply no evidence there. If there is one virus in ME/CFS, or different viruses for different sub-groups, I am confident that Lipkin finds them but I am equally confident that there will not be a retrovirus found. My icon/avatar shows what my bet of the involved virus is (with far better available evidence of involvement in ME/CFS than anything that Mikovits or Ruscetti or Lombardi or whoever presented) but I am anything but sure that this virus (or virus group) is the culprit, and I wait till I know more. We'll hopefully get an answer soon.
You should really read "Myalgic Encephalomyelitis and Postviral Fatigue States: The saga of Royal Free disease" by A. Melvin Ramsay
I liked your post Tony - though I can predict the critiques already I am afraid. But here's the paper I believe you were talking about.
I found it very interesting at the time: Severe restriction of xenotropic murine leukemia virus-related virus replication and spread in cultured human peripheral blood mononuclear cells: http://www.ncbi.nlm.nih.gov/pubmed/21325415
I know you also read ERV but for those that don't: http://scienceblogs.com/erv/2011/02/xmrv_and_human_pbmcs_do_not_wa.php
The first critique will be: Ruscetti's paper isn't talking about XMRV!!
Full Ruscetti paper free pdf.: http://www.mdpi.com/1999-4915/3/12/2442/pdf
The human lung adenocarcinoma cell line EKVX produces an X-MLV that is infectious to human cells. Because the EKVX cell line was established following the passage of the original tumor cells in nude mice, the source of the virus may be the activation of an endogenous virus in the mouse rather than the original human tumor. Regardless of the origin of the X-MLV in the cell line EKVX, its discovery serves as a reminder to handle all human-derived cell lines, even those tested for known human pathogens, with caution.
We thank Frank Ruscetti, Kathryn Jones, Ying Huang, John Coffin, and Michael Alley for helpful
Hi Tony Mach, I disagree for two reasons.
1. As I explained, the restriction factors including APOBEC3G are in the BLOOD. Tissues in the lung are directly vulnerable, it does not have to pass through blood. Once in the tissues you have a viral source, and blood defences only serve to slow its spread, not halt it. It remains to be seen if the XPR1 expressing cells in the lung lining also express APOBEC3g or other restriction factors. Even if they do this only reduces risk, it does not eliminate it.
2. Pursuant to point one, what we expect to see with such defences is a low rate of infection, not a zero rate of infection. These are not infallible protective mechanisms. The only way to get guaranteed protection is to have cell receptors that a virus needs for entry to be mutated until useless to the virus or completely absent. Blood restriction factors mean its cleared from blood. Once its in the tissues no amount of blood restriction factors are going to clear it. NO restriction factor in blood can do this. Now some cells will also have the restriction factors, but some wont. Cells that don't are potential targets. The idea that such factors guarantee immunity is absurd and extreme and is not in accordance with known biochemistry. They only reduce the risk, perhaps a lot, but its still only a reduction. So the transmission rate person to person will be low, but not non-existent unless there are other mechanisms at work. Similarly the tissue spread may be decreased, especially in some tissues with higher resistance.
So I again assert there is a clear RISK. Risk is NOT about certainty, its about covering your ass and protecting yourself. Ignoring risk puts everyone at peril. You might get away with it 999 out of a thousand in the biosciences and especially pathogen research, but that one time could be a catastrophe. Risk managment is mandated in pathogen research, its not optional. Anyone who is in pathogen research who thinks its optional should be barred from all further research, and prosecuted to the full extent of the law if anything goes wrong.
I have yet to read the full paper let alone ask for scientific interpretation as to relevance - so this probably a dumb question - but what has this paper to do with CFS/ME? And is it relevant at all to anything so far produced by Lombardi and/or Lo et al.? I am guessing not.
Not that I am doubting the interesting nature of the paper itself - how could I when I have yet to read it properly - but this says little if anything about it being a human pathogen does it?
No doubt more analysis will be forthcoming and interpretations as to relevance.
Ok I still haven't read the paper as thoroughly as I might. However, the following paper published in 2010 is relevant here I think:
Disease-associated XMRV sequences are consistent with laboratory contamination: http://www.retrovirology.com/content/7/1/111
Check out Table 2. See anything familiar? http://www.retrovirology.com/content/7/1/111/table/T2
Question: Is Sandra Ruscetti confirming (and adding) to this already established conclusion or is there more to this cell-line that Hue et al. have not previously determined i.e. is this not contamination?
I also don't agree, Tony Mach. Very recently (12 dec. 2011) a paper appeared that suggests that XMRV downregulates APOBEC3G. It even suggests these viruses might have novel mechanisms to counteract APOBEC3G!
So it seems XMRV might have some tricks still...
Anyway, the big question remains: did the virus get in the humans cells because they transplanted them into mice or was the virus already in the human cells? This study leaves that question open.
Thanks Jemal for posting the link to the recent paper concerning downregulation of APOBEC3 by XMRV. I was hoping that somebody would do so. I recall that there was earlier evidence of this effect published a year or more ago, and that it's still an open question as to how effectively APOBEC3 restricts XMRV in vivo. It's surprising to see that argument still being repeated as evidence against any potential danger from PMLVs when the downregulation of APOBEC3 by XMRV has been reported here frequently, and that evidence has never been challenged here as far as I have seen.
Tony, I find this argument of yours rather interesting...
I agree with your premise that 'bushmeat' theories of viral transmission can reasonably be expected to have exchanged viruses between animals and humans of the order of 10,000 years ago, and on that basis I consider that any new viruses and diseases that have occurred in humans within a much more recent timeframe are highly unlikely to be explained simply by 'bushmeat' theories. Your argument seems to say the same thing - but in that case I'm confused as to why you make an exception for close relatives (SIV -> HIV), and surprised that this understanding doesn't focus you on wondering how new human diseases like AIDS and ME have emerged within such a historically recent timeframe.
Doesn't it seem dubious, by your own argument, to accept that SIV jumped from monkeys to humans within the last century but not before? Isn't it more likely, given the very clear timeframe of the emergence of AIDS as a disease within the last century at most, that the emergence of HIV is in some way a consequence of modern conditions? I know that the vaccination theory of the emergence of AIDS is considered to be 'debunked', but I don't personally find the evidence of that debunking at all compelling, and there remains the suspicious fact that Koprowski's polio vaccination was grown in tissue cultures taken from macaque monkeys before being administered to about a million people in Burundi, Rwanda, and what is now the Democratic Republic of the Congo, shortly before the emergence of HIV in those areas.
That's a little way away from your point about mice, though, so on the specific point about mice, it's important to note that many strains of mice came into existence within the last century or two due to breeding as pets, and the specific strains of mice we are interested in (nude mice, specifically) have been widely used as laboratory mice due to their suppressed immune response. The emergence of novel (retro)viruses like XMRV during laboratory experiments on selectively-bred immune-compromised mice is quite clearly a reality which nobody is disputing, and there is no guarantee at all that these novel viruses and retroviruses cannot be pathogenic in (at least some) humans.
It would be very rash indeed to make assumptions that any such novel viruses and retroviruses (a) cannot infect humans, and (b) must behave in the same ways (eg re: cancer incidence) as the two human-infectious retroviruses we are currently aware of. There just isn't enough evidence to rely on those two assumptions, and even though there's now no evidence on the books of XMRV infection in humans, the more general risk of infection of humans from laboratory-created retroviruses is very clearly a genuine risk and a genuine possible explanation for novel (and potentially vaccine-mediated) human diseases - especially so since the infection of animal vaccines with previously-unknown retroviruses, and their transmission across species through vaccination, is also accepted as scientific fact. The most that can be said against this entirely plausible hypothesis is that there is currently no clear evidence (on public record, at least) that this scenario has ever occurred. So it does remain merely a hypothesis, but it's unquestionably a hypothesis that demands extremely close scrutiny.
Yeah, full ack, if you do this research, you have to check for this and be extra extra extra careful.
But in the context of our disease (or any other disease, like say Autism) running around and crying Wolf about these risks is just scaremongering. Especially after "OMG XMRV is in the blood!!!!" turned out to be BS, then people go around and say "WELL, then it MUST be in the TISSUE!!!!" and "We got it throug VAXXINES!!!!". No, there is no prove, not even a viable hypothesis, just fearmongering BS. You post this as if this were proof that there are retroviruses (other than HIV) circulating in humans - no, there aren't. What do you want? That 100 scientist spent another 10+ Million USD going on a wild goose chase? Again? This time in the tissue? Cutting up patients? Without a clue as to how XMRV/P/MLV/WHATEVER could even establish an infection, not to speak of spreading it? How is trying to hunt down a phantom going to help you? If we don't look like hypochondriac clowns to the medical profession already, two years down the road we will. Let other people give it a try as to the cause(s) of our disease(s) (and there are actually qualified people working at it, who are motivated and qualified to find something), and stop hanging on to retroviruses as if it would solve anything. XMRV is dead as a human pathogen, there never was any "HGRV".
I am sick and tired of this BS and I am not going to take it anymore.
1. The argument with pathogens from close relatives is this: If SIV "knows" how to evade the immune system in our close relatives, it stands a big chance to evade the human immune system we share some considerable history and are in some points quite similiar after all. A retrovirus from a mouse, or a pig, knows its ways around its hosts immune defense, but is not so well adapted to other animals.
2. Why do you think that ME is a new disease? Correctly recording this kind of disease has been a problem in the last century, what makes you think that the records before that are any good?
3. I think ME/CFS is caused by viruses that we have for a long time in humans (say Herpes- or Enteroviruses) and our body acquired defences against it enough to keep it in check not to cause death, but not being able to clear it (or its damage) completely. But that is just my theory we'll see.
I wonder if this Ruscetti paper has been published by mistake.....surely we are to expect another forced retraction...?
This paper destroys the Paprotka argument that "XMRV" was a unique event. It is clear that XMLVs exist in other cell lines, are continuously created in the lab by xenografting, and are infectious in human tissues.
"Suzuki et al found that cells from 6/9 tumors transplanted into nude mice produced infectious murine type c virus."
PCR looking for the VP62 sequence would not find this XMLV.
"The propensity for acquisition of a virus" (in a cell line) "may depend on the strain of mouse, the means of immune suppression, the characteristics of the xenografted tumor, and whether the experimental protocol includes any additional factors,(chemical exposure, radiation,) that could promote the activation of an endogenous virus."
What about the biosafety issues here on the handling of this cell line in the lab?
To continue my thought:
If the ME/CFS bug were a new virus, it would have probably come from another species. And viruses from other speciecis are either not able to make the jump and then they don't cause disease. Or if they do, they cause massive disease, catastrophic disease (think SARS or HIV/AIDS). Which makes sense, because human immune systems hasn't seen that bug before, so it does not know excactly how to fight it (and a immune system reacting too much is as dangerous as reacting not enough). And the bug itself probably does not show restraint, because it is adopted to another species.
What we see usually in ME/CFS is a flu that won't go away, with results that are definitly devastating for the individual, but no AIDS/SARS/black death like disease so I would suspect a bug that has been around in humans a long time. A bug that "knows" not to overstep the boundaries, so it can keep hanging around in its host, and a immune system that "knows" how to fight it (in most cases).
If you take a look at the polio bug, it causes polio only in half a percent of people it hits, other serious disease problems in one to two percent and maybe slight some kind of flue in some of the rest of the pople. Most people who got the polio bug cleared it. And that is my hypothesis for ME/CFS: some bug hits many people, for most it is just another flu like illness that goes away, for the few unlucky it is ME/CFS.
Well, this is all speculation, I could be completely wrong and I hope we will find the cause(s) within reasonable time. But I want to know the actual cause and not something that fits my confirmation bias. If finding the real thing means showing that I am wrong I gladly take that. And I will not take it anymore if other people think they have to push their fearmongering stories. You have no evidence, no model, no nothing to connect this human disease.
I don't understand why you don't think there's a 'viable hypothesis' here, Tony. It's now known that novel retroviruses that can infect human cells are being accidentally created in labs, and this has been known to scientists since the 1970s - true? It's also known that these retroviruses have been spreading worldwide, in labs, without being recognised - true? It's further known that animal vaccines have been known to become unknowingly contaminated with retroviruses and transmitted across species - agreed? Retroviruses typically cause immune and neurological dysfunction, yes? You're aware of the outbreak of a novel form of narcolepsy in Finland, and then reported by 9 other countries, which has been associated with the H1N1 vaccine and with certain susceptible genetic types? And we all have a new kind of neuroimmune disease, yes? And this paper does warn of the dangers involved in handling these lab-created viruses, doesn't it? Surely there is at least a 'viable hypothesis' here?
Where did Alex post anything 'as if it were proof' of this? He clearly said this is a 'risk', and not certainty. I read nothing Alex posted that suggests this paper is 'proof' of anything. Please don't misrepresent what he said.
Yes, of course there are! Surely you're aware of HTLV if you're posting with such conviction on this subject?
Please calm down Tony. XMRV, PMLVs, HRGVs, retroviruses in general are clearly going to continue to be discussed on this forum along with a wide range of other subjects. I can't see any BS in the discussion above, and if you are intending to react to any such discussion with anger and aggression then that won't do any of us any favours. If you would prefer everyone to focus on different research, then it would be better to focus positive energy on that, because focusing negative energy on people discussing MLVs is only likely to fuel fires.
If you are worried about "biosafety issues", fine. Go ahead and look into all problems there.
But that won't make the Lombardi et al 2009 paper any better. It was bad science and it got retracted for scientific reasons mainly because THERE ARE NO XMRV VIRUSES IN THE BLOOD OF PEOPLE while the paper said so. And finding the second cell line in which a X/P/MLV hangs out will not somehow justify doing bad science like Lombardi et al did.
And neither your new found interest in "biosafety issues" nor the Lombardi paper is a step into the direction of finding the cause(s) with regards to our disease(s).
You are just being angry that somebody took away your saviour(s), and you don't even care if they would bring actual salvation in the form of scientific results that have anything to do with our illness.
Oh sorry, I forgot HTLV. Surely this changes everything I have written.
Other people write about X/P/MLV/WHATEVERS as if they were human pathogens, without a shed of evidence, with deep convictions, and you don't call them out. And I forget HTLV and am not to be trusted?
Your scepticism is loop-sided.
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