Science Mag: Fresh Doubts About Connection Between Mouse Virus and Human Disease

[Mya Symons]

Here's Gerwyn's analysis:

I have read Dr. Deckoff-Jones blog and I know she is involved with the WPI. She also gives some of her background information on her blog. However, I am not familiar with Gerwyn, but I have seen his or her name mentioned ofter. Jace, could you please tell people who do not know who Gerwyn is and what his or her background is (in the science and or medical field. Please and Thankyou).

 

[Megan]

This has always been a possibility, I was worried about XMRV as soon as I learned it was a blood-borne retrovirus, which seems inconsistent with CFS epidemiology. In particular, CFS is not an STD, and not a drug user disease, not a hemopheliac disease. And CFS is not ubiquitous so it is not a 'vaccination disease.' Also CFS outbreaks are inconsistent with a bood-borne pathogen.

Kurt I had some similar questions when I first heard about it, like why doesnt it infect the same groups as HIV etc? So I looked up the epidemiology of HTLV and was amazed to discover a completely different pattern of infection to HIV, based on very subtle differences in the virus and it's history. In the case of HTLV human breast milk is the major mode of transmission, and though it is infectious by blood and sex it seems to be far less so than HIV. I am no epidemiologist but it became apparent to me that understanding the substances that might transmit viruses is not near enough to get the full epidemiological picture.

Of course the other major thing missing here is the assumption that if you are infected it will always cause disease (unlike HIV, HTLV does not always lead to illness). Obviously if this is not the case and other co-factors are involved, then it will be almost impossible to recognise the pattern of transmission in CFS.

One point that was striking about HTLV was that it is equally prevalent amongst male and female children but infects far more female than males in adulthood (approx. 70:30 in adults). In the January lecture on XMRV by Dr Bell last year he said any explanation for CFS would need to explain why it occurs in equal numbers in children but affects more women than men in adulhood? On this basis I wouln't be confident at all that a retrovirus does not fit the epidemiology of CFS.

 

[Ernie]

Well here's some interesting info: http://forums.aboutmecfs.org/showthread.php?10564-Controls-Versus-Contamination

 

[kurt]

Kurt I had some similar questions when I first heard about it, like why doesnt it infect the same groups as HIV etc? So I looked up the epidemiology of HTLV and was amazed to discover a completely different pattern of infection to HIV, based on very subtle differences in the virus and it's history. In the case of HTLV human breast milk is the major mode of transmission, and though it is infectious by blood and sex it seems to be far less so than HIV. I am no epidemiologist but it became apparent to me that understanding the substances that might transmit viruses is not near enough to get the full epidemiological picture.

Of course the other major thing missing here is the assumption that if you are infected it will always cause disease (unlike HIV, HTLV does not always lead to illness). Obviously if this is not the case and other co-factors are involved, then it will be almost impossible to recognise the pattern of transmission in CFS.

One point that was striking about HTLV was that it is equally prevalent amongst male and female children but infects far more female than males in adulthood (approx. 70:30 in adults). In the January lecture on XMRV by Dr Bell last year he said any explanation for CFS would need to explain why it occurs in equal numbers in children but affects more women than men in adulhood? On this basis I wouln't be confident at all that a retrovirus does not fit the epidemiology of CFS.

Where did you find that info on HTLV? When I just now did a google search all I found was epidemiological studies that pretty much prove HTLV is a blood-borne pathogen (STD, or blood transfer), which does include vertical transmission, but nothing beyond that I can find. But that would be interesting if there was some other significant vector. I believe WPI actually found HTLV in a certain % of CFS patients in their 2009 Virachip study. However, XMRV is considered a blood-borne infection, which puts it closer to HIV in terms of epidemiology. So that would make XMRV either an STD, a hemophiliac or drug user disease, or possibly a tick-born or mosquito-born infection (which would require a complex animal vector like Lyme and I don't know of any evidence for that). None of these sound like the epidemiology of CFS, particularly given the outbreaks. If there is some other vector, then it must be novel for a blood-borne retrovirus.

What seems more probable to me for CFS is something waterborn or airborne acts as a 'hit and run' trigger pathogen. An organism or virus that can cause real neurological damage to a certain subset of people, or under certain co-infection conditions. Like what happens with the enteroviruses in the Polio family for example. Coxsackie or echovirus, for example, are Polio type viruses. In fact I believe there was one study that proved coxsackie can cause Polio type damage in the brain.

 

[Ernie]

More interesting info about whether XMRV can infect lab mice, wonder if the researchers knew? http://www.retrovirology.com/content/7/1/101

Here's a bit from the conclusion: Further characterization of these viruses should further elucidate their evolutionary past and describe their pathogenic potential and the adaptations that favor co-existence of these infectious agents and their new human hosts

 

[CBS]

My bolds

None of these sound like the epidemiology of CFS, particularly given the outbreaks. If there is some other vector, then it must be novel for a blood-borne retrovirus.

What seems more probable to me for CFS is something waterborn or airborne acts as a 'hit and run' trigger pathogen. An organism or virus that can cause real neurological damage to a certain subset of people, or under certain co-infection conditions. Like what happens with the enteroviruses in the Polio family for example. Coxsackie or echovirus, for example, are Polio type viruses. In fact I believe there was one study that proved coxsackie can cause Polio type damage in the brain.

Kurt,

One of the central issues with determining the epidemiology is being able to identify a period of infection.

One of the big unknowns with CFS is whether or not we are seeing symptoms, or the emergence of co-infections, at a point in time that is anywhere near what may be the original infectious event.

I also strongly suspect that genetic vulnerability may be playing a role. I'm not aware of any published research on the percentage of CFS patients with first degree relatives that have CFS compared to the number of significant others but a recent poll on PR showed a significantly greater number of CFS patients with relatives that had contracted CFS versus those with SO's that had contracted CFS.

Lastly, the words of Dr. Kathryn S. Jones (Laboratory of Experimental Immunology, National Cancer Institute-Frederick) @ CROI 2011 -

I know a lot of people who are working on just the basic biology of the virus, particularly people who have worked with these mouse viruses and it does seem to be behaving differently. And it is worth mentioning, weve said this in regards to Gregs question, this is a replicating, at least in culture this is a replicating virus that can cause a productive infection in primary human cells in addition to cell lines, you can pass it to other cells and as you said, and as Jonathan said, it is different from a lot of known MLVs so from a basic science perspective there is some interest in this virus. [FONT=&quot][/FONT]

 

[kurt]

I also strongly suspect that genetic vulnerability may be playing a role. I'm not aware of any published research on the percentage of CFS patients with first degree relatives that have CFS compared to the number of significant others but a recent poll on PR showed a significantly greater number of CFS patients with relatives that had contracted CFS versus those with SO's that had contracted CFS.

Which does suggest strong genetic factors.

This is a bit OT, but did anyone notice that in the proteomic study the CDK5 signaling pathway was enriched, as is also the case in Alzheimer's and Parkinson's? Well, there is evidence of genetic methylation problems in Parkinson's. And Alzheimer's is treated with B12. Sounds like CFS belongs with a family of neurodegenerative diseases that have some genetic involvement.

 

[CBS]

Which does suggest strong genetic factors.

This is a bit OT, but did anyone notice that in the proteomic study the CDK5 signaling pathway was enriched, as is also the case in Alzheimer's and Parkinson's? Well, there is evidence of genetic methylation problems in Parkinson's. And Alzheimer's is treated with B12. Sounds like CFS belongs with a family of neurodegenerative diseases that have some genetic involvement.

I have personal reasons for thinking that there may be something to the Alzheimer's/Parkinson's relationship.

Beyond that, genetic predisposition almost always requires a some triggering event to express itself. I think that leaves the door open for a lot of possiblities but the co-infection issue may be obscuring the timing of the possible triggering events/agents.

 

[Sean]

I think that leaves the door open for a lot of possiblities but the co-infection issue may be obscuring the timing of the possible triggering events/agents.

I have long suspected that the onset issue is a lot murkier than it might first seem, even allowing for patient selection criteria problems.

There is a good chance that patients have actually had the underlying pathological process present for possibly many years, before it starts expressing itself clinically after some trigger.

 

[Megan]

Where did you find that info on HTLV?

Kurt I have made a post about this earlier that has a couple of references and key quotes: http://forums.aboutmecfs.org/showth...transmission-of-XMRV-MRVs&p=116601#post116601. The two key references from this post were:
http://www.nature.com/onc/journal/v24/n39/full/1208968a.html
http://virology-online.com/viruses/HTLV2.htm

Please note that I am not disputing theat HTLV is blood bourne, or that it is more prevalent among drug users, it was the difference between the pattern of epidemiology of this virus and HIV that I found interesting. The key question at the time I was trying to understand was why was there no apparent epidemic of CFS among gay men? Equally you could ask this question of drug users which I understand is the question you might be asking? I now recognise my original question about gay men was somewhat ignorant as they are only one population affected by HIV - in Africa it has spead broadly through the heterosexual population, which is a different pattern than has happened in the west (again reason not to make assumptions).

In addition here's some follow up info I posted on the other forum:

One of the most interesting references I came accross was a book called Viral Sex written by a HIV researcher called Jaap Goudsmit in which there is a chapter on the epidemiology of HTLV. It was available on google books but appears unavailable now. I don't know how reliable his theories are but he seemed to be the only one that got down to the detail on different modes of sexual transmission. in short this is some of what he says:
* HTLVI infected cells need to be transmitted from one person to another eg. blood, breastmilk or semen, with breastmilk being the main mode of transmission.
* sexually, men can more easily transmit the virus to women than vica virca because they transmit semen. it is hard for a woman to transmit HTLV to a man. this naturally hampers the spread in the heterosexual population because the virus is more likely to 'stop' with the woman (supposedly)
* but when it comes to sex the virus is basically not easily tranferred via anal sex, but is probably more easily by oral and vaginal sex. ie. it depends on how readily the cells inside the 'recepticle' in question are infected by the virus. He says the cells of the throat 'take up' this virus more readily than other body tissues.
* because the oral route is most important, breaskmilk is the major mode of transmission as the cells of the mouth and throat are exposed (and presumably because of the quantities of milk a baby drinks).
* He also discusses other factors such as the history of the slave trade that may have affected the distribution of the virus worldwide - ie where it takes a foothold first is important.
* and one wonders about oral sex....he attributes two gay people in one study as acquiring HTLV through oral sex.

I think I also heard Judy refer in a recent talk somewhere to how they had significantly lowered the HTLV infection rates in Japan, where it is endemic, by restricting mothers from breastfeeding.

With regard to all of the above, I don't know what the answers are, but it was quite clear that many factors can make the virus distribute in various different ways with some of it still poorly understood. I understand that HTLV is more prevalent among injecting drug users, but I'm not aware that there has been the same degree of epidemic among them that there has been with HIV? Since HTLV only makes a small percentage of infected people sick then would they even know of the higher prevalance of HTLV among IDU's without a proper blood test?

 

[kurt]

I have personal reasons for thinking that there may be something to the Alzheimer's/Parkinson's relationship.

Beyond that, genetic predisposition almost always requires a some triggering event to express itself. I think that leaves the door open for a lot of possiblities but the co-infection issue may be obscuring the timing of the possible triggering events/agents.

Agree, this combination of genetics plus environmental trigger is particularly evident with Parkinson's. I believe over the years many of the proposed CFS triggers have also been proposed Parkinson's triggers. Including Lyme, pesticide exposure, flu-like illnesses, etc. Probably someone has looked for retrovirus also in Park.

 

[Megan]

Some other references on HTLV epidemiology:

Further on the question of gay men, here was also this interesting paper from 2010 on Trinidad http://jama.ama-assn.org/cgi/reprint/257/19/2604.pdf. This indicates that, yes, gay men do have HTLV I at a higher rate than the 'comparison' population, though this is hard to really conclude from the paper because the gay men are recruited from an STD clinic but the comparison population is from a more broad based heath survey (you would expect people from an STD clinic to be infected at higher rates). But what is striking about the paper is that it shows that the HIV infection rate among gay men is 3 times higher than HTLV even though HIV is newly introduced and HTLV was endemic in that area. Even more significant is the difference between the gay men (from the STD clinic) and the comparison population (not from STD clinic): gay men were six time more likely than the comparison population to have HTLV, but 200 times more likely to have HIV. The paper suggests HIV is more efficiently transmitted than HTLV among gay men.

Here's a recent paper showing HTLV infection rates of different risk groups. Injecting drug users (IDU) are way out in front of female sex workers, men who have sex with men (MSM) or even people from STD clinics. The infection rate for MSM seems very low here when taken out of the STD clinic context.

http://www.ncbi.nlm.nih.gov/pubmed/17935172

Here's a few more recent articles from pubmed that seem to have similar results to the Trinidad paper (relatively low rate of infection of HTLV compared to HIV for MSM):

http://www.ncbi.nlm.nih.gov/pubmed/19480577

http://www.ncbi.nlm.nih.gov/pubmed/16540880

 

[kurt]

Please note that I am not disputing theat HTLV is blood bourne, or that it is more prevalent among drug users, it was the difference between the pattern of epidemiology of this virus and HIV that I found interesting. The key question at the time I was trying to understand was why was there no apparent epidemic of CFS among gay men? Equally you could ask this question of drug users which I understand is the question you might be asking? I now recognise my original question about gay men was somewhat ignorant as they are only one population affected by HIV - in Africa it has spead broadly through the heterosexual population, which is a different pattern than has happened in the west (again reason not to make assumptions).

In addition here's some follow up info I posted on the other forum:

...

With regard to all of the above, I don't know what the answers are, but it was quite clear that many factors can make the virus distribute in various different ways with some of it still poorly understood. I understand that HTLV is more prevalent among injecting drug users, but I'm not aware that there has been the same degree of epidemic among them that there has been with HIV? Since HTLV only makes a small percentage of infected people sick then would they even know of the higher prevalance of HTLV among IDU's without a proper blood test?

That is a slight variation in epidemiology, but really does not expand the blood-borne retrovirus vector enough to explain CFS epidemiology, at least in my understanding. That is my only point. I don't doubt there might be novel ways a gammaretrovirus might spread. But think people are stretching this too far, and have ignored the seriousness of this obvious problem with an XMRV explanation of CFS.

 

[Megan]

I agree that many people have stretched things too far in speculating about possible epidemiology, but I dont think I have done that in the above posts. As I said it was simply the information I came across when I asked myself a similar question but different one to the one you were asking in relation to HIV (the references are all there). I would not call the differences between HIV and HTLV a slight variation.

There is nothing novel either in suggesting breastmilk might be a vector - it is clearly the case that both HIV and HTLV are transmitted via breastmilk, and there is also a paper around showing the same thing with regard to MLV's in mice.

 

[currer]

Hi Kurt and CBS,
What none of the arguments here have engaged with is that ME/CFS has become more common in the last couple of generations. It cannot just be a genetic problem even though the association with autistic disorders and Parkinsons apply in my family too. There must be some other reason for it becoming more common, and the most likely is an infective agent of some sort.

Megan, your points about HTLV1 are spot on.

My feeling is that if XMRV is not the cause, then an enterovirus is the most likely option - but then you would need to account for the cases where you see parent to child transmission (quite common) - could that happen with an enterovirus? There are no records of a mother who has contracted polio in the past passing the virus on to her child, for example.

 

[CBS]

Hi Kurt and CBS,
What none of the arguments here have engaged with is that ME/CFS has become more common in the last couple of generations. It cannot just be a genetic problem even though the association with autistic disorders and Parkinsons apply in my family too. There must be some other reason for it becoming more common, and the most likely is an infective agent of some sort.

Hi Currer,

I didn't intend to convey that I thought that the primary cause of CFS was genetic. I don't believe that to be the case. However, I do wonder if there is a genetic vulnerability that some agent is able to exploit. Again, I haven't seen any published articles comparing first degree relatives to significant others but the poll here was strongly skewed towards first degree relatives with a much smaller fraction of SOs having CFS. This doesn't seem consistent with a purely infectious agent where genetics does not play a role. Presumably, we are sharing a lot more bodily fluids, etc with our SOs than with our first degree relatives (even here in Utah - although its always a good idea to compare your genealogical records just to be on the safe side ).

 

[currer]

Perhaps the infectious agent is not very infectious/ requires certain conditions to infect/passes on best in breast milk etc etc.?

It does not have to pass on like flu - in other words it could be transmissible but not very contagious - tho I guess living in Utah does complicate matters!

I used to work for a large patient support group and the PR poll on family members and transmision patterns is consistent with the pattern of transmission I saw in the group - family members most common, SOs some transmisssion but not as much.

 

[kurt]

Hi Kurt and CBS,
What none of the arguments here have engaged with is that ME/CFS has become more common in the last couple of generations. It cannot just be a genetic problem even though the association with autistic disorders and Parkinsons apply in my family too. There must be some other reason for it becoming more common, and the most likely is an infective agent of some sort.
...
My feeling is that if XMRV is not the cause, then an enterovirus is the most likely option - but then you would need to account for the cases where you see parent to child transmission (quite common) - could that happen with an enterovirus? There are no records of a mother who has contracted polio in the past passing the virus on to her child, for example.

Actually, if we borrow from the Parkinson's model, CFS could be either/or, because that is now current thinking in Parkinson's. There is a subset that is considered genetic and a subset that is acquired from the environment, and also a subset that may have both elements. So there are various ways to get to the same disease endpoint in Park.

I agree with your last comment, enterovirus seems like a logical candidate to me as well, particularly given the outbreaks. Perhaps along with a few co-factors.