UK XMRV Study
WPI started a study in March 2010 to look for HMRV (Human MLV Related Viruses - both X and P) in UK ME/CFS patients.
The study included 50 patients with ME who met the Canadian Consensus Critera, 50% male and 50% female, along with 50 controls.
It was a blind study.
The 100 samples were tested blindly by two labs who had never worked with MRV or mice (to ensure there was no possibility of contamination).
The labs first tested plasma and 48% of the ME plasma samples were positive for XMRV (all were also tested for mouse DNA and were negative).
Other samples were detectable only after culturing (some sort of special sample preparation).
In some samples, only the virus was detectable; on others, only the antibodies were detectable.
Multiple testing methods were necessary in order to find all of the XMRV positive samples.
In all, 80% of the ME patients in the study were positive for XMRV.
4% of the controls were also positive for XMRV (in line with the original WPI study).
Dr. Mikovitz emphasized that the XMRV was very difficult to find.
They have learned that subtle differences in storage, handling, and testing make a big difference and that multiple methods must be used to find it all.
The above was from Learning to Live with CFS blog here
Read her full post at the above link.
Showing posts with label MLV. Show all posts
Showing posts with label MLV. Show all posts
Thursday, 21 October 2010
Thursday, 16 September 2010
THE THIRD HUMAN RETROVIRUS AND CO INFECTIONS
Questions and answers with Dr Garth Nicolson 09/13/10
richvank
- The retroviruses
Will you please comment on the newly discovered MLV-related retroviruses in CFS patients, and what relationship they might have to the other infectious pathogens you have found in CFS.
Thanks.Rich Van Konynenburg
Reply:
Hi Rich,
The newly evolving field of human gamma retroviruses (HGV), also called XMRV , and chronic illnesses like CFS/FMS is fascinating. This type of virus has now been found at high incidence in some but not all studies on CFS patients. There may be technical reasons why some groups have not found these infections, but the field is new and in constant flux.
My guess is that similar to other related retroviruses the HGV may cause changes in our immune systems rather than directly causing the most obvious signs and symptoms associated with CFS. Their effect may thus be indirect, just like the HIV-1 retrovirus causing immune suppression in AIDS rather than directly causing the symptoms of AIDS.
Thus HGV may set up patients for other opportunistic infections, such as Mycoplasma, Chlamydia, Borrelia, CMV, HHV6 and other bacteria and viruses that actually cause most CFS symptoms.
This is why patients who have these other infections, such as bacterial infections, benefit from their specific treatment in the absence of anti-viral treatment. This would not occur if the symptoms were entirely caused by a retrovirus.
Thus I predict that anti-retrovirus treatment will not eliminate most symptoms in CFS patients, because they are more likely caused by other infections.
However, modulating immune responses by suppressing viruses that could affect immune systems could have some positive effects. Eventually this will all be worked out, and we will find out what role retroviruses, along with other bacteria and viruses, play in chronic illnesses like CFS and FMS.
From Prohealth here
All questions and answers can be found here
richvank
- The retroviruses
Will you please comment on the newly discovered MLV-related retroviruses in CFS patients, and what relationship they might have to the other infectious pathogens you have found in CFS.
Thanks.Rich Van Konynenburg
Reply:
Hi Rich,
The newly evolving field of human gamma retroviruses (HGV), also called XMRV , and chronic illnesses like CFS/FMS is fascinating. This type of virus has now been found at high incidence in some but not all studies on CFS patients. There may be technical reasons why some groups have not found these infections, but the field is new and in constant flux.
My guess is that similar to other related retroviruses the HGV may cause changes in our immune systems rather than directly causing the most obvious signs and symptoms associated with CFS. Their effect may thus be indirect, just like the HIV-1 retrovirus causing immune suppression in AIDS rather than directly causing the symptoms of AIDS.
Thus HGV may set up patients for other opportunistic infections, such as Mycoplasma, Chlamydia, Borrelia, CMV, HHV6 and other bacteria and viruses that actually cause most CFS symptoms.
This is why patients who have these other infections, such as bacterial infections, benefit from their specific treatment in the absence of anti-viral treatment. This would not occur if the symptoms were entirely caused by a retrovirus.
Thus I predict that anti-retrovirus treatment will not eliminate most symptoms in CFS patients, because they are more likely caused by other infections.
However, modulating immune responses by suppressing viruses that could affect immune systems could have some positive effects. Eventually this will all be worked out, and we will find out what role retroviruses, along with other bacteria and viruses, play in chronic illnesses like CFS and FMS.
From Prohealth here
All questions and answers can be found here
Saturday, 11 September 2010
XMRV WORKSHOP Q & A
XMRV Global Action transcript of 1st International XMRV Workshop Q&A here
extracts
On the question of clarity of the diverse study results
Dr Mikovits: We saw at this meeting several posters and we heard from 4 physicians, Dr Cheney, Dr Bell, Dr Peterson, Dr Komaroff on the Lo study.
These are experts at the diagnosis of, and they are diagnosing the same patients generally and we saw the same percentage of positive patients in those.
Those are patients geographically located from as you heard Dr Cheney say, from around the world… from the NE US in the case of the Hanson-Bell study, I know that Nancy Klimas gets a lot of patients form Florida.
So we can begin to address that because there are clinicians that have been identifying similar positivity rates so we can pull positive samples from each of those and really begin to put together literally hundreds to do that very thing.
and
Joe – clinician – I also want to support the comments from the person from Pittsburgh.
I have a question because the golden standard that is normally presented during these presentations is the CDC or the Fukuda criteria, but are there data on the performance and the variability with doctors using these criteria?
In other words is it conceivable that one doctor would rank a person “in” and another doctor “out” (of these criteria)?
Dr. Mikovits: Yes, the criteria are highly variable and probably some of the physicians in the - they’re really, really subjective,
and unless if you look for various immunological defects rather than just subjective defects, that you get a lot closer to seeing what we see in our patients,
the patients that we identified in UK in the London area, and what Drs Bell and Komaroff are (seeing)…
Dr (indecipherable): If that’s the case, if you’re going to compose clinical cohorts I think it’s important that you have different clinicians selecting and that you also create some data of other doctors looking at the same patient and confirming whether a patient is in or out.
Dr Mikovits: Well they’ve been looking for that for decades, biomarkers and things that could help better define this disease because it is so heterogeneous in how it’s defined.
Dr. Joe Barrascano, Clinician. Over the past day and a half I’ve been struck by the consistent inconsistencies of the results. In other words the groups that find the virus find it in 2/3 or ¾ of patients, and maybe 5% who are not.
And then there are groups who find it in absolutely nobody. It’s very important to work out methodology and so forth. But I think what could explain this tremendous difference that is consistent.
And I think it might go one step before. Maybe it’s the collection and storage of the blood prior to processing that’s really causing the problem here… because if it were a methodological problem you’d see variation from 1,2,10,20,40,50% rather than zero or 80%.
Dr. Mikovits: Actually that is true Joe, and … we have learned literally in past 2 wks in the BWG that processing may be a key
and we may have found an opportunity to have a processing protocol where everyone would at least find viral RNA in plasma and blood products without culture.
Dr. David Wilford, GSK – My question is to Judy but other people are looking at detection of XMRV. Before the XMRV studies, specifically the Virochip showed I believe that there were multiple viruses present in some of these CFS samples.
I’m just wondering with these XMRV positive samples if we’ve being looking specifically at serology or PCR for other types of viruses being more reactivated than controls or if anybody else there is doing these XMRV studies looking for other viruses, or just specifically for XMRV.
Dr. Mikovits – Yes, we set up this program as a study to look at all the viruses, because CFS patients have a lot of activated things like CMV and HHV-6a herpes viruses, mycoplasma, Lyme.
So the idea in the beginning is, as with HIV-AIDS that the retrovirus creates an underlying immune deficiency as-yet-unknown, allowing the immune system not to be able to control pathogens the rest of us can control, because we don’t have that underlying immune deficiency.
So that what we see is the sickest of the sick, the tip of the iceberg, as in the earliest days of HIV-AIDS, where we saw Kaposi’s Sarcoma, pneumocystomonia and the other 25 AIDS-defining illnesses.
So that is the hypothesis we’re following.
And we’ve developed chips to look at all the Herpes viruses and pathogens in correlation with expressed virus in our patient population. . bec we don’t have that underlying immune deficiency, we’re seeing sickedst of the sick.
We’re seeing tip of iceberg – so that is hypothesis we’re following – we’ve developed chips to look at all the herpes viruses and pathogens in correlation with expressed virus in our patient populations.
Dr. Wilford – What I’m worried about, is XMRV the cause of this immunosuppression or is it just another of these viruses that is being expressed.
Dr Mikovits – Retroviruses are not ubiquitous and they’re not generally benign – so the kind of biology that we’ve looked at with HTLV1 with the HTLV1-associated myelopathy and the acquired immunodeficiency virus, HIV.
That’s a reasonable hypothesis. So it has not been a passenger in the other human retroviral-associated diseases so there is no reason to expect that it would behave other than another human retrovirus.
But of course this is the first human gammaretrovirus. So Sandy (Ruscetti) knows in that family of viruses the envelope is both an oncoprotein and a neurotoxin.
We heard yesterday about HIV creating a dementia distinct from the immune deficiency based on the viral envelope protein, so these are all hypotheses that we’re following.
then -- an earlier question by
Mindy Kitei, Journalist – My question is about treatment because that’s what people who go to my blog want to know. When are we going to start drug trials, what drugs are going to be used? Monotherapy, triple cocktail. Where, when, why.
I will skip many of the replies and jump to one of Judy Mikovits final comments.
Dr. Holmberg:-------------------So I think it’s really a step-wise approach:
- Define the prevalence of the pathogen
- Focus on those with it
- Determine whether it’s quantifiable
- Do initial phase 1-2 experiments to see whether you can alter the level of the pathogen short-term and then longer term treatment to see if there’s a clinical benefit.
Dr Mikovits: So I’ll just comment on that.
So I think that what the group back there and what we were saying is,
we have identified hundreds of certified XMRV +ve people,
from whom we have isolated the virus, who are very sick.
And I think that the commentary that accompanied the paper last week, the Lo paper by andy mason
– in those pts who have been bedbound, have not left their house, have not had a life for 25 yrs,
the benefit far outweigh the risks of multiple therapies that we have used for now more than 25, 20 yrs in HIV-infected individuals.
Dr. Mellors: I think you’re on the right track. But I think that what’s really important in this field Judy is for your findings to be validated independently so that there are a couple of sources that agree upon your findings so that there’s not the underlying skepticism generated by 0% prevalence in people who are bedbound.
And we’ve heard several examples of that. And so yes, you’re right. But it needs to be extended beyond WPI to different groups.
Dr. Mikovits: We have independant confirmation from 3 groups doing those studies you heard of today in several posters that were not from the WPI.
But the patients exist with XMRV, with disease.
And if we could put something together with them in advance of the larger prevalence studies.
They’re infected, they’re ill, they have what you’d expect from a gammaretroviral infected associated disease – and we could begin to do clinical trials, where we crossed over infected people, and switched the drugs and looked for benefits and followed markers, followed infectious virus by assays like the Dersey assay,
we’re getting more sensitive assays, serology assays, learning about the immune response, learning about the inflammatory cytokine and chemokine profiles that we have associated with these infections.
There are significant numbers of very sick people with this virus in whom these things could be started.
(Applause)
Those of us following developments with ME/CFS and Lyme Disease have to wonder if only CDC, Infectious Diseases Society of America and our Health Authorities around the World had listened over the last 30 years, instead of as is the case of Lyme Disease relying on just a handfull of people denying the existence of Chronic Lyme and with ME/CFS listening to the Psychobabble, whether science would have moved forward at a much quicker pace.
Instead it has been private funding pushing science forward and patients suffering the consequences of years of denial by our Health Authorities.
extracts
On the question of clarity of the diverse study results
Dr Mikovits: We saw at this meeting several posters and we heard from 4 physicians, Dr Cheney, Dr Bell, Dr Peterson, Dr Komaroff on the Lo study.
These are experts at the diagnosis of, and they are diagnosing the same patients generally and we saw the same percentage of positive patients in those.
Those are patients geographically located from as you heard Dr Cheney say, from around the world… from the NE US in the case of the Hanson-Bell study, I know that Nancy Klimas gets a lot of patients form Florida.
So we can begin to address that because there are clinicians that have been identifying similar positivity rates so we can pull positive samples from each of those and really begin to put together literally hundreds to do that very thing.
and
Joe – clinician – I also want to support the comments from the person from Pittsburgh.
I have a question because the golden standard that is normally presented during these presentations is the CDC or the Fukuda criteria, but are there data on the performance and the variability with doctors using these criteria?
In other words is it conceivable that one doctor would rank a person “in” and another doctor “out” (of these criteria)?
Dr. Mikovits: Yes, the criteria are highly variable and probably some of the physicians in the - they’re really, really subjective,
and unless if you look for various immunological defects rather than just subjective defects, that you get a lot closer to seeing what we see in our patients,
the patients that we identified in UK in the London area, and what Drs Bell and Komaroff are (seeing)…
Dr (indecipherable): If that’s the case, if you’re going to compose clinical cohorts I think it’s important that you have different clinicians selecting and that you also create some data of other doctors looking at the same patient and confirming whether a patient is in or out.
Dr Mikovits: Well they’ve been looking for that for decades, biomarkers and things that could help better define this disease because it is so heterogeneous in how it’s defined.
Dr. Joe Barrascano, Clinician. Over the past day and a half I’ve been struck by the consistent inconsistencies of the results. In other words the groups that find the virus find it in 2/3 or ¾ of patients, and maybe 5% who are not.
And then there are groups who find it in absolutely nobody. It’s very important to work out methodology and so forth. But I think what could explain this tremendous difference that is consistent.
And I think it might go one step before. Maybe it’s the collection and storage of the blood prior to processing that’s really causing the problem here… because if it were a methodological problem you’d see variation from 1,2,10,20,40,50% rather than zero or 80%.
Dr. Mikovits: Actually that is true Joe, and … we have learned literally in past 2 wks in the BWG that processing may be a key
and we may have found an opportunity to have a processing protocol where everyone would at least find viral RNA in plasma and blood products without culture.
also
Dr. David Wilford, GSK – My question is to Judy but other people are looking at detection of XMRV. Before the XMRV studies, specifically the Virochip showed I believe that there were multiple viruses present in some of these CFS samples.
I’m just wondering with these XMRV positive samples if we’ve being looking specifically at serology or PCR for other types of viruses being more reactivated than controls or if anybody else there is doing these XMRV studies looking for other viruses, or just specifically for XMRV.
Dr. Mikovits – Yes, we set up this program as a study to look at all the viruses, because CFS patients have a lot of activated things like CMV and HHV-6a herpes viruses, mycoplasma, Lyme.
So the idea in the beginning is, as with HIV-AIDS that the retrovirus creates an underlying immune deficiency as-yet-unknown, allowing the immune system not to be able to control pathogens the rest of us can control, because we don’t have that underlying immune deficiency.
So that what we see is the sickest of the sick, the tip of the iceberg, as in the earliest days of HIV-AIDS, where we saw Kaposi’s Sarcoma, pneumocystomonia and the other 25 AIDS-defining illnesses.
So that is the hypothesis we’re following.
And we’ve developed chips to look at all the Herpes viruses and pathogens in correlation with expressed virus in our patient population. . bec we don’t have that underlying immune deficiency, we’re seeing sickedst of the sick.
We’re seeing tip of iceberg – so that is hypothesis we’re following – we’ve developed chips to look at all the herpes viruses and pathogens in correlation with expressed virus in our patient populations.
Dr. Wilford – What I’m worried about, is XMRV the cause of this immunosuppression or is it just another of these viruses that is being expressed.
Dr Mikovits – Retroviruses are not ubiquitous and they’re not generally benign – so the kind of biology that we’ve looked at with HTLV1 with the HTLV1-associated myelopathy and the acquired immunodeficiency virus, HIV.
That’s a reasonable hypothesis. So it has not been a passenger in the other human retroviral-associated diseases so there is no reason to expect that it would behave other than another human retrovirus.
But of course this is the first human gammaretrovirus. So Sandy (Ruscetti) knows in that family of viruses the envelope is both an oncoprotein and a neurotoxin.
We heard yesterday about HIV creating a dementia distinct from the immune deficiency based on the viral envelope protein, so these are all hypotheses that we’re following.
then -- an earlier question by
Mindy Kitei, Journalist – My question is about treatment because that’s what people who go to my blog want to know. When are we going to start drug trials, what drugs are going to be used? Monotherapy, triple cocktail. Where, when, why.
I will skip many of the replies and jump to one of Judy Mikovits final comments.
Dr. Holmberg:-------------------So I think it’s really a step-wise approach:
- Define the prevalence of the pathogen
- Focus on those with it
- Determine whether it’s quantifiable
- Do initial phase 1-2 experiments to see whether you can alter the level of the pathogen short-term and then longer term treatment to see if there’s a clinical benefit.
Dr Mikovits: So I’ll just comment on that.
So I think that what the group back there and what we were saying is,
we have identified hundreds of certified XMRV +ve people,
from whom we have isolated the virus, who are very sick.
And I think that the commentary that accompanied the paper last week, the Lo paper by andy mason
– in those pts who have been bedbound, have not left their house, have not had a life for 25 yrs,
the benefit far outweigh the risks of multiple therapies that we have used for now more than 25, 20 yrs in HIV-infected individuals.
Dr. Mellors: I think you’re on the right track. But I think that what’s really important in this field Judy is for your findings to be validated independently so that there are a couple of sources that agree upon your findings so that there’s not the underlying skepticism generated by 0% prevalence in people who are bedbound.
And we’ve heard several examples of that. And so yes, you’re right. But it needs to be extended beyond WPI to different groups.
Dr. Mikovits: We have independant confirmation from 3 groups doing those studies you heard of today in several posters that were not from the WPI.
But the patients exist with XMRV, with disease.
And if we could put something together with them in advance of the larger prevalence studies.
They’re infected, they’re ill, they have what you’d expect from a gammaretroviral infected associated disease – and we could begin to do clinical trials, where we crossed over infected people, and switched the drugs and looked for benefits and followed markers, followed infectious virus by assays like the Dersey assay,
we’re getting more sensitive assays, serology assays, learning about the immune response, learning about the inflammatory cytokine and chemokine profiles that we have associated with these infections.
There are significant numbers of very sick people with this virus in whom these things could be started.
(Applause)
Those of us following developments with ME/CFS and Lyme Disease have to wonder if only CDC, Infectious Diseases Society of America and our Health Authorities around the World had listened over the last 30 years, instead of as is the case of Lyme Disease relying on just a handfull of people denying the existence of Chronic Lyme and with ME/CFS listening to the Psychobabble, whether science would have moved forward at a much quicker pace.
Instead it has been private funding pushing science forward and patients suffering the consequences of years of denial by our Health Authorities.
Friday, 10 September 2010
DR PAUL CHENEY ON XMRV CONFERENCE NIH
The following comments were written by Dr. Paul Cheney.
Posted on the ME/CFS Forums here
and thanks to Lannie in the Lymelight for posting here
I attended and was a poster presenter at the recently completed XMRV conference at the NIH. It was fascinating and I took perhaps 30 pages of notes.
The bio-political undertones were also intense but I have to say that the presentations of XMRV association with CFS (4 presentations) were much stronger than the presentations of negative XMRV associations with CFS (4 presentations).
They were stronger specifically because of the multiple methods they employed and not just PCR.
Very interesting in this regard were comments by the head of the blood working group at the NIH who is trying to determine the cause of the discrepancy. He hinted strongly that it is the way blood is collected and processed for nucleic acids and not the detection methods for XMRV itself that divides the two groups.
In an NIH blood group sponsored study, a group comparison study with both camps represented detect successfully, in a blinded fashion, XMRV spiked buffer in varying concentrations but they nevertheless divide into two camps when clinical blood samples are taken and processed for XMRV nucleic acids.
Using only PCR, one camp sees ~80% positive in CFS and one camp sees 0% positive in CFS There is no one in between and no middle ground between the two groups which was striking and noted by Joe B. (BURRASCANO ) who was also in attendance.
There is no evidence by mouse mitochondrial DNA probes, that any of the positive associations were contaminated. However, one of the negative association speakers found non-human mouse virus MLV contamination perhaps localized to heparin tubes used for blood collection. Heparin is often produced in China where mice are common as pets. When the contamination was cleared, she found no association of XMRV with CFS.
I also wanted to share some other highlights of the conference Among them, a very interesting presentation was made by a group connected to Abbott Labs that infected male and female Macaques (monkeys closely related to man) with human XMRV to see what happens and where the virus ends up or concentrates itself.
Within a few weeks, the virus was largely cleared from blood where it was initially injected in high concentration. Even antibody response was lost over time (months) as the infection was largely removed from the blood and virus did not appear to persist in the blood.
Apparently, there was not enough viral antigen to keep antibody levels high or persistent. However, the virus was found more or less in every organ, at least initially, and thought to be carried around the body in T-cells and B-cells during the active phase of infection. This is consistent with the ubiquitous nature of the Xpr1 receptor used by the virus to gain access to almost all cells of the body.
Organs where the virus was initially most concentrated appeared to be lymphoid organs such as the spleen, liver and mesenteric nodes of the GI track and in sex organs and in particular the epithelium of the prostate gland where it was highly concentrated at first and then the infected cells later apoptosed and infection disappeared from the epithelium and then the virus was more likely to be seen in the interstitial cells in the stroma or matrix of the prostate, especially the fibroblasts which may be one reservoir in all the various organs that are initially infected.
The virus was also found in the epithelium of the cervix in the female macaque. Over time, the infections of various organs tended to be cleared by either immune mechanisms but especially by restriction enzyme systems present in almost all human cells that hypermutate the virus so it cannot persist as a competent infectious agent.
Indeed, mutated viral strains are almost always found in CFS cases by both Judy Mikovits at WPI and Frank Ruscetti at NCI. Sometimes this makes the virus incompetent as an infectious agent and sometimes has no effect on infectiousness.
Very interesting is that another cell that appears to be a reservoir of XMRV other then fibroblasts within tissue stroma are tissue macrophages The pulmonary alveolar macrophages were absolutely loaded with XMRV virus and other tissue macrophages could also be a potential reservoir in other tissues as well, especially in the GI tract, sex organs and sinuses.
Tissue macrophage reservoirs would be analogous with HIV as well. It would seem that bronchial secretions, nasal secretions and sex organ secretions as well as feces and urine are well positioned to help the virus to spread itself to other macaques, especially if activated.
As for activation of more or less low level or quiescent but persistent infectious virus, there seem to be several mechanisms.
The virus has both a glucocorticoid response element (GRE) and an androgen response element (ARE) in its promotor region. It also has binding regions for NK Kappa B proteins in its response elements.
In any organ with high levels of local androgenic stimulation such as the prostate and perhaps during puberty, the virus could activate. No mention was made of the effect of the predominant female sex hormones but estrogen is the equivalent androgen-like hormone in females.
As for the GRE in the promotor region, severe stress will activate the virus or the use of glucocortocoid hormones and perhaps any precursor steroid hormone such as pregnenolone.
As for the NF Kappa B sites, any strong immune response with an associated cytokine storm would also be a strong stimulant and such stimulation certainly occurs in the bronchial tree which is frequently stimulated with antigen, especially during allergy season.
Perhaps most interesting of all was what happened with the injection of a bolus of foreign peptides into macaques that had apparently completely cleared the virus from blood.
There was a huge reactivation of infectious virus in the blood proving that latent but persistent virus is just below the surface and that XMRV infection cannot be completely cleared from all reservoir sites.
The peptide injection mimics an acute infection (? borrelia or the flu), an immunization or even acute mold exposure.
The effect of XMRV infection over time was not studied in the macaque but a similar gammaretrovirus called Feline Leukemia virus (FeLV) has been well studied in cats for decades. I will in another post describe a most interesting talk at this conference by a veterinarian on the life history of infection by a gammaretrovirus in cats.
Paul Cheney, M.D.
Posted on the ME/CFS Forums here
and thanks to Lannie in the Lymelight for posting here
I attended and was a poster presenter at the recently completed XMRV conference at the NIH. It was fascinating and I took perhaps 30 pages of notes.
The bio-political undertones were also intense but I have to say that the presentations of XMRV association with CFS (4 presentations) were much stronger than the presentations of negative XMRV associations with CFS (4 presentations).
They were stronger specifically because of the multiple methods they employed and not just PCR.
Very interesting in this regard were comments by the head of the blood working group at the NIH who is trying to determine the cause of the discrepancy. He hinted strongly that it is the way blood is collected and processed for nucleic acids and not the detection methods for XMRV itself that divides the two groups.
In an NIH blood group sponsored study, a group comparison study with both camps represented detect successfully, in a blinded fashion, XMRV spiked buffer in varying concentrations but they nevertheless divide into two camps when clinical blood samples are taken and processed for XMRV nucleic acids.
Using only PCR, one camp sees ~80% positive in CFS and one camp sees 0% positive in CFS There is no one in between and no middle ground between the two groups which was striking and noted by Joe B. (BURRASCANO ) who was also in attendance.
There is no evidence by mouse mitochondrial DNA probes, that any of the positive associations were contaminated. However, one of the negative association speakers found non-human mouse virus MLV contamination perhaps localized to heparin tubes used for blood collection. Heparin is often produced in China where mice are common as pets. When the contamination was cleared, she found no association of XMRV with CFS.
I also wanted to share some other highlights of the conference Among them, a very interesting presentation was made by a group connected to Abbott Labs that infected male and female Macaques (monkeys closely related to man) with human XMRV to see what happens and where the virus ends up or concentrates itself.
Within a few weeks, the virus was largely cleared from blood where it was initially injected in high concentration. Even antibody response was lost over time (months) as the infection was largely removed from the blood and virus did not appear to persist in the blood.
Apparently, there was not enough viral antigen to keep antibody levels high or persistent. However, the virus was found more or less in every organ, at least initially, and thought to be carried around the body in T-cells and B-cells during the active phase of infection. This is consistent with the ubiquitous nature of the Xpr1 receptor used by the virus to gain access to almost all cells of the body.
Organs where the virus was initially most concentrated appeared to be lymphoid organs such as the spleen, liver and mesenteric nodes of the GI track and in sex organs and in particular the epithelium of the prostate gland where it was highly concentrated at first and then the infected cells later apoptosed and infection disappeared from the epithelium and then the virus was more likely to be seen in the interstitial cells in the stroma or matrix of the prostate, especially the fibroblasts which may be one reservoir in all the various organs that are initially infected.
The virus was also found in the epithelium of the cervix in the female macaque. Over time, the infections of various organs tended to be cleared by either immune mechanisms but especially by restriction enzyme systems present in almost all human cells that hypermutate the virus so it cannot persist as a competent infectious agent.
Indeed, mutated viral strains are almost always found in CFS cases by both Judy Mikovits at WPI and Frank Ruscetti at NCI. Sometimes this makes the virus incompetent as an infectious agent and sometimes has no effect on infectiousness.
Very interesting is that another cell that appears to be a reservoir of XMRV other then fibroblasts within tissue stroma are tissue macrophages The pulmonary alveolar macrophages were absolutely loaded with XMRV virus and other tissue macrophages could also be a potential reservoir in other tissues as well, especially in the GI tract, sex organs and sinuses.
Tissue macrophage reservoirs would be analogous with HIV as well. It would seem that bronchial secretions, nasal secretions and sex organ secretions as well as feces and urine are well positioned to help the virus to spread itself to other macaques, especially if activated.
As for activation of more or less low level or quiescent but persistent infectious virus, there seem to be several mechanisms.
The virus has both a glucocorticoid response element (GRE) and an androgen response element (ARE) in its promotor region. It also has binding regions for NK Kappa B proteins in its response elements.
In any organ with high levels of local androgenic stimulation such as the prostate and perhaps during puberty, the virus could activate. No mention was made of the effect of the predominant female sex hormones but estrogen is the equivalent androgen-like hormone in females.
As for the GRE in the promotor region, severe stress will activate the virus or the use of glucocortocoid hormones and perhaps any precursor steroid hormone such as pregnenolone.
As for the NF Kappa B sites, any strong immune response with an associated cytokine storm would also be a strong stimulant and such stimulation certainly occurs in the bronchial tree which is frequently stimulated with antigen, especially during allergy season.
Perhaps most interesting of all was what happened with the injection of a bolus of foreign peptides into macaques that had apparently completely cleared the virus from blood.
There was a huge reactivation of infectious virus in the blood proving that latent but persistent virus is just below the surface and that XMRV infection cannot be completely cleared from all reservoir sites.
The peptide injection mimics an acute infection (? borrelia or the flu), an immunization or even acute mold exposure.
The effect of XMRV infection over time was not studied in the macaque but a similar gammaretrovirus called Feline Leukemia virus (FeLV) has been well studied in cats for decades. I will in another post describe a most interesting talk at this conference by a veterinarian on the life history of infection by a gammaretrovirus in cats.
Paul Cheney, M.D.
Tuesday, 24 August 2010
HGRV-XMRV-MLV NEWS
The Whittemore Peterson Institute would like to congratulate Harvey Alter, MD, and Shyh-Ching Lo, MD, PhD, on their publication of the replication study.
A quote from Dr Joe Burrascano for patients with Lyme Disease-
'Definitely stay tuned - the volume of new and important information about this virus and its disease associations is increasing rapidly and in my opinion should be a concern to every patient with chronic neuro-immune diseases, including those with chronic Lyme.'
The Wall Street Journal here
The Washington Post here
The New York Times here
CNN here
The LA Times here
The Scientist here
Pro Health here
VIP dx tests here
Living with Chronic Fatigue Syndrome many links here
CFS Central an excellent read here
CFIDS here
Other articles as posted by Life as we know it here
Fox10TV here
MSN Health here
Science here
Business week here
Monday, 23 August 2010
DETECTION OF MLV-RELATED VIRUS GENE SEQUENCES IN BLOOD OF PATIENTS WITH CHRONIC FATIGUE SYNDROME AND HEALTHY BLOOD DONORS
The long awaited Alter/Lo paper thanks to blog Life as we Know it.
http://cfs-facts.blogspot.com/2010/08/and-here-it-is-long-awaited-paper.html
http://www.pnas.org/content/early/2010/08/16/1006901107.full.pdf+html
Detection of MLV-related virus gene sequences in
blood of patients with chronic fatigue syndrome
and healthy blood donors
Shyh-Ching Loa,1, Natalia Pripuzovaa, Bingjie Lia, Anthony L. Komaroffb, Guo-Chiuan Hunga, Richard Wangc,
and Harvey J. Alterc,1
Chronic fatigue syndrome (CFS) is a serious systemic illness of
unknown cause. A recent study identified DNA from a xenotropic
murine leukemia virus-related virus (XMRV) in peripheral blood
mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested
PCR, as compared with 8 of 218 (3.7%) healthy controls. However,
four subsequent reports failed to detect any murine leukemia virus
(MLV)-related virus gene sequences in blood of CFS patients. We
examined 41 PBMC-derived DNA samples from 37 patients meeting
accepted diagnostic criteria for CFS and found MLV-like virus gag
gene sequences in 32 of 37 (86.5%) compared with only 3 of 44
(6.8%) healthy volunteer blood donors. No evidence of mouse
DNA contamination was detected in the PCR assay system or the
clinical samples. Seven of 8 gag-positive patients tested again positive
in a sample obtained nearly 15 y later. In contrast to the
reported findings of near-genetic identity of all XMRVs, we identified
a genetically diverse group of MLV-related viruses. The gag
and env sequences from CFS patients were more closely related
to those of polytropic mouse endogenous retroviruses than to
those of XMRVs and were even less closely related to those of
ecotropic MLVs. Further studies are needed to determine whether
the same strong association with MLV-related viruses is found in
other groups of patients with CFS, whether these viruses play
a causative role in the development of CFS, and whether they represent
a threat to the blood supply.
http://cfs-facts.blogspot.com/2010/08/and-here-it-is-long-awaited-paper.html
http://www.pnas.org/content/early/2010/08/16/1006901107.full.pdf+html
Detection of MLV-related virus gene sequences in
blood of patients with chronic fatigue syndrome
and healthy blood donors
Shyh-Ching Loa,1, Natalia Pripuzovaa, Bingjie Lia, Anthony L. Komaroffb, Guo-Chiuan Hunga, Richard Wangc,
and Harvey J. Alterc,1
Chronic fatigue syndrome (CFS) is a serious systemic illness of
unknown cause. A recent study identified DNA from a xenotropic
murine leukemia virus-related virus (XMRV) in peripheral blood
mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested
PCR, as compared with 8 of 218 (3.7%) healthy controls. However,
four subsequent reports failed to detect any murine leukemia virus
(MLV)-related virus gene sequences in blood of CFS patients. We
examined 41 PBMC-derived DNA samples from 37 patients meeting
accepted diagnostic criteria for CFS and found MLV-like virus gag
gene sequences in 32 of 37 (86.5%) compared with only 3 of 44
(6.8%) healthy volunteer blood donors. No evidence of mouse
DNA contamination was detected in the PCR assay system or the
clinical samples. Seven of 8 gag-positive patients tested again positive
in a sample obtained nearly 15 y later. In contrast to the
reported findings of near-genetic identity of all XMRVs, we identified
a genetically diverse group of MLV-related viruses. The gag
and env sequences from CFS patients were more closely related
to those of polytropic mouse endogenous retroviruses than to
those of XMRVs and were even less closely related to those of
ecotropic MLVs. Further studies are needed to determine whether
the same strong association with MLV-related viruses is found in
other groups of patients with CFS, whether these viruses play
a causative role in the development of CFS, and whether they represent
a threat to the blood supply.
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