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Written by thefreeprisoner
[If you missed it, part 1 of this transcription is here]
When you look at XMRV at this point, it seems to me that this is a very good theorietical cause for the illness but that’s gonna take some time before that’s proven. And I’m happy to say that if it’s proven to be the cause then we’ll go from there. If it’s disproved, then I’ll say OK, but I want it to be disproven by science not politics. If it’s put aside because of political inconveniences then I’m not going to be able to accept that. But if scientifically, it can be shown that this is not the cause, then ok, we’ll go from there.
Something is the cause of Chronic Fatigue Syndrome. I have that as a certainty in my own mind. I have no question about that. What it’s going to turn out to be? Well, we’ll have to wait and see.
[slide not shown. Laughter.]
OK the doctor sits there [inaudible] and the patient says “I really look forward to your cheery little visits”. This realates of course to the controversies about is it real, is it not real.
The WPI finds XMRV in lots of people and then this London group finds that out of 186 there’s not a single sample was there. But this is what sicence is all about. We have to look at the methods. Did the London group use different methods? Did they use a different way of storing it? Did they use different PCR primaries and so on? And here’s where over a period of time we’ll come up with the answer. I’m quite optimistic that there will be about 10 groups that will try to replicate the WPI studies. So that if one or two groups can’t find it that doesn’t mean that all 10 or 15 groups are not going to find it. If all 10 or 15 groups can’t find it then we have to come to some understanding about just what’s going on and why they can’t find it in those tissue cultures.
[slide shows virus picture]
So these slides that I’m going to show you are what a retrovirus is. These slides are coutresty of Dr Jones at the NIH. HIV is one of the retroviruses in the human population and as such it is a good model for us to use when we’re talking about XMRV. Back in 1980 when AIDS first came on the scene, people were saying it was a type of psychosomatic illness and this went on for several years even with patients with HIV were dying, they were saying “Well, it’s a real bad psychiatric disease.” [laughter] I’m not kidding… there was a big controversy.
Then the virus was discovered and the research took off from there. It didn’t take off right away, it actually took a couple of years for people to get the message that this was really important. The reason they got that message was because patients started getting HIV from blood transfusions. When that happened the politics started to change. But HIV as a retrovirus, a human retrovirus, is now somethng that can be treated quite well.
There have been 2 clinicians, Dr Mark Loveless and Dr Nancy Klimas who have large clinics, half of the whom have HIV and half of whom have Chronic Fatigue Syndrome. Recently somebody had said to Dr Klimas, “Well at least your patients aren’t as sick as those with AIDS” and she said “What are you talking about?” Because of the anti-retroviral drugs, the patients with HIV Disease are hail and hearty, that was the term that she used — and the patients with Chronic Fatigue Syndrome are bedridden, at least in her clinical practice.
What this means is that while HIV is still a terrible disease, the anti-retrovirals have changed the clinincal course so dramatically that patients can go out and do things and sometimes work full jobs. What this means for patients with Chronic Fatigue Syndrome – if XMRV is the cause of Chronic Fatigue Syndrome, I would anticipate that there will be good treatment in the near future; however, there are lots of steps to go through before that.
[Slide with diagram [undreadable – something about Free Virus, Binding and Fusion, CD4 receptors, CCR5 receptor, CXCR4 Receptor, Transcription, Integration]]
This is what happens in a retroviral infection. First of all the free virus attaches itself to the cell membrane and it chooses certain cells to attach to. For example, the HIV, it’s the CD-4 primarily. Fusion proteins connect, and then, right at this stage, the HIV RNA goes into the cell and because of reverse transcriptase enzyme, it turns it into HIV DNA. This DNA goes and inserts itself in the human chromosome. This is the insertion or integation. And now the HIV DNA becomes a part of the normal human chromosome. And this is what defines a retrovirus.
When it is inserted or integrated into the DNA, it can use the normal cellular mechanisms and transcribe itself back into viral DNA, and then back into… er, it buds off from the cell and then becomes a mature infectious [barrier?]. How much of this is in your bloodstream is called the viral load, and that’s one of the critical issues in the infectivity part of this illness.
So we’ll skip this slide…
Also, we’ll skip this slide which just shows the basic structural elements of the retrovirus.
[Slide: Protease
Cuts Gag polyprotein to MA, CA, NC
Exquisite cleavage specificity.
Major classif… [undreadable]… Inhibitors]
Now the Protease is an enzyme which cuts the Gag part of the gene into certain pieces which will then make it infective. The nucleus for HIV Disease are protease inhibitors. So what they do is they get into this enzyme and they change the confirmation of the enzyme so that the enzyme doesn’t work. And as such, the HIV which is still integrated into the DNA now becomes kind of just a bystander or a passenger in the DNA. It will always stay there but it is not able to go out and make infections [varials?].
So this is the latest class of drugs for HIV disease. There are many different classes of drugs. There are fusion inhibitors. There are protease inhibitors. There’s the reverse transcriptase inhibitors. So you can attack the virus at many different points and as a result you can render this virus much less pathogenic.
Now this has taken 20 years, well, 1985 to 2010, going on 25 years, but the scientists are pretty close to getting these treatments right. These drugs are incredibly expensive, they have significant side-effects, but if XMRV turns out to be a real cause of Chronic Fatigue Syndrome, we will be able to use the experience from the HIV community in formulating treatments that will work for Chronic Fatigue Syndrome.
[Slide: Diagram of 2 different T Cells
a) Latent infection
Shows CXCD4 coreceptors, CD4 receptors, Proviral DNA, T Cell, Chromosomal DNA
b) Active infection
Shows Viral DNA, Proviral DNA, mRNA, Envelope, Core with viral RNA, Virus budding from T cell and Progeny HIV]
2 seperate possibilities. Here you have a cell for the pro-viral DNA, again this is HIV but it could be the same for any retrovirus. Again it’s just sitting in the cell, it’s not doing anything. And then over on this cell you have an active infection where the pro-viral DNA comes out here, it’s making the envelope and the other parts of the virus, it buds off here and becomes an infections [varia?].
So this is the difference between a latent infection and an active infection.
Now, why am I enthusiasitc about the possibility that XMRV is the cause of Chronic Fatigue Syndrome? Now first of all I can say that because I’m just a country doctor from way out in the rural countryside, so I’m not going to lose my job for saying something that’s politically incorrect. Most of my regular patients have no clue that there’s such a thing as Chronic Fatigue Syndrome. Every once in a while they say “Gee, have you heard that in the paper about Chronic Fatigue Syndrome?” They’re as unfamiliar with it as everybody else in the country. So I can say what I want because I’m not an author of that paper and I have my own opinions.
[Slide: Chronic Fatigue Syndrome
70% of Lymphocytes activated
Abnormal RNAse L
Decrease NK cell number and function
Immune Activation
Activated T cells
Cytokines / Chemokines]
This is one of the reasons why I have the opinion that XMRV is a perfect candidate for the cause of CFS.
Studies for years have shown that the lymphocytes in this illness are activated. Nancy Klimas has said roughly 70% of the lymphocytes are in the activated state. What that means is they’re doing something — they’re fighting something. Now everybody’s saying “Well we can’t find anything that they’re fighting.” That doesn’t mean that it’s not there, it means we can’t find it. So the lymphocytes are active and they are trying to fight against something. Even though with every theory; well, it’s EBV or mycoplasma or whatever it is; we haven’t been able to prove that. But what we do know is that the lymphocytes are activated.
Secondly there’s abnormal RNase-L. Now this is an enzyme which is very important in the anti-viral pathways. What it does is it’s an RNA enzyme… it’s a non-specific RNA destroyer. It breaks up RNA. The studies have been very complex but they’ve shown for probably at least 15, maybe 20 years that this enzyme is clearly an important factor in CFS. Why? Because there’s clearly some retrovirus circulating around and this enzyme gets activated that way.
Thirdly there’s a decreased Natural Killer Cell number and function. Natural Killer Cells are one of the arms of the immune system aand it’s one of the areas that again over the years has proven to be a consistent abnormality in Chronic Fatigue Syndrome. Interestingly Natural Killer Cells have a role in keeping yeast suppressed. I remember reading about all the yeast studies. A lot of them were taking place right here in Southern California and I was saying “Well, who cares about yeast?” I see babies every day with thrush; that’s yeast in their mouth; but adults shouldn’t have thrush. But you find a lot of CFS patients with thrush. That’s because the Natural Killer Cells are not working properly.
In addition Natural Killer Cells are one of the first natural lines of defence for herpes group viruses such as mono, EBV, cytomegalovirus, and these are exactly what we’ve been looking at for the past 25 years. Again Peterson at the CFSAC meeting said that the three types of cells that XMRV seems to have a preference for is the Natural Killer Cells, some B cells and some T cells. So we know that this is an illness that can affect Natural Killer Cells.
And then of course there’s immune activation with activated T Cells and the cytokines.
So if you would put this together as a possible chain of events, what happens? And again this hypothesis is certainly not fixed; it’s too early to know whether this is true. Dr Dan Peterson had mentioned this at the CFSAC meeting, so I’m happy to call it his particular theory on it, but it really makes a lot of sense.
First of all you may have an infection with XMRV. We don’t know how people get it. People are going to say “Oh, how did you get it?” Don’t know. That’s something that there are a million theoretical possibilities. Right at this point it’s best to say, “Just don’t know.” Then these B cells, T cells, get infected.
[Slide: Possible Chain of Events with XMRV
Step #2
NK Cell function impaired
NK Cell numbers decreased
[graph showing how viral load increases as these go down]]
Then the Natural Killer Cells function becomes impaired and the NK Cell numbers are decreased, and when that happens, the viral load can go up. In AIDS the same thing happens only this is CD4 cells and this is the viral load. As the CD4 cells go down, the viral load goes up. It’s quite possible the same thing happens with XMRV.
[Slide: Possible Chain of Events with XMRV
Step #3
“Subtle” Immunodeficiency
Allows infection / persistence of:
Herpes group viruses
Numerous other agents]
So then the next thing that happens is that you have “subtle” immuno-deficiencies. I say “subtle” because it’s nowhere near as drastic or as dramatic as HIV where you have these overwhelming infections that turn out to be lethal. So I would say in comparison the immuno-deficiency of CFS is subtle. But it’s there. You do see patients with yeast. You do see patients with higher than normal viral loads of EBV or Cytomegalovirus. You do see patients with CFS who have difficulty with immunologic function. And there are numerous other agents that can be involved.
[Slide: Possible Chain of Events with XMRV
Step #4
Symptom Production from Secondary Infection
Cytokine release
chronic inflammatory changes
NO
Inhibition of ATP production
Vasoconstrictors]
Step four. You can have symptom production from the secondary infections. So what happens is you have increased release of the cytokines. You have chronic inflammatory changes. This leads to nitric oxide and inhibition of ATP production and loss of energy because of that, and the area that I’ve always been very fond of, which is the systemic vasoconstriction, which is probably due to the isoprostates which is related to oxidative stress. But it really doesn’t matter quite exactly the mechanism is here, because whatever is the underlying cause of Chronic Fatigue Syndrome is causing these symptoms.
I think that XMRV makes an excellent candidate for that.
[Slide: Possible Chain of Events with XMRV
Treatment of secondary infections is of limited value
Treatment of secondary infections in AIDS patients causes symptomatic improvement
No-one dies of HIV, they die from secondary infections
Difference between NK cell immune defect and CD4 immune defect]
There’s been a lot of hope in the past that if you treat one of the secondary infections then you will cure the illness, and that’s been a great carrot dangling in front of us. 2 years ago there was tremendous hope in the Stanford Study that if you use Valcyte and treat the EBV and the Cytomegalovirus and other herpes viruses then people would have a dramatic recovery, and in their first trial they did have an extremely good result. Howeer, in the subsequent double-blind study the results were not all that good, so you can treat secondary infections and when you do that you will have some improvement of symptoms. But this also occurrs in AIDS. So in AIDS if you have secondary infections and you treat them, patients will feel better. However it doesn’t make the disease go away. Nobody dies of HIV infection, they die of secondary infections.
The difference with XMRV — if it turns out to be the cause of Chronic Fatigue Syndrome — and HIV, is basically the cells that are being targetted are probably quite different.
[Slide: Results from Dr Paul Cheney as of 11/20/09
Of the 13 CFS cases tested to date by VIP, all were positive at least by one test.
7 out of 10 tested positive on whole blood PCR
5 out of 9 tested positive on serum PCR]
Dr Paul Cheney shared with me that he’s had a number of patients that he’s had tested, and he feels that this is quite likely to turn out to be true. So it’s not just patients that are in the Western part of the United States. His patients are mostly in the Eastern part of the United States.
[Slide: Dr K DeMeirlier
Described 34 patients in Belgium who developed CFS (CDC criteria) within 2 to 7 days of a blood transfusion. In 9 of these patients, low molecular weight RNAseL assay was performed – all]
Kenny DeMeirlier presented a paper where he described 34 patients who developed CFS within a couple of days of having had a blood transfusion. Now this is the only reference to blood transfusion in Chronic Fatigue Syndrome in the current literature. Actually this paper is not part of the peer review literature but he had presented this.
I’ve seen patients who had got sick immediately after a blood transfusion, and if XMRV is the cause of Chronic Fatigue Syndrome and if it is in 3% of healthy persons, then the blood supply of the country is probably contaminated. This is an area that I think has the Red Cross quite nervous, obviously they are working quietly behind the scenes to see if this is what’s going on. We don’t have a simple test now to be able to exclude XMRV but I’m sure that will come up as quickly as possible.
Oh, of these patietns that he did, they had a low molecular weight fragment of RNase-L; let’s not go into that [laughter]
I’ve never understood that paper very well [more laughter]
[Slide: Fletcher, MS, Klimas N; et al
Journal of Translational Medicine
2009:7:96
doi:10.1186/1479-5876-7-96
Results: The following cytokines were elevated in CFS compared to controls: LT alpha, IL-1 alpha, IL-1 beta, IL-4, IL-5, IL-6 and IL-12.
The following cytokines were decreased in CFS: IL-8, IL-13 and IL-15.
The following cytokines were not different:]
Nancy Klimas recently published this paper. There’s new technology which allows you to simultaneously measure 16 different cytokines all at the same time. In the past this has been very difficult to do. One group will measure IL-2 and one group will measure IL-6 and it’s difficult to draw comparison because of different technologies and different days that the blood is drawn. In this study she was able to see that there were certain [inaudible] and cytokines were decreased in CFS and certain that were increased. And then there were a couple where it didn’t seem to have any effects.
Her discussion said “The results imply a disorganised regulatory pattern of TH1 function, critical to antiviral defense.”
The results from the study support a TH-2 shift, which is a pro-inflammatory cytokine up-regulation, and a down-regulation of important mediators of cytotoxic cell function. Essentially this means, this is not random. There’s a method to these cytokine abnormalities. There’s a pattern which emerges.
And she goes on to say “The observations of abnormal cytokine patterns in (ME)CFS patients support the reports of retrovirus infections.”
So that she also seems to feel that XMRV makes a very good candidate as the etiologic agent. Now for the past 25 years we’ve been arguing like mad over the definitions of this illness. So there are 3 different criteria that you can use. Actually there are about 15 different criteria. My favourite is the one for the [Takinoue?] flu which nobody else seems to be interested in, but I got to visit Takinoue in Finland and I think that their criteria there are much better than anybody esle’s. But the CDC has their criteria, the Canadian Consensus criteria and then the Myalgic Encephalomyelitis Ramsey criteria, so people have been arguing about this.
In my practise, I don’t know where to draw the lines. I probably have 5 patients where they are so close to Multiple Sclerosis that it’s very hard for me not to say they have MS. And then there are other patients that are very close to other illnesses; for example Fibromyalgia, Multiple Chemical Sensitivities and so on. So where we draw these lines in clinincal medicine has been very difficult to do, and it’s part of the problem of studying this illness.
If in fact XMRV is the cause of Chronic Fatigue Syndrome, early reports from WPI have suggested that these other groups also look like they’re positive, in which case, we won’t actually be caring about the present criteria.
[Slide: XAND
Xmrv Associated Neuro-immune Disease]
There will be the disease called XAND – Xmrv Associated Neuro-immune Disease. And this is where AIDS went. Initially it was called Gay Cancer, then it was AIDS and now it’s called HIV disease, and there are many different variations; there are malignancies, there are pneumonias, there are all sorts of different clinical variations, but it all traces back to an infection with one specific retrovirus.
[Slide: Conclusion
This new virus is a very big thing
It is a very hopefuly thing
The research necessary to bring treatments that are effective is already being mapped out
You can make a difference
Volunteer
Give
Spread the word]
Conclusion.
Now this is a slide courtesy of Dr Klimas. She knows that I’m stealing her material. But I think she’s presented this so beautifully.
First of all this new virus is a very big thing. I was trying to figure out how to express this, but couldn’t find the right word. This is it. It’s a big thing. This is not just a casual detail. This is something that is very important.
It is a very hopeful thing. Now there are some people who have said “Oh my word. If there’s a retrovirus that causes CFS then this is bad.” Well, we know the illness is bad. That’s not telling us anything we don’t know already. We know what this illness does and it’s a disaster even though the majority of physicians in this country still don’t quite get it; they don’t understand the seriousness of it; this is a disastrous illness from some people. Even though it’s still a very mild illness for some people, in my original patients that got sick back in 85, 80% got better. Now why did they get better? I like to think it’s because of the outstanding clinical care I gave them [laughter]. That actually wasn’t it. I did a couple of sub-studies. Many of them had no health insurance, so I didn’t do any tests on them; I didn’t give them any medicine to speak of. I watched them and followed them and they got better at the same rate as those who got an enormous amount of testing and an enormous amount of treatment. I don’t think I affected their course at all. However, 80% got better. We published that in a study in 1995.
We now studied that same group again and we found that unfortunately they are not staying well. Many of them are falling off the wagon and falling ill again. This is worrisome. So we ought to have that data in the near future.
So this is hopeful. If this virus is the cause, then we ought to have treatments in the near future. The research necessary to bring treatments that are effective is already being mapped out. Now this I’d like to emphasise. I have some patients in my office who have said “Hey Doc, can you slip me some AZT?” I said “No, no I can’t do that. It’s not that I don’t like you” [laughter] “It’s that I really really don’t want to harm you.” This is not the time to start experimenting with anti-retrovirals. When and if the time ever comes that anti-retrovirals are going to be used, they need to be used carefully by someone who really knows how to manage them.
I will never be able to do that because I’m in a rural area and if somebody’s being treated with an anti-retroviral, they need somebody on call 24 hours a day who knows what they are doing with this. And so therefore I’m not going to be able to do it. However, there are lots of infectious disease clinicians who are supreme at treating retroviral infections, and if XMRV turns out to be for real, they will be able to treat Chronic Fatigue Syndrome.
Number 4 – you can make a difference. Volunteer, give and spread the word. This I think is very important. People with this illness have just been really stressed, but the enthusiasm has fallen off over the last 10 years because it looked like it was going to just never go anyplace. But it does appear at this point that there’s something that is a very real lead.
This is a picture taken years ago of a C-type retrovirus and we’ll know whether or not this is going to be the etiologic agent for Chronic Fatigue Syndrome and I would hope that within 6 months we will be able to say, you know what, the evidence is coming in, this is going to be for real or “Sorry it’s just another a dead end” but I really don’t think it’s going to be a dead end.
OK, well I’d like to thank you, you’ve been very patient, and I wish you the best of luck in the future.