Part 2: Transcript with slide citations of the Jan 22 Santa Barbara XMRV Seminar by Whittemore Peterson Research Director Dr. Judy Mikovits – compiled and edited by long-time ProHealth subscriber and contributor Sandy Miarecki. (To return to Part 1, click here. To download the slides, click here.)
[SLIDE 34: WPI Research Priorities]
What are our research priorities? At the WPI, we’re actively working with the federal government to develop that next generation of tests. We expect that serological assay (Rachel will get mad at me) within a month. She told me yesterday that the data were looking really good. And we want to investigate the prevalence of XMRV. The federal government – the National Heart, Lung, and Blood institute – actually called as soon as the paper came out, and we set up a Blood Working Group to investigate what is the true prevalence. Prevalence means the presence, the distribution, not necessarily the disease; and we use incidence with disease, and prevalence of XMRV in the blood supply. Our numbers were small – they were only 200 or 300, that’s 4%. But 4% is still 10 million Americans, so you want to look at that, and they actively are. And they’re working on that second generation test as well.
We want to understand those tissue reservoirs, and clearly it may not be the PBMCs (peripheral blood mononuclear cells). Is it the lymph nodes? Is it bone marrow? It’s possible (I don’t expect it), but it could be the brain. We don’t know at this point. We are actively working, as I said, with drug companies to develop anti-retrovirals and immune based therapies.
We want to understand how it’s transmitted. We’ve got a family study going on in the research plan; it’s just getting IRB (Institutional Review Board) approval and ready to start. Hopefully we can get families who have any number of diseases across the spectrum, fibromyalgia, other neuro-immune diseases, maybe a higher incidence of cancer, but we need healthy people as well, so we’ll take essentially anybody into that protocol. And, as I said, that protocol will help us investigate the incidence of XMRV in other neuro-immune diseases.
[SLIDE 35: Questions]
Important questions that the field is working hard to answer (and we are as well, but we won’t be able to do all this):
• Is XMRV a causal factor in CFS, and possibly some aggressive prostate cancer? And we’ll talk a little bit about how you think about a causal factor. One way to do that is, we have several patients who came to Dr. Peterson, and they said “I was fine until I got into a car accident. I got a blood transfusion in the hospital and I got CFS” or “I had a surgery and had a blood transfusion.” So if you can identify a blood transfusion exchange of an acute infection that causes the disease, and the virus wasn’t there before in the human, and it’s there afterwards, and it’s in the donor, then of course you’ve got causality, and that is one way that causality was shown in HIV as causing AIDS. I think we all know the tennis player Arthur Ashe, and that is how he got HIV/AIDS and subsequently died.
• How does XMRV enter the human population? Is it a zoonotic [from animals] transmission? We know it’s not a mouse, at least not any of the mice we know. It could be a field rodent of some kind, but we’ve never found the virus in another animal. This is the first animal that is the “Xeno,” and that is man. So, how does it enter the population, and when did it enter?
• What’s the worldwide incidence of XMRV disease; that should say, “or prevalence” of XMRV. Where is it? Is it in England, in Europe, at what level? We know it’s 1.7% in Japan because of a study done earlier this summer.
• And does it alter the risk of cancer development? Because HIV & HTLV-1 both, by causing immune deficiencies, do.
[SLIDE 36: WPI Collaborations International]
A lot of people wanted to know: are we working internationally to replicate the studies? Everyone you see on this slide, a lady in Canada, part of the blood group in Canada also had called me since the study came out. We’ve been working with Jonathan Kerr, and we have a 5-year RL1 with him. Ellie Barnes is in MRC in Oxford. Norbert Bannert on that German paper, he was working with an advocacy group led by Regina Koch, I think, and they found a few samples that were maybe positive. So he called me and said “Can we work together and have that antibody?” Again everybody you see on this list, Jonas Blomberg in Sweden. Norway, Germany, the Netherlands, Italy, Spain. We can’t handle the samples we’ve got so far, but we’ll try, and we’ll send the reagents out to anybody to replicate the work and find out more about the disease.
[SLIDE 37: Additional Incidence Studies]
We also know of additional incidence studies that we’re not involved with but are occurring at Kiel University, again in Germany. And here in the USA, Sam Chow is working and has identified the virus in China, and I do know that Richard Huber has had success at finding virus in CFS and other patient groups. And of course I mentioned that blood working group that’s working throughout the United States, and I didn’t list the number of US collaborators we have. There is a lot of interest. A lot of the world’s best labs are working on this, and we’re going to get there a lot more quickly than we would because of everything we have learned from HIV.
[SLIDE 38: XMRV Clinical Diagnostic Tests]
What about Diagnostic Tests? Should your physician or you want to be tested currently (the last time I looked online), there were only 3 companies offering the diagnostic test. Of course the WPI licensed the technology to VIP Dx (we’re a non-profit institute), who is using our proprietary culture method and PCR, in combination along with a Western Confirmation. So, we look for both antibody and PCR positives in the cultured and co-cultured cells. And we use 20 mls of blood to do this, and make sure of the accuracy of the result, and the price is $450. Clongen lab has a real time PCR that is just looking for sequences on 1 ml of whole blood, and their price is here [$375]. You won’t find this virus in 1 ml whole blood by PCR. I think I’ve shown you that with the negative cases in the prostate cancer. And also a company known as Cooperative Diagnostics in South Carolina. We don’t know what their PCR method is, but they’re using a drop of blood on a piece of paper. So, they tell you if you put a drop of blood on a piece of paper, you don’t need a doctor or anything, just send a check, and of course they won’t find anything.
[SLIDE 39: Your Help is Critical to Advance the Science]
Your help is critical to advance this science. At the WPI, we either want your money or your blood. That’s the only two choices! We need you to participate in these research studies, and we have a form online where you can register: https://www.wpinstitute.org/patient/volunteer_form.html, and you can email me.
We’re asking for some clinical characteristics, but we’re asking for those more to help us put it in a study. We won’t turn anybody away. We will look for the virus, if we can get those studies. We’re waiting for the IRB approval, that’s the human assurance to make sure we’re not hurting you and we’re protecting your privacy. So, we expect that this week.
Donate funds to the WPI research and clinical programs that will be established later this year. The clinical programs will really come from the research and the diagnostics. And then write to your government officials, and encourage them to support XMRV research. This is an infectious disease. Why isn’t the National Institute of Allergy and Infectious Disease considering this virus? They’ve been pretty quiet, haven’t they? We haven’t heard a word from them. So, we need our government agencies to look at this virus because it’s an emerging infection, as I said, of unknown pathogenic potential.
[SLIDE 40: Acknowledgements]
I’d like to thank the people who – we couldn’t have done this study without them. This has been a 3-way collaboration between the National Cancer Institute and its contractor SAIC, Cleveland Clinic, and the WPI. As I said earlier, when Vinny Lombardi and I, together with Max Pfost, first saw the few sequences of the virus, I called Bob [Silverman] because obviously we were doing the work with him, and then I called Frank [Ruscetti], and said, “I need you,” and he said, “I won’t go,” and I said, “I’ll pay your way to San Diego on the beach for a week!” and he said, “Not any more of your schemes, Judy! I’m not going to do that again!” At any rate, we met at a restaurant, and we showed Bob, and he didn’t know what I was going to tell him. Interesting, Frank’s a bit cantankerous because I gave him about a week’s notice because we’d had 3 weeks, and I was pretty sure I knew what we had. We had to get a 3-way inter-institutional confidentiality agreement. Frank called the office in the government, and they said: “No, we’re not going to do that,” and he said, “Look, we’re talking next Saturday. You can either have a confidentiality agreement or you won’t,” but they got one. So Frank and his lab, like Dan Bertolette, did every one of those beautiful Western’s that I showed you, just a magician. Mike, Dean, and Burt Gold sequenced the entire RNAse-L gene in more than 100 patients. Ying Huang did all of the PCR that we had done, totally blinded, where samples never came to our labs to show it wasn’t contamination.
And, of course I’ve mentioned the lab of Sandy Ruscetti, Charlotte Hanson, and Jami Troxler, who were key in providing all of those reagents, without which this study clearly wouldn’t have been done. Cari Petrow-Sadowski developed that immune-response assay in a real hurry this summer, and I mentioned Kunio & Rachel, who did bioinformatics support and electron micrographs. We couldn’t do it without Dan Peterson’s diagnostic skill. I mean, he biased the patients such that we could find the needle in the haystack, but these are the patients that come to the institute. They have classic symptoms of CFS. When we have taken patients that have emailed us with exactly those same symptoms, we find the virus every time we look, including in Europe, in England, Ireland. We couldn’t do it without the CFS patients and advocates. We do so appreciate the support all along.
This was a tremendously difficult year in trying to keep quiet. Knowing what you had and don’t say anything until you are sure you’re sure you’re sure. Every day was just, “are we sure?” And so, we were able, with the small crew you see here, and this supportive staff. Vinny, Katy and Max – they pretty well have worked 24/7 for at least the last year… So, at any rate, with that I’ll thank you for your attention and take questions.
QUESTIONS – Audience Q&A Session
Question: Before any of the questions, I just wanted to say thank you because through your work and your collaboration, you’ve brought more excitement to the CFS community, you and your collaborators have, than in 2 decades. And you’ve also brought more interest in the illness than we’ve probably seen ever, so I thank you.
Judy Mikovits: You’re welcome. [Applause]. That’s interesting, because the reviewers of the paper didn’t really know what CFS was. They said: “oh, that’s a poorly understood and complex disease” and they went on to the virology. So we were able to get that reviewed without any kind of bias. And I think that was significant as well.
Question: What percentage of the population has this virus?
Dr. Mikovits: We found it in 3.75 percent of the U.S. population, and it was from across the United States. And in Japan they found it, just screening the blood supply of a couple thousand people, they found it in 1.7 percent. So we don’t know the true prevalence.
Question: So, only in 3.7 percent? What about the other 96 percent of CFS?
Dr. Mikovits: No, that’s the healthy population. It’s in 90-some percent of the CFS population. I stuck this slide in here, and Frank keeps taking it out, but you might have heard in the press after the paper came out, we didn’t do all of the tests, all four tests, on all of the people prior to the submission in May. We just looked for evidence of infection and looked to see if we could isolate the virus, looked to make the point, and it wasn’t so much about the CFS.
What we did, after the paper was published, we went back and we looked with all four assays for evidence of XMRV in those PCR negatives. Because now we know that indeed those negative samples may have evidence of infection, and what we found was that 19 of the 33 had antibodies in the plasma. We found transmissible virus in the plasma of 33 of those people, and then we looked at that latent virus because the company I used to work at here in Santa Barbara was called Epigenics, and it was developing methylation-inhibitors for epigenetic silencing, and that’s what happens to viruses. So we used Decitabine, which is a demethylating agent that opens up the genome and turns on the virus and found that there was latent virus in 10 of those people. And when we summed it all up and tabled it out, 99 of the 101 patients in the Science paper had evidence of XMRV infection. Another way that HIV/AIDS causality was established was by saying, “So, the statistics of this means there’s a 10 to the minus 35 chance that you had CFS in our study without having XMRV.” So I’ll go back to the AIDS analogy. You can have HIV. So, we wrote in the paper “virtually impossible,” and the editor took it out. We wrote, “highly significant.” The editor took it out. Finally we said, “significant.” But at any rate, 35 zero’s in front of a 1 would tell me it’s virtually impossible to have had CFS without having XMRV in this study.
So, you can be infected with HIV and not have AIDS. We know that. People are being treated. A lot more elite-controllers are coming out, but you can’t have AIDS without having HIV. So if we can establish that XMRV is to CFS as HIV is to AIDS, which is what we’re trying to establish through that immune system understanding. So HIV kills CD4 cells and leads to AIDS. XMRV does what to the immune response? To the T, B and NK cells to lead to CFS? To turn your question around, sir. What about – the incidence of CFS in this country is 1 to 2 million – is that more or less what is said? By the Canadian or the Fukuda criteria? So I said 10 million people were infected. Where are the other 8 million? Do they have cancer? Do they have nothing? I showed you that only 20 percent of HTLV-1 infected people were actually sick with one of those diseases.
So you can be infected with retroviruses and be carriers and not be sick. And that’s one reason to be tested. If there is a genetic susceptibility, which we’re looking to, maybe a reason, an immune defect that was unknown as to why some people get sick and others don’t. You certainly want to know where the virus is, so if you’re a carrier you can protect your family.
Question: Do you know how many have tested with VIP-Dx, and how many are positive?
Dr. Mikovits: I don’t work with the company. They only take samples two days a week because it takes three days to do that, so they’ve done hundreds of samples in the last couple of months, and at least half of them are positive. Or 40 percent. And again, their doctors are looking at, the doctors who are well versed with CFS, so they’re immediately sending off. Dr. Cheney, Dr. Klimas, a doctor in Canada, Ellie Stein, maybe even Susan Levine in New York. I’m not sure, because it’s illegal for me to know those data because there’s confidentiality between the patient and the physician. But quite a number and, yes, it’s there.
CFS is a heterogeneous disease. I mean anything based on fatigue. So certainly everything is not going to be this virus. But maybe there is a disease, and of course that’s what we’re looking for, biomarkers for understanding how you can get sick and be sick forever and not have drug targets, not have diagnostics. Certainly there are going to be lots of people who have what might be called CFS today, and that’s why we’ve also coined the term XAND, for XMRV-Associated Neuroimmune Disease, and that would be because we’ve seen (inaudible). I had done a number of studies with family members after the paper came out and prior to now, where I just said there’s a family member where the children have autism, there’s fibromyalgia, there’s excess cancer, and when you look, you find the virus. So, we’ve found the virus in Atypical MS. Atypical MS is a non-demyelinating MS – it looks like MS, it has some brain lesions like MS on SPECT scans. At any rate, I’m not a physician.
Just looking at families with different types of neuroimmune disease, we started seeing that the virus was there, and so that’s why we started thinking it might be involved in a broader spectrum of neuroimmune diseases, with overlapping symptoms because in fibromyalgia, pain is the primary symptom, but, in a lot of people, it’s this body-numbing fatigue, so fatigue goes along with it. In fact, Cindy Bateman, who’s a fibromyalgia expert at the University of Utah, says fibromyalgia is CFS with pain, and she can distinguish those who get better with fibro with certain therapies and compounds, and she takes the others away who don’t respond at all, and puts them more into the CFS group. So definitely XMRV is not going to be everywhere. It’s not – it’s 4%, but the people who are infected are sick.
Annette Whittemore: Earlier you said that 40% were positive. So describe the fact that if you’re positive, you’re positive. But if you’re negative, you’re not necessarily so?
Dr. Mikovits: Yes, that’s correct. I answered that question based on the samples that came through there. Everyone who is positive is definitely positive for having the virus. But we don’t know what the people are, what the doctor is sending in, so the people might not have that disease. So it could be a clearly, distinguishing delineating marker – biomarker – or diagnostic at that point for various diseases. So a doctor might see a spectrum and say “I don’t know, maybe I’d better check.” Because the earlier you catch it, just like cancer. Early detection. Make sure the reservoir is (inaudible), make sure you don’t have that virus multiplying, and you can live a normal life. Don’t let it get (inaudible). You know the commercial out right now is “HIV doesn’t have to equal AIDS”; well XMRV doesn’t have to equal disease. If we keep it down, we keep the immune system strong.
Question: So what you’re saying is you may test negative but not be negative?
Dr. Mikovits: That’s correct. If you do it by the PCR. If you do it by VIP-Dx, at least right now, it’s running along the lines of (inaudible). We’ve got the antibody, and we’ve got three of the four tests. We’ll license it to anyone. We’re a non-profit institute, so everybody pays the same royalty, so any diagnostic company could do the gold standard. But right now, if you test negative, you’re not necessarily negative, even at VIP-Dx. Because we want to go do that serology test. Maybe we can’t find evidence of the virus. But you’ve been exposed, which would be a good thing because your levels are theoretically low, and you’ve just now made the antibodies, so you can prevent disease, as we did with Magic Johnson. But we don’t know anything about the immune response to the virus.
Question: What about transmitting it, when you get pregnant, to a child? I mean, you were talking about breast feeding?
Dr. Mikovits: Well, it is theoretically possible. We don’t know. Gamma retroviruses are vertically transmitted, so the egg and the sperm can be infected and you can actually vertically transmit gamma retroviruses. But this is the first (inaudible), we’ve only studied it for two months. We don’t know. Theoretically it’s possible. If we make those data, it will certainly fall out when we start looking at family studies. The horizontal transmission is the only thing we know about right now. Because, of course, you have to find somebody who just gets infected in order to understand the disease. And since a diagnosis of CFS is being sick for six months. Well, if that’s the only thing we can do is to stop that practice, making somebody wreck their immune system, or be totally sick for six months, that would be a great thing with the discovery. If that’s the only thing that comes of it.
Question: Would you not recommend getting the test again if you did [test negative]? I just took the blood test with my doctor… and he’s part of a study. He didn’t tell me who he sent the samples to, it’s a 20-patient study, so if that came back negative …
Dr. Mikovits: It depends on where it is sent.
Question: Take, for example, VIP-Dx?
Dr. Mikovits: If it’s at VIP-Dx, as soon as we have the serology, we’ll go back and do all the negatives. We save them… We do isolate virus from all of them, but it costs a lot. So if they’re really negative, we won’t isolate virus either. That’s correct. At VIP-Dx, we’re going all the way to virus isolation, because we want to make sure we are sure.
Question: So, at a non VIP-Dx?
Dr. Mikovits: They’re only doing PCR. All bets are off. I showed you almost 60% of them are probably, they’re all false negatives, because very few people can find them. And participate in our research studies, because as I said, there’s no hurry. There’s no real reason to pay for a diagnostic test because we can participate in research studies and fund those studies and you get better data. Because I’m not privy to those data. I can’t answer the question of where they came from, where they are in the United States. Those patients and doctors have to release that information, and that’s not the job of the diagnostic company. So the information is not usable in that way. We’re pretty good right now. We’ve been as responsive as can be. By the way, if anybody thinks they might have been in our repository, if you simply e-mail me, we did decode that study over the Christmas holidays, so we can tell you if you’re positive or not. We can tell you whether or not you were in the study. Because there’s more than 500 samples, who are patients in the repository, and we only pulled about a hundred of those for this study. I don’t remember everybody, but we did decode it, so we know who the positives are at this point, and we are sending letters, but you have to ask me first for our human-assurance protocol, so just ask me and we’ll tell you.
Question: In the beginning, you mentioned that the virus uses lipids to grow?
Dr. Mikovits: It actually uses the cell lipids to make its lipid membrane. It’s an envelope virus, and it has lipids, so it pulls cholesterol in to make its (inaudible), so it uses all the cell machinery. It only codes the enzymes and the envelope proteins and cells, so the lipid bilayer of the envelope virus, there’s lipids in it. It’s from your cells, and cholesterol’s a part of that.
Question: Because I’m wondering, I’ve met a lot of other CFS patients who like me have high cholesterol. That just made me think: might there be a correlation?
Dr. Mikovits: Yeah, and nobody’s ever looked. It’s certainly something that they could look at correlating. I can’t think of a reason why. You might presume you’d have less, if you’re using it up for another purpose.
Question: What about children?
Dr. Mikovits: We do have a little bit of data on that because we have two children in a study who have a genetic disease of cholesterol. It’s called Niemann-Pick’s Disease. It’s also known as Childhood Alzheimer’s. And these kids, you know it’s a cholesterol metabolism disease where eventually your brain, you’ll eventually die of it because if you get too much cholesterol, it messes up your brain and everything. And those kids have been treated by James Hildreth in Nashville, Tennessee, at a small college… He’s using Cyclodextran and some of the cholesterol drugs. He’s actually an HIV drug developer, and the kids are showing some improvement when he modulates that pathway and stops the virus from entering or exiting the cell, so we don’t know anything about XMRV. We just know what other viruses do, so he is having success, suggesting that there are some opportunities there.
Question: Are you working with him?
Dr. Mikovits: Yeah, we’re working with him as well. That’s why I didn’t list all the collaborators in the United States. We’re providing reagents and whatever intellectual knowledge we have, and whatever physical abilities and instruments we have, to these collaborative efforts as well.
Question: Until forthcoming therapies are established for those who have XMRV, what are people doing once they are tested? Are they taking immuno-modulating therapies or whatever?
Dr. Mikovits: Some of what I showed you here, that turn on/off switch, suggests non-steroidal anti-inflammatories. So non-steroidal anti-inflammatories could help. Things that will balance cortisol. Maybe – these are just thought processes – because you know inflammation turns on the virus, and I don’t know much about hormone therapies and how lowering hormone levels might help. But I do know anecdotally that a lot of women in a particular time in their cycle get much, much sicker and can’t get over it. I do know in the laboratory progesterone really up-regulates the virus, so if you have a birth control pill – and again I don’t really know anything about this (I’m not a physician) – you might think about just keeping the levels balanced and avoiding the fluctuation.
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So certainly supplements can help a lot. Retroviruses cause a lot of oxidative stress. So things like N-acetyl-cysteine and glutathione, the detox type. People do take supplements. I know that a lot of people have had success with immune modulators, just helping their disease, or supplements, because they know about them. I caution against taking too much or taking a bunch of things. Try to learn as much as you can, because supplements aren’t controlled by regulatory agencies, and therefore, if you’re not using a high quality, you could actually be putting poisons in you. Since we don’t know much about the virus, you could modulate the wrong way. But things that up-regulate Natural Killer (NK) cell function (and there are known compounds out there that do that, that are marketed in our state), so that could help you. So, we don’t know a lot about it, but that’s how people are actually starting to help themselves.
The other thing is to stay out of stressful situations. It’s hard to do. In fact, we’ve seen a lot of people get worse just with the stress of the discovery, which is sad. That’s why I want you to call me. Because we don’t want you to think: “Oh no, I have a retrovirus!” We want to talk to you because it’s serious and you can have untold (inaudible). I mean most people say: “Wow I got it!” you know they’re congratulating people when they come up positive, which is really strange… [laughter] Then they get really scared, because they don’t know anything about it. And we’re here as much as we can to help, but we don’t know anything about that retrovirus. All we can say is the same thing I’ve been saying today. I hope you would walk home and say: “It’s not a mouse retrovirus. Retroviruses are not ubiquitous, and they’re not benign. So I have to think about those facts.” It’s wide open.
The drug companies – the one thing, if you do get tested, and we know you’re positive, a confirmed positive – we’ll get you into the earliest clinical trials. And they’ll have things pretty soon because it’s major Pharma, and I’ve given them the reagents and the cell lines – we’ve made several cell lines from people that make a lot of virus. And so we’ve given them those cell lines. All they have to do is take something off the shelf that rationally might inhibit a particular path, say the integrase gene or another gene that’s conserved across the three retroviruses [HIV, HTLV, XMRV] and show that they can see the efficiency, efficacy and knock down levels of the virus in the lab to levels, which they’re the known blood levels of the drug can achieve, and they can submit and do the paperwork for a clinical trial. And it’s already known to be safe because it’s already passed Phase 1, or safety trials, in humans. So we looked at those first. And there are a number of companies who, as I say, they are high quality companies, and they are more than interested. They are doing it now, and have been doing it since October.
Question: What about cancer, especially the hormone-responsive cancers?
Dr. Mikovits: We very much expect that some of the breast cancer incidence – we hypothesize that inflammatory breast cancer is a lot like what we saw with the inflammatory prostate. But yes, it is a very real hypothesis because the incidence of breast cancer in young women that you never used to see before, is rising at levels that suggest something environmental, and not necessarily genetic. You know, “we never had cancer in my family,” and you see young women that way, so it certainly is something that we’re looking at. The “we” here – I always say “we,” and it’s everybody but me usually – it’s the National Cancer Institute. We’re also looking at lymphoma, because CLL (chronic lymphocytic lymphoma) is a lymphoma, a B-cell lymphoma and it’s also been going up and up, and it suggests to us some kind of role of an infectious nature. So we are looking at a number of lymphomas with a group in New York, a group in Florida, and the Nevada Cancer Institute. I don’t have a breast cancer study set up.
Question: There’s actually an anti-retroviral vaccine that’s been used…
Dr. Mikovits: Yeah, a vaccine is a real opportunity, and we know that they still don’t have an HIV vaccine yet that’s efficacious, but HIV is a complex retrovirus. So when you’re thinking about the reason why you have to take a flu vaccine every year, it’s because the virus changes. Well, an HIV virus in a person in a week will change too much. They call them quasi-species. One of the really interesting things about this study is that we only isolate one thing out of these people. When we do the sequencing, it’s clean. We don’t isolate quasi-species. We don’t have the virus have these changes here in one week or one year – we have patient samples across dozens of years. We isolated XMRV from a 1984 plasma sample from a patient. We got it in 2008 and we got it in 1984, which again suggests that the virus has been around at least 25 years, and it might have a role in the disease but is not causative. So yes indeed, it could play a role in other things.
Question: People with CFS have shown a lot of evidence in other studies of being immune-suppressed. How are you certain that it’s XMRV that’s causing immune-suppression as opposed to say 8 other viruses like Kerr is suggesting, or other viruses that are causing immune suppression and making XMRV opportunistic?
Dr. Mikovits: Well, there are a couple of things for that. First of all, we’re not certain of anything. So I’d say it’s a hypothesis. It’s because of what I know about HIV, and HHV-8, herpes viruses, where it’s the underlying immune deficiency. The other viruses aren’t retroviruses, the other pathogens too, the bacteria, and they don’t live in your immune systems forever and replicate and have reservoirs. They’re across the board, so everybody’s infected. Probably 90% of this room has an EBV infection. But very few people express EBV, have chronic active EBV. That suggests that your immune system has something wrong with it. It could certainly go either way, but retroviruses don’t do that.
The CFS world has looked at many of those pathogens, so here’s chronic Lyme and here’s EBV and here’s… It’s never one place, something that unifies all of those. So it’s certainly a testable hypothesis, and that’s one of those things that will just happen. If you get an anti-retroviral and the chronic EBV goes away, and a lot of the symptoms go away… I’m not saying that the EBV doesn’t cause a lot of those symptoms. That’s what makes it so hard to figure out the disease. But if there’s an underlying immune deficiency that’s created… that’s not simply depression… but is getting worse every year, could be an explanation. So we’re happy that we can test that, because we do have different populations where we can see what the role of the co-infection is. We’ve never looked. We’re looking with various groups at big cohorts of chronic Lyme and big cohorts of chronic EBV, Q Fever – things like that have been associated with. Jonathan Kerr, in fact, he’s working actively with us to see if it makes sense, that you need the combination or you need one or the other. But, in the general population, the incidence of XMRV is something between 2% and 4% right now, whereas it’s 90% of some of the herpes viruses. And most of us are exposed to some of these other pathogens, so I certainly don’t have an answer, but again, this gives us a testable hypothesis to look.
Question: I’m XMRV positive. And I have a son who is. I was told that he also had Lyme when he was 7. Explain the chronic Lyme connection in him?
Dr. Mikovits: Well, again, we don’t know – it’s our hypothesis that, especially in Lyme disease, where it goes away and it’s almost cured and you only see some proteins that don’t necessarily; you know; it suggests you almost cure it with the antibiotics, but you have to keep the antibiotic there because there is a low level that your immune system can’t clear, and maybe it can’t clear it because you’ve created an immune deficiency with the retroviral infection. We’ve never looked at a Lyme cohort yet. Again, we’re setting that up, but we don’t know the connection. The hypothesis is, if we can treat the retrovirus, then the chronic Lyme will go away. And you’ll treat both.
Question: But he was untreated until about 7, and was bitten in Europe, and no-one understood that there. He had the rash on his legs, and no one believed me that that’s what it was.
Dr. Mikovits: Well, we can still clear the Lyme. For instance, in the AIDS population, you treated the pneumocystis pneumonia. You treat it with the appropriate antibiotics because you don’t want the co-infections to kill him, and then do the anti-retrovirals too. There’s no reason, for instance, one of the questions that I got online was, “Well, I’m taking antivirals. Do I need to stop in order to get tested?” No, because antivirals don’t target retroviruses. Retroviruses are very distinct viruses, so no you don’t need to stop. We’ll still find the virus.
Question: But even 10 years later, because he was never treated. That was 10 years ago. You’re still saying you would still treat for Lyme?
Dr. Mikovits: Yeah, well you probably should be at this point. Treated for both the Lyme and once we have a treatment, for the retrovirus.
Question: If XMRV is transmitted sexually, how come it’s not seen as CFS in couples?
Dr. Mikovits: The possibility is that it’s transmitted sexually, but we’ve never actually shown human-to-human transmission, meaning we caught the day when the other got sick. I don’t actually have an answer for that, other than that I know that it might well be more in couples than we think, because it’s a milder form of symptoms, or maybe this person’s a carrier. There’s still a lot we don’t know about why prostate cancer and why CFS… What is the hormone component that turns on the virus? They may be carriers and not know it, and certainly there’s a lot to study there, to understand the gender differences in these diseases.
Annette Whittemore: Maybe part of the answer is that, if XMRV turns out to be the cause, would you have said that you wouldn’t have CFS without it, given you can have the virus without having CFS?
Dr. Mikovits: We have looked in a limited number of families that we’ve done, and in fact, maybe only one member of the family has CFS, and so it will be an interesting year, but, once we really get to the data of looking at these families and the various diseases and trying to understand – it’s a very low replicating virus, so it really just sits there for a long time. If you can keep the reservoirs low, you might have the virus your whole life and never get sick. We don’t know how long it’s been in the population. We think, like with other retroviruses, the younger you get sick, the more severe the disease. When Sandy Ruscetti gives the rats the viruses when they’re neonates, they get cancers. When they get it when they’re 30 or 40, they don’t get anything.
The immune system is educated and grows as you go along. It can be more fragile at different times in your life. We’ve seen a lot of puberty, boys and girls alike. There’s a lot of infection or at least apparent infection, disease occurrence at 12 or 13. And I do know that’s when Andrea got sick [to Annette Whittemore]. And yet presumably, your family was in the same space, but there was no child who had hit puberty at that point, and that might have been the difference. Retroviruses don’t infect people differently. You can’t go to Germany and say the reason they don’t find it is because they have hardier genes in Germany (although my husband might argue that) [laughter]. Because everybody gets infected. It’s just which immune system can control the virus and keep it down. Since we’ve been able to treat HIV/AIDS now – we found elite controllers, people who are walking around with HIV who never knew they had HIV, and the copy numbers are all low. Their immune system is fine, and they have no idea when they got it.
Question: A lot of patients say they had a flu, a weird flu-like condition, a week or two before they got CFS. What you’re saying is that flu-like illness is a bug that came along and allowed the XMRV to create CFS?
Dr. Mikovits: Well, no. I know almost nothing about CFS, but what we think is happening is – remember the slide where I showed you with those little events? You know, what was the event that was the straw that broke the camel’s back? Where did the balance tip between here you’ve got your immune system working well and the virus and the immune system are co-existing just fine, then some other, that other bug, whether it be Lyme, a flu, anything, gets you. Then the virus, the cells divide, and so do the B and T cells you need to mount an immune response. And now you’ve got your memory population that might have been harboring the virus, and it’s replicating because it’s seen that same pathogen before, so it could be a common everyday pathogen, and then you just tip the scale to where now your immune system can’t handle it. And every day you’re seeing more infection because your NK cells aren’t working, your B cells aren’t working.
We put that antibody up there for a reason. We haven’t been able to correlate the levels yet, because we haven’t been able to find high enough numbers. But we do see these infected families where infected spouses have very high levels of antibodies, that suggest maybe antibodies in this retrovirus can be protective, and maybe there’s an immune therapy on the horizon as well. So you can think about it in that way. It doesn’t have to be the insult. You might not know how long you harbored that virus.
Question: So what you’re saying is XMRV was there, it wasn’t the insult, then something else came along that was the tipping point?
Dr. Mikovits: Yes, that was the tipping point, that’s correct. That’s our hypothesis. And again, it’s testable, we don’t know.
Question: You’ve got a big population of patients with sudden onset and then you’ve got a big population that had gradual onset. And a lot of the gradual onset patients are worried that “Maybe I don’t fit this equation.” What would you say to that?
Dr. Mikovits: That little bump is smaller, so it’s not a huge burst. That it was little insults over time. I think, for me anyway, I know only a handful that I’ve looked at, that I know the patients, and I know what the onset was. But the gradual onset – there’s no real difference. It just depends on that environment, what the other triggers and events were that spurred it on. So, I don’t see, if you are gradual onset, it doesn’t mean that you might not be infected as well. Questioner: That’s an important thing to know.
Question: Have you tracked any of the inflammatory markers in the blood with the XMRV virus?
Dr. Mikovits: Yes.
Question: What are you finding?
Dr. Mikovits: We find a signature suggesting a viral infection, an unclear viral infection. We have 5-10 inflammatory cytokines and chemokines that will cluster in an infected person. The problem is we don’t know if it indicates active infection. Certainly, when the virus is quiet, that inflammation will go down, and those cytokines will change. And it might be a nice biomarker for following active infection, but we haven’t analyzed the data in that way yet. It very well could sit, and some of those go down and up very quickly. So, like in 3 days, your IL-8 and your IL-6 and some of the chemokines are elevated and then they go back, like an EEG. Just like you might assume the retrovirus could be an EEG, depending on where in the body that is. We don’t know the reservoirs, so we don’t know what’s controlling it.
Question: I’m confused about something. You say you can’t find it very easily by PCR, so you are culturing it. Then how did you find it for the Science paper?
Dr. Mikovits: Well, because I found it in 67%, by PCR, of the patients, but I looked at samples collected at several times. I just said it’s like an EEG. So I got lucky and I found it at a time when the patient was high. They’ll come to the doctor when they’re sick, which might mean they’re replicating more white blood cells, and there’s more virus in their white blood cells.
Question: So you took like 10 samples from one patient?
Dr. Mikovits: Not that many, usually it was 4. The copy number could be as low as 5 or 10 copies per mil of blood, so there’s a statistic called a Poisson distribution, where you might find it one out of three times, so we went more than one of that and went 4 on most people when we found it.
Question: So the UK paper had studied patients, if they had looked at 4 or 5 per patient, do you think they might have found it?
Dr. Mikovits: They might have certainly found more, yeah.
Question: They essentially accused you of contamination.
Dr. Mikovits: Right. But why would I have contamination in my sick people and not my healthy people? How would I do that? I did it in three different labs. I did it in Cleveland Clinic. When I first came to the Institute, we didn’t have a lab. So everything we drew from around the world, I sent to Frank’s office. They processed it. I went there, I put it in the microarray or did whatever I was going to do, and we worked there for a couple of weeks, you know, while we were building our lab and it got started.
From the way we did the study, there’s just NO possible way there was contamination. And that’s what the reviewers concluded. And the phylogenetic analysis was one of the things they asked for (they asked for 3 things after the initial submission). The phylogenetic analysis proved two things. It wasn’t a mouse virus, it’s a human virus; it wasn’t a contaminant from a lab. We never do mouse work, but it wasn’t a contaminant from mouse feces or something in the lab, and it clearly was a new branch in the [phylogenetic] tree, a human virus. And our virus wasn’t exactly the same as the prostate cancer virus. It’s still XMRV, because it’s 99% similar. But that’s enough to show it’s not a contaminant. One of the things you have to use to get a good PCR is at least 750 nanograms of DNA. They have no idea how much DNA was there. And they quantitated 3-9 out of 186? Sure they found a band of globins, but globins are in every single cell, so again you’re making an unfair comparison of what you’re saying you see. And then you amplify it for fewer cycles than what would really push the envelope.
We’ve also done – to show no mouse contamination with the CDC, and Bill Switzer – after he saw the results in the paper before it became published. He said, “I have an assay that’ll show it’s a mouse contamination. It’s a very sensitive, very specific PCR. Will you do it?” I said, “Sure, send it to me.” We did it on all 100 and not a one. Not one cell line in our lab. He’s found it in a couple in his lab, but we didn’t find any. Perfectly controlled. He said, “Congratulations, it’s not a mouse contaminant.” So there’s little else we can do, except wait for the rest of the community. It’s there. And the prostate cancer people didn’t say: “oh you didn’t find it in 500 people; it must not have anything to do with prostate cancer.” Because it just didn’t have anything to do with that population.
And again, Norbert Bannert is a high-quality scientist. As soon as he saw the paper, he called me and asked for the reagents. Because he’s gonna go back and look to see if it really is there, and help us find some answers. He’s also looking at a CFS group. So it just depends on what you really want to find. We weren’t biased in our study. You know, I’m a cancer cell biologist, and we aren’t biased. I had to work really hard to get most of the people – not Frank and company – the National Cancer Institute (NCI) didn’t know what CFS was. You know, fortunately, our scientists can to some level do what they want, as long as it’s along with the mission. I remember one gentleman, high level NCI official, said “tell ‘em to get over it.” Again that’s the credit to Annette and the formation of the WPI – we got a grant where we literally named XMRV within my first six months in 2007, because of the juxtaposition of seeing that paper in prostate cancer, right when we met.
And thinking about the possible mechanisms, and the grant got rejected three times, you know, because scientifically, retroviruses aren’t in CFS. If you went to Wikipedia in August, it said retroviruses aren’t in CFS. It doesn’t say that anymore. So we made progress. [Audience: Wow!]
So, will there be a variant? Maybe England is the variant. Maybe there’s XMRV2, and one causes more. Maybe we found the one that causes the least severe disease, and maybe there’s XMRV2. A group emailed me from China, and the guy said “please,” you know in very broken English, “please don’t leave me, please write me back. Please help me.” And so Sam Chow was going over there, and I said will you look up this group? And Sam Chow has found a virus that looks like it might not necessarily be the same virus, might be a lot more aggressive virus over there in disease, but that’s just anecdotal.
So, we don’t know. The good news is we have something to work with that is a very testable hypothesis. This has been very rigorous. You don’t get more rigorous than Science, and certainly not Frank and Sandy Ruscetti. They’re highly regarded. That entire team contains world experts. So, the CFS population had the opportunity to have them look at us, and they are good enough scientists that they didn’t show any bias. They looked, you know – I asked Frank to come out to Reno before I took the job, because I said, I hear a lot of things about this. So he came out and stayed a few days and talked to some patients and spent some time with them. And I was on an East Coast trip working with my drug company. I came back a few days later, and I said, “Well, what do I do?” And he said, “Take the damn job!”
So, if you’re really looking unbiased, and you look at this, it could be only 10 million people in America, it could be only endemic right here, it could be like Japan. And HTLV is pretty-well innocuous. 5% of people get ATL and 20% get that tropical spastic paraparesis or HTLV-1-associated myelopathy. I was glad when they changed that thing, by the way, because I can’t say that and I couldn’t spell it either! Those patients, they actually go on steroids to dampen the inflammation, the immune response, and they are fine for decades. But you know, in the Caribbean and in Japan, it was a health problem, so maybe we only have a health problem and the distribution is not – but we do have at least 10 million Americans, and maybe a majority of the CFS population here in America, that we have a lot of work, just to treat, and that will be the focus of the Institute in the coming years. Certainly, we will treat everybody else, but obviously we don’t see anyone else. Dan was funny, he was like “Well, Judy, I have to take care of everybody else” and I said “of course, there’s not anybody else!” So it’s an interesting and an exciting time for sure.
Question: I just wanted to say, you know, it is really exciting to hear you say we need to do this, we’re gonna do this. The virus you are studying, it’s our virus, and I think it is really important to note everyone that for you to do what you’re talking about, and for other researches to do it, we patients need to get behind funding the research in a way we’ve never done before, or it is not going to happen.
Dr. Mikovits: But have your government fund the research. HIV incidence in this country is about 800,000 people, I just quoted 10 million….. I shouldn’t say this, but when I saw it was a prostate cancer virus, I said “man, those men can’t possibly ignore this now!” [laughter]. I never said that publicly.
Question: Would you talk about what is coming up in the next years, what are the next steps, where are possibilities with your treatments, with the replication studies?
Dr. Mikovits: Yeah, all of those people I showed you internationally are working to replicate the study as is the Blood Working Group. We have been intensely working with them. We have another conference call on Monday, these things are happening. We will put probably 20% effort in our lab into that study. We are very serious about transmission studies in our lab and in the Institute, and we have one starting where we’re simply comparing infected people, people who we isolated from the blood, and just taking DNA in their saliva, for example, to see if there is any evidence in saliva or of that kind of transmission just again. That is just because of anecdotal stories, where people say, well, you know a bunch of kids on the playground with a water fountain, or at school. I don’t know what the anecdotes are, but just thinking about ruling those kinds of things out is a study we are doing.
We are also actively looking at the incidence in other neuro-immune diseases, so we are looking at that study I told you about. We are looking at cancer and CFS, we are looking at Fibromyalgia, Atypical MS. We’ve got a study going with Vanderbilt in POTS, which is Postural Tachycardia, because of the overlapping symptoms. He is simply just sending me a bunch of samples, both sera and DNA, and we are just going to take a look to see if we see it there. Autism – we do have families with some autism, and there are some immune defects characterized by Judy Van de Water at the Mind Institute in Sacramento, and she sees some NK cell dysfunction, some inflammation, some of the things I told you about there. So, in that group of autism, we are looking to see if maybe there is not an underlying pathogen or XMRV infection. Those are just the priorities, just in the coming year.
The NCI, the National Cancer Institute, has already put $1 million into the development of the reagents and the assays, so very soon the best of tests and all the reagents can be distributed. So, the AIDS reference program (there is an AIDS Reagent Reference Program that if you just google that you will find them) has agreed to set up for XMRV and send reagents around the world. We’re spending considerable time and resources just shipping…We are continuing the studies of the immune system, so I had an entire program set up from the beginning where we are looking at the genetics with Mary Carrington. We are looking at the type 1, so Vinny Lombardi will continue his studies. Just because that single nucleotide variant, we didn’t find having any correlation with XMRV infection, doesn’t mean there’s still not something wrong with RNase-L, and that might be a therapeutic target. So Vinny is actively studying research, the type 1 interferon pathway and RNase-L.
Isabel Barao-Silvestre is a faculty member that’s just joined us, she is a professor, and she is at UNR as well, and she is an expert in Natural Killer cells and killer cell function, so she is doing a lot of the innate immune response and understanding how XMRV infection in NK cells might contribute to disease. As I hypothesize, we don’t know how yet, so those are the internal programs going on. Because of my background I’m actively perusing all the drug development efforts in our laboratory by working with at least three companies right now, to look at that.
Those of you in the audience and around the world, if you email a question, we try to answer every one of them (email@example.com). One that came up which I think is good to address is, a lot of people wanted to know if XMRV somehow “piggybacked” on EBV or other pathogens to get into an affected individual, and I didn’t know what that term meant. It’s not a scientific term. But if it meant that you couldn’t get XMRV unless you had come in with another infection, there is just no evidence of that in any retrovirus. So, yes, people think that people got infected with HHV-8 and HIV at the same time because of the Africa thing. You can get infected with 2 pathogens at once, but there is no need for any to piggyback. You don’t need another pathogen in order to be infected with XMRV or any other retrovirus.
And any other question, if you have written them down, I am happy to answer them. Some people are like “I emailed you yesterday and you didn’t answer” and I say “oh, I slept yesterday.” If I don’t answer you within a week, then write me back because sometimes I miss it, and sometimes our emails are so full these days, that they are throwing things into spam. So, if you haven’t heard from me, you will usually hear from me within a week because I really do try and answer essentially every one that I get, which is probably foolish, but I like to actually, I like to work with the patients.
ProHealth Organizer: That was wonderful, thank you.
Note: This compilation was made possible by the collective efforts of many dedicated people on the Phoenix Rising (aboutmecfs.org) and ProHealth.com message boards, Whittemore Peterson and HHV-6 Foundation staffers, and audience members whose notes and recordings filled in where the interchange was hard to hear.