Transcription of Judy Mikovits Prohealth Lecture: Parts IV and V

January 31, 2010

Posted by Cort Johnson

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1063-DrJudyMikovits.jpgTranscribed by Sproogle

…the response elements that might give us a clue as to the pathogenesis and then Bob Silvermans lab showed the same thing. He showed that androgens stimulate transcription (the replication and division of the virus). So here’s a clue to the disease because we know the only two diseases so far that are associated with this retrovirus are prostate cancer (a hormone responsive disease) and CFS (one that’s thought to occur primarily in women).

Interestingly that I didn’t say that I knew is LNCaP is androgen responsive. So you can make it do a lot of good things and that’s why we use it in drug development for prostate cancer. So lets look at I showed you that organisation of the gag col and envelope of this simple retrovirus. This U3 region is highlighted because this is sort of the on/off switch of the virus. This turns it on to make more of the particle in your genome so this signals your cellular machinery to start making more virus and what Steve Goths lab showed (and he graciously gave me these slides about mid summer) was that there’s only three responsive elements that turn on this virus that he can find so far.

Two are called glucocorticoid response elements and their shown here. When a protein actually recognises that exact sequence and sits down it tells the virus to turn on replication. And so interestingly enough, what turns on the virus? Hormones. Progesterone, androgen receptor and testosterone and we don’t know all the other hormones. There are a lot of oestrogens and oestrogen like compounds even in our environment these days which might tell us maybe there’s an oestrogen compound that’s not a naturally occurring oestrogens in a plastic in the environment that is actually turning on the virus.

So we don’t know all of the things that turn it on at this point. And the other thing that turns it on is cortisol. So what is cortisol? It’s the stress hormone and so right there your turning on the replication so it’s an on/off switch for the virus with the stress response. When your told that you respond poorly to stress there might be a reason for that if your replicating a retrovirus! (laughs).

Sorry I shouldn’t laugh.

So then we went back into thinking about this virus, we thought about the clinical research findings that had occurred throughout laboratories around the world throughout the years. What it mentioned in part was we know that CFS is a multi system disorder (and in Spanish I say sequelae) but there’s lots of inflammation going on, you have allergies, multiple chemical sensitivities there’s a lot of inflammation and increased numbers of activated T cells and the production of these inflammatory molecules I mentioned known as cytokines and kinokines. Also a key dysfunction in the immune system of CFS patients is this low natural killer cell activity and sometimes numbers.

The natural killer cell has two jobs in the body, kill tumour cells and kill virus infected cells. In CFS it’s long been recognised (I think first identified by Nancy Klimas and her colleagues more than 20years ago) that natural killer cells in CFS patients don’t function normally although the dysfunctions not known, but that again gives us a clue to the pathogenesis. So this suggested to us that this chronic infection with a retrovirus (retroviruses are associated with immune deficiencies) might lead to the creation of actually immune deficiency that has patients succeptible to opportunistic infections and more likely to develop cancer.

So I’ve schematically drawn our hypothesis on the next slide and I basically just lifted the graph of what happens in HIV and changed it to what we know happens and changed it to all the data that we have so far. In HIV what happens is that there’s an early infection, the green line is actually the plasma viral load and it goes up in a spike. This might be a flu like syndrome or it might be nothing at all, you might never know that you were actively infected at this point and get sick. But then you have multiple other infections, stress hormone, advance inflammatory responses that cause these various spikes of the virus throughout a time course which we don’t know.

I’ve heard the incubation period of this virus is 21 days. We don’t know anything about the incubation of this virus we’ve just discovered it! So at any rate, all these events operate to set the viral load higher because every time you divide a cell, that your white blood cells, the cells in your immune system and actually our paper shows its the TB and NK cells are infected. Those cells are getting infected, more and more and more of them and some of them are long live memory cells that you need or they’re going to the tissue then and they’re infected and they’re spreading the virus to other cells and we don’t know where that tissue reservoir is and as I said the receptor theoretically is on every cell.

Not every cell can replicate the virus but virus can get into every cell. So it’s infecting more and more NK cells as the load keeps coming up and at this point something happens to your NK cells, this envelope antigen comes to very high levels like we see in our patients plasma and white blood cells and we know that that in animal models or in animal viruses of this family is actually a noctogene and a neurotoxin. So we hypothesise that the envelope alone is creating some of the neurological sequelae and that they’re different from the virus replicate. So it can be sort of the envelopes around a lot more, I showed you the defective particles we less infectious virus and more defective virus but those proteins can affect your body.

So we know you’re making antibodies but some of the sicker patients don’t make antibodies and CFS patients are known to have problems with antibody production for whatever reason, we’re not saying that’s direct to the virus but you know it’s not a great leap of faith because that’s what we saw in the early eighties with AIDS patients we had no idea how long those men had the virus.

All of a sudden there were getting Pneumocystis and Kaposi’s Sarcoma (a form of cancer that only occurs in older men in Italy) and that’s because as you age your immune system loses effectiveness too. So all of a sudden we’re seeing a virus that is not endemic in the United States, well actually from these patients they actually indentified HHV8 (Human Herpes Virus 8) which actually is causative for Kaposi’s Sarcoma and that virus, I led a drug development program about a decade ago just before I came to California and we were going to make drugs to target AIDS associated malignancies and we found as soon as we got the highly active anti-retroviral therapy and got rid of the HIV and silenced that the Kaposi’s Sarcoma went away as did the HHV8 so they cut the budget for that drug program and rightfully because there’s no need to develop these drugs because they learned that at that point all you have to do is control the retrovirus, get the immune system back to functioning, and also the good news is most of those men their immune systems are functioning well. You can get a lot of them back to at least a level of health even though they have to stay on various drugs the rest of their lives at least they could cure the immune deficiency.

So in summary then of the science part of the talk:

XMRV is the first simple human infectious retrovirus. It’s a gamma retrovirus it’s not complex so it’s the first one known in this family and we know nothing about the pathogenic potential other than the two diseases that we’ve seen it in. We know that human retroviruses are not ubiquitous I’ve shown you the distribution can be quite low in various places in the world. We don’t know how it spreads across continents.

They’re not benign, meaning they cause disease. All three known human retroviruses are associated with the neurological diseases and cancer. And importantly they are not airborne, retroviruses are not contagious you don’t get them in the air. We know that for instance with AIDS patients that it’s not a problem to kiss AIDS patient and hug AIDS patients and so that knowledge is there for this virus as well. So there’s three known now, the complex and now the simple and I’ve mentioned that a number of times.

Interestingly and something we should think about in light of the replication studies and the other studies as we’re going on, I say HIV and HTLV but I’ve been saying one but there are variants of HIV there’s a HIV2 that is less pathogenic, there’s a HTLV2 that is less pathogenic in fact hardly pathogenic at all. And these are clearly different and have different pathogenic profiles and just a short extension of that suggests that there could be variants of XMRV there could be subtly different sequences of viruses out there that are associated now with different phenotypes, so the way the disease looks, and different cancers or different neurological diseases.

So I know that the scientific community is actively looking for variants so that’s another good news about these studies is that there are a lot of exited retro virologists and immunologists who started as soon as these learned this in July to the put the world resources and the best minds on this virus associated with CFS and that’s probably the first time that’s happened in the world so they’re excited about that.

So a lot of the questions that I got, and I wrote this talk around the question that I got, had to do with reasons to be tested. You know we don’t have the best diagnostic test yet because we still haven’t validated that serology test. That serology test is done in a labratory it’s very cumbersome we need to validate it clinically in order to look for antibodies in the population against this virus and that is the number one test when you go look for HGLV. But that said there are opportunities to get tested and you might have your own reasons to get tested. Now generally a physician won’t test because there are no treatment options. There are no known anti retrovirals currently that are known to be good for XMRV so why go get a test for it if you can’t treat it?

But it can give you additional validation that your illness is an organic illness and that can have a huge psychological boost because you can begin then to think about immune support and things you might do and changes in your life style where you may be able to support your immune system in the meantime while we develop drugs. And importantly you want to protect your personal family and public health, we need to know where this virus is. And it does help, physicians then start to see, physicians like Dr Peterson will know how that might relate to your other infections your other immune issues if you have cytokine profiles some of the tests he does. It might help him or some of the other physicians with your therapy to know that this is a player in the game now.

And again it underscores the more people that are infected, that 3.75% is 10 million Americans, so that I didn’t have to say anything the drug companies called me the next day and said “Gee we’d like to help!” and so we’re actively working with them and they are helping because there’s another piece of good news which is that there are drugs that were on the shelf that were developed all the way through phase 2 clinical trials so they were shown to be safe in people but they just didn’t work as well against HIV as the drugs that were out there so why spend a lot of money developing them? So there are real targets that you can go after that can serve regions between these viruses right now and maybe come up within the next year with a drug and a clinical trial for that drug that would go along way toward treatment.

So right now we recommend to prevent the spread of XMRV, if you have CFS and you wanted to be as prudent even if you didn’t get tested say “Okay I might be infected”. So what would we recommend? The HIV precautions because it’s a retrovirus we know it’s spread we found it in blood in the body fluid secretion prosthetic secretions so you just want to assume that these precautions that are very stringent, and have prevented the spread of HIV in some countries, that if you don’t donate blood or sperm (this virus can infect sperm cells) so if you have CFS or maybe a history of aggressive prostate cancer in your family you might think about not being a blood donor.

Follow the HIV precautions. Don’t share toothbrushes because you can have bleeding gums or razors. Use safe sexual techniques and I say here do not breastfeed. It’s don’t breastfeed after six weeks when the maternal antibodies go away. When they did that in Japan where ATL (that aggressive leukemia) was rising in the late seventies and early eighties, all they did was say “Okay no breast feeding!” and 40% reduction of ATL rates in Japan. So prevent the spread of this virus and you can reduce the disease and protect your family and your children.

Part V Transcribed by Garcia

So 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 but) 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 & 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, we use incidence with disease, and prevalence of XMRV in the blood supply. Our numbers were small they were only 2 or 3 hundred that’s 4%. And so, 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 PBMC’s. 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 approval and ready to start so 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.

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.

So how does XMRV enter the human population? Is it a zoonotic [from animals] transmission? We know its 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 & HTLV1 both by causing immune deficiencies do.

So 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, but Ellie Barnes in MRC in Oxford. Norbert Bannert on that German paper, he was working with a 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.

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 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.

So what about Diagnostic Tests? I said 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 positivities in the cultured and co-cultured cells. And we use 20mls 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 1ml of whole blood and there price is here [$375]. You won’t find this virus in 1ml 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 their 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 cheque and of course they won’t find anything.

Your help is critical really to advance this science. At the WPI we either want your money or your blood. That’s the only two choices! You decide what you’d rather do. But we need you to participate in these research studies and we do have a form online: www.wpinstitute.org and you can email me. We’ve got a form online to register.

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 programmes that will be established later this year. The clinical programmes will really come of 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.

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 [Sliverman] because obviously we were doing the work with him and then I called Frank [Roscetti] and said you know “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! Whee!” and he said “Not any more of your schemes Judy! I’m not going to do that again!”

So 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.

So 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, Dan Bertolette did everyone of those beautiful Western’s that I showed you, just a magician. Mike Dean & 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 & 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 then just 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 and we have our lab meetings at the bar. They said they were going to make a drinking game based on my talks, I’m not sure if it’s how many times I said “umm” or whatever! So at any rate, with that I’ll thank you for your attention and take questions.

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