RESEARCH

Dr. Klimas's Lecture on XMRV Presented By PANDORA and ME/CFSCommunity (Nov 2009) 

Congratulations to PANDORA for sponsoring Dr. Klimas' scintillating lecture and Dan Moricoli and the CFSKnowledgeCenter for editing it and getting the video's onsite

(Check out the Original Video's Here)

(Transcriptions were all made by chronic fatigue syndrome (ME/CFS) patients from the Phoenix Rising Forums and may not accurately reflect Dr. Klimas' Lecture.)

 Section I: Intro and Background

Thank You. So what brings us here today is this new discovery that you all might have seen in the paper. (skips) Erm, let's. Can you just dim the lights down so that people can see that slide OK. That's great, super. So let's just go ahead and get stared. I'm starting with a little background stuff.

There's three parts to my talk, OK.

• Part 1, a little background for those of you who that are sort of new to the world and don't realise all the work that's been going on.
• Part 2, all about this virus and it's implications. Most of my talk's about that.
• Part 3, is plenty of time for questions and answers, so there's going to be a lot of informal time.

That's usually the best anyway, so if I get too long winded, you all can just tell me to stop. (laughs) I do get excited.

Some of you might recognise this. (Image of four faces shown, with text above: “CFS/ME and Viruses Chronic Fatigue Syndrome”). This is the CFS faces project from the CFIDS Association, the CAA. It's a really neat thing they have that goes around the country and shows up in shopping malls. But the point of the faces project is that it's an invisible illness. The people that have this illness look fine, but they are not fine.

And it's a very important message, because Chronic Fatigue Syndrome's a very debilitating condition. And there's been research that looked at how severely ill people are with Chronic Fatigue Syndrome. And it was the same, or worse than, congestive heart failure. The same, or worse than, very late stage AIDS. It's very impressive how very ill people are.

It's been a hard illness to understand, because we had to diagnose it by symptoms only, OK. But the symptoms are pretty impressive, and some things are special, to really help make the diagnosis. One is the profound nature of the fatigue. It's not that 'Oh I'm tired fatigue', it's the profoundly debilitating fatigue that prevents you from being able to do the normal things that people try do in their lives. And they defined that by saying, you cannot do at least one aspect of your life well. If you're working, that's more or less all you're doing, you're not taking care of your family. If you're trying to take care of your family, you probably aren't having any real social or recreational time, or work for that matter. So it takes away the very big, and crucial ways that we define ourselves as people, and how we value our contribution.

But it's also defined by pain and inflammation. Muscle pain, joint pain, sore throat, tender lymph nodes, headaches, non-restorative sleep and most importantly, concentration and cognitive problems that can interfere with your ability to be as quick as you would like to be.

Slide: Definition - CFS 6 months of  debilitating fatigue unexplained by preexisting illness or psychiatric co morbidity and at least 4 of eight symptoms:

...how severely ill people are with Chronic Fatigue Syndrome. And it was the same, or worse than, congestive heart failure. The same, or worse than, very late stage AIDS. It's very impressive how very ill people are

• post exertional relapse
• concentration and cognitive complaints
• myalgia
• arthralgia
• sore throat
• painful lymph nodes


• new headaches
• unrefreshing sleep

Theres also a clinical case definition. That was a research case definition. The clinical case definition was more of a teaching thing, to try to teach doctors who use this that there is something underneath all of that.  That those are autonomic symptoms. That those are immune symptoms. That those are neuro-endocrine symptoms. Then they cluster those symptoms around the type of underlying system that's acting badly to cause those symptoms. This was a clinical case definition made by an international group in Canada, and I was a member of that group. I wasn't a member of that first group. I didn't name this disease. No one blame me. I was not there. I was not invited.

Slide shown during previous section: CFS/ME Clinical Case Definition

• 1 Substantial reduction in activity level due to new onset, persistent fatigue
• 2 Post exertional malaise
• 3 Sleep dysfunction
• 4 Pain - myalgia, headaches
• 5 Neurologic/Cognitive Manifestations
• 6 At least one symptom from 2 of the following: Autonomic manifestations eg. OI, IBS Neuroendocrine manifestations eg. temperature intolerance, weight change Immune manifestations eg. tender lymph nodes, sore throat, flu-like symptoms Link to full report www.iacfs.net

There are overlapping conditions.  About 60% of the people with Chronic Fatigue Syndrome also have Fibromyalgia. Fibromyalgia is a painful condition, and that's what it is, it's a painful condition. It's defined by pain. You poke people in eleven different places, sorry, eighteen different places  and if a lot of them, or more hurt, then they may meet the case definition.

Slide Other overlapping conditions

Fibromyalgia Gulf War Syndrome (VA CSP 16 fold increased risk of CFS in Gulf War veterans) Eisen et al Ann Int (?) Med 2005 7.142(11)??1 Multiple Chemical Sensitivity (plus image of 'Classic 18 Tender Points')>

But underneath that is a very complicated cause.  There's a pain ramp up that happens in the spinal cord and brain, sending more and more and more pain signals up to the pain centre, and even very light, non painful touch can be very, very painful. Even.. you've heard people say, even my skin hurts.

Slide: Fibromyalgia Based on the 1990 ACR classification guidelines:

Historical feature = widespread (axial) pain of 3 months or more Physical finding = pain in at least 3 of the 4 body segments + a finding of at least 11 tender points on digital palpation of 18 designated tender points No exclusion criteria (??? et al, 1994; Portenoy et al, 1996; Wall et al, 1994; Wolk (?) M, 2002) (plus image of 'Classic 18 Tender Points')

the attitudes of doctors who don't even recognise the illness is real. And it works out about 50/50. And the doctors that do, generally have a family member who's ill.

Gulf War Illness is something near and dear to my heart, and I knowGulf War Illness is something near and dear to my heart, and I know Mac (? Matt?) cause we both do research in this area. We have some Gulf War guys in the audience here. Gulf War Illness can also meet the case definition for Chronic Fatigue Syndrome. They overlap, and much of our research in Miami is trying to decide if they are the same or not. And if they are, you know, if the treatments might be the same. That's one of the main focuses we have, and we have some really cool studies going on. And I want the Gulf War guys to know, that I shipped off those boxes to the Whittemore Peterson Institute yesterday, so anyone who's in my Gulf War study, is having their XMRV serology and blood testing done very shortly. So I'll be getting back to you as soon as they tell me. So we'll know if it's truly overlapping in the same ways. And then Multiple Chemical Sensitivity is an even more poorly understood, difficult illness, to have, and a difficult illness to diagnose.

& One of the issues with Chronic Fatigue Syndrome all along has been the attitude of physicians. And there have been a number of studies done. Lenny Jason did one that looked at the attitudes of doctors who don't even recognise the illness is real. And it works out about 50/50. And the doctors that do, generally have a family member who's ill. Generally speaking their connection's not their speciality or their training or anything else, it's that they're linked personally to a person with the illness.


Slide  

• Attitudes of Physicians li>Of 811 GP's 44% did not feel confident making the diagnosis, 41% did not feel confident treating
• More likely to have confidence if they had a friend or family member with CFS, having more patients with CFS.
• Concludes that education emphasising acceptance of CFS as a real entity results in improved confidence in treatment

So, what about viruses? We found most of the work that's been done on Chronic Fatigue Syndrome has been on mental illness, and depression, and atypical depression. And the patients have gotten a bad rap.

part of the reason that there's so much psychology work done is that this is a very interesting illness from the psychologist's point of view. As is any really serious chronic illness. Patients with HIV have a huge mental health literature.

And I'm gonna say this in sort of in a funny way. This is my own personal opinion, that part of the reason that there's so much psychology work done is that this is a very interesting illness from the psychologist's point of view. As is any really serious chronic illness. Patients with HIV have a huge mental health literature. Patients with renal disease, or renal failure, have a huge mental health literature. Because one thing you can really do for people with a chronic disease, is try to help them live with it, cope with it better, and try to have the best quality of life that is reasonable. And so, most of that mental health literature is actually focused on that. All that Cognitive Behavioural Therapy work and so on is focused on that.

II think where Chronic Fatigue patients got really angry, and I totally understand, is when some researchers went off on the tangent that this is some atypical form of some primary mental condition. And I think we disproved that in 1993 or 4. I mean it was a long, long time ago that all those endocrine studies came out that showed that basically the illness goes in the opposite direction from all the neuro-endocrine point of view, than depression or that sort of thing. But still, there's been this cloud lying over folks with this illness because we never came up with a very clear understanding of what the primary cause might be. And much of the excitement about this virus, is that it is itself a candidate for being a primary cause. So it's a very exciting time.

Slide:  Viruses and CFS/ME

Much of the research here and internationally has examined the role of the immune system and possible chronic infection in CFS. It found:

• The viruses studied all have several things in common:
• they infect cells of the immune system and the neurologic system;
• they are capable of causing latent infections;
• they can reactivate under certain conditions

((Thanks to 'Blackbird" for transcribing this)

Check out the original Video on the CFSKnowledgeCenter

Section 2: Viruses & CFS/ME; WPI & XMRV

The other half of the medical literature was looking at pathophysiology, just what's wrong. And this group in Miami has from the very first day, actually the very first group, to look at the immune system as a major mediator of the cause of this illness. In 1989 we wrote a paper from our first series of patients that show that the chronic fatigue patients had immune activation and poor antiviral cell function. We wrote that paper in the Journal of Clinical Microbiology back at the beginning, very early on, and a couple papers right after by Jay Levy's group that say the same thing, and that’s what launched us in this field.

Epstein-Barr Virus - So we've been focused on viruses from the very first day. So what do we know. The very first day we looked at Epstein-Barr virus and other herpes family viruses. Epstein-Barr and Cytomegalovirus were the first viruses that were looked at. Dr. Levy's paper and my own and others said, what we saw in all these virus serologies we looked at, when we looked at the antibodies, was EBV is there, we can't say it's not. There's all kinds of other serology for other things that didn't pan out. But Epstein-Barr over the years, time after time, there's been at least a subgroup of patients that looked to have a higher level of Epstein-Barr virus than they should have. CMV a little less so. 

The First Retrovirus - In the 1990s two things happened. First, Elaine DeFreitas and Mike Holmes from New Zealand both published papers at about the same time, 1991-92, saying that they saw a retrovirus in chronic fatigue syndrome. And Dr. Holmes paper had all these beautiful scanning electron micrographs of little budding viruses coming off of white blood cells that looked for all the world like a retrovirus. And Elaine DeFreitas who was at the Wistar Institute at the time published a paper that said she had fairly good evidence that there was a retrovirus.

Instead of trying to pick off one virus at a time, should we maybe be backing up and saying can we fix the immune system... and prevent these common viruses from reactivating?

What happened next was a little complicated, partly from our point of view--we recruited Elaine down at the University of Miami and she joined our faculty, but unfortunately she became very ill very shortly after and left. So we never got to pursue her work which is a shame. I’m sure she’s feeling very good right now about this new work.

The other thing that happened was that the Centers for Disease Control published a paper and presented at a number of conferences that they failed to find that retrovirus. And it was a shame because that was how it was left. There was this positive finding from two different groups, one group saying absolutely not, and then nothing much went further from there. So we lost unfortunately that time from then to now. I’ll have to say, though, we didn’t know this virus hadn’t been identified yet. I don’t think it would have been a rapid thing there, but certainly we would have been further along than we were now.

HHV-6  - HHV-6 was the second big thing that happened in the middle of the 90s. This other new virus was discovered, human herpes virus type 6, the virus that also causes the three day measles, another childhood virus—another herpes family virus. And it turned out to be reactivated in a whole lot more people than the Epstein-Barr virus.

So this was the first virus that got a lot of credibility as really being there by all the groups that were looking. And there was some excellent work, Dharam Ablashi who was the discoverer of the virus, discovered the virus, Connie Knox, and a private foundation, the HHV-6 foundation, that did some excellent fundraising and really did some pointed research to drive this home and push that along to the point where clinical trials had been going on to try to suppress this virus, with some efficacy. So that was very exciting.

Enteroviruses - So then we enter this decade and we’ve got enteroviruses. That’s Dr. Chia’s work, where he did a lot of gastric biopsies and he found coxsackie virus, which is a whole different family of viruses also very common reactivated, and he found it in the gut wall with a gastroenterologist who was biopsying stomach. And they found virus.

So it made us stop and think, well wait a minute, if the immune system is broken enough that more than one kind of virus is getting out, how are we going to focus our work so that we’re covering this immune system problem? Instead of trying to pick off one virus at a time, should we maybe be backing up and saying can we fix the immune system that’s broken and prevent these common viruses from reactivating?

..the reason why this paper is so important is that this virus is a really good explanation for why the immune system is broken, unlike the others. And .. also... because this virus is not common.

XMRV - And then finally we come to this definite landmark paper of October 8th in Science by the Whittemore Peterson’s group with Judy Mikovits and Vince Lombardi. It is a very important paper, and the reason why this paper is so important is that this virus is a really good explanation for why the immune system is broken, unlike the others. This one would explain why the immune system is broken. And it is also a really important paper because this virus is not common. There are very few people that have this virus, and yet most chronic fatigue patients in their study did have this virus, and so it’s a candidate virus for causation. And that’s, I think, why everyone’s so darn excited.

I put up this slide because this is going to be video'd and someone is going to read this who’s not here, and I want people to know when I’m using someone else’s slides. I borrowed these slides from Dan Peterson and the Whittemore Peterson foundation. These are the people that work him on this, and even though I wasn’t part of this particular group, I feel like I’m a member of their family because I spent a lot of time in Reno when they were first setting up, and I really admire these people. They’re really very talented.

So there at the Whittemore Peterson Insitute...even though Annette Whittemore’s name is not on this slide, it should be right up there on the top. Annette Whittemore is the reason why the Whittemore Peterson Insitute came to be. Harvey and Annette are these lovely people who know how to get something done. Their daughter is very ill, and they realized that they were getting the best possible care because Dan Peterson was their doctor. And they said how sad it is for people who don’t have access to such talented doctors. So they established this, the WPI, Whittemore Peterson Institute. 

And then in a very targeted way and a very brilliant way, they said this is the kind of research we want to do what we want to focus on, and they made a team that could do that. They were absolutely virus hunters, they were looking for viruses, and they put a team together to find viruses. And they got an excellent team put together, and by gosh, two years into this work and they have scooped us off. Good job. So they did a fine job.

And they did that with their colleagues at the NCI, Frank Ruscetti, who’s a very famous virus hunter in oncology, is one of their senior partners and that whole team there, and then Bob Silverman at the Cleveland Clinic with Dr. Gupta. These are two people, Dr. Silverman’s one of the discoverers of XMRV several years ago and he was a member of the team that went after it. So it’s very impressive work.

(Thanks to 'CFS Since 1998' and 'Koan'  for transcribing this)

Section Three: XMRV, NK and T Cells, Latent and Retroviruses

So what is this virus X-M-R-V? Well, the RV means retrovirus. So that puts it in a family of viruses, retroviruses, that we actually know quite a bit about. And the X is xenotropic. M was mouse. This virus started in a mouse. Now there’s…ya know viruses start somewhere. They’ve got to start somewhere. Like the HIV virus started in a monkey. It’s a monkey virus that eventually evolved several hundred years ago into a virus that could infect humans. So we got this lousy virus, HIV. 

XMRV is in its own evolution. And it jumped from mouse to human at some point. We don’t know when, but probably not in the too terribly distant past. Well, that doesn’t mean a lot, because in Darwin terms, distant past could be 100 million years, but these guys think like that, the evolutionary biologists. That wasn’t long ago, a thousand years ago or so. But in this mouse virus, it could have been in the last century. That’s the sense of it. 

About 3-4% of people have this virus and they’re not sick. And that’s another part of this. So there’s this background population. Now, I’m just saying that flat out, but you know I gotta tell you that the research on this virus is only 2 years old. And so, we don’t know very much about it. And there’s probably regional differences. There might even be continental differences. We don’t know. There’s been nothing done anywhere else. They did some studies – originally this virus was found in prostate cancer. So most of the work was done in that area and there’s two studies: one in Germany and one in Ireland that failed to find this virus in their patients. Now, whether they’re using the same technique or it’s not in Germany, it’s not in Ireland, we don’t know. So, there’s a lot of questions still to be answered with this virus. 

And for those of you who aren’t in the land of science, Science is like the Mecca of publication. If you get your stuff in Science, that’s the best place you could possibly put them.

The Science Paper - This Science paper was amazing for a number of reasons. First, this team had put together such strong science that they could go for a Science paper. And for those of you who aren’t in the land of science, Science is like the Mecca of publication. If you get your stuff in Science, that’s the best place you could possibly put them. And they don’t take just anything and they sure, sure, sure don’t take something unless it’s extremely well done, validated and tested out. So they took this paper. And if you read this paper, they not only took it, they put it in Science Express. They thought it was so important, they published it on a very fast track. And so, that was important. 

And if you read the paper, you’ll see they found this virus the first way they looked. They backed up and looked from a whole different angle. Still found it. Backed up and looked from another angle. Still found it. Then, in two other ways, they had five different kinds of ways they looked for this virus. And they were able to find the virus. So I think that’s why Science was so impressed. They also used a very big population. They had 100 Chronic Fatigue patients – 101. And they had more than 200 controls. So that’s usually…scientists like that kind of stuff. 

And then, the interesting thing was in this paper, the first 20 patients they studied were Chronic Fatigue patients that had developed some kind of Cancer. That’s actually how they got the Cancer guys’ attention, I’m assuming. Because Dr. Peterson’s got 30 years of stuff in his freezer and dug out everybody in his whole population that had ever gone on to develop Leukemia or Lymphoma or any other kind of Cancer. They pulled those out first and that’s actually where they first found it and that’s what got their interest up. And then they went back and looked at a bunch of others. The way they looked is very sophisticated and they found 67% that way. And then they tried to find it in all these other ways, when they added everything together, they could find the virus in roughly 95% of the patients using one technique or another, but not necessarily consistently, no matter what technique they used. But it means that there’s at least 67% of people in that Reno cohort and possibly quite a bit more.

they found this virus the first way they looked. They backed up and looked from a whole different angle. Still found it. Backed up and looked from another angle. Still found it..they had five different kinds of ways they looked for this virus. And they were able to find the virus....that’s why Science was so impressed.

A Mouse Virus    - So, what is this virus? It’s a mouse virus. It was first discovered in 2005. It was discovered by prostate cancer researchers looking for a virus, viral causes of Cancer. So they found it in that study in 40% of prostate cancer. Another group looked and found it in 23%. And so there have been two studies that said: the virus is in prostate cancer. Other groups though, have not found it - in Germany or Ireland – so it’s still considered somewhat controversial.

It’s a different strain than the one seen in prostate cancer. It’s not exactly the same. Okay? I’ve already had patients whose husbands had prostate cancer thinking that they somehow infected their husband. Oh my God, I gave my husband prostate cancer. Don’t think that way, okay? It’s a different strain of the virus. They’re related, they’re closely related. But we don’t know enough to even pretend to go that far with assumptions. 

It’s a virus that doesn’t have a lot of mutations. And what that means to the virology world is that it doesn’t change very much, it’s not shifting around, there’s not a whole bunch of different kinds of it. Like there is with HIV, where within a few weeks of applying an antiviral, the HIV virus can mutate away and escape and go off and do its own thing. So this is a pretty stable virus. That bodes well, particularly for vaccine work. That bodes extremely well. We don’t know what that means to the antivirals yet. It just depends on how much replication is going on. 

I’ve already had patients whose husbands had prostate cancer thinking that they somehow infected their husband....Don’t think that way, okay? It’s a different strain of the virus.

ME/CFS - Why does it fit into Chronic Fatigue? Well, there’s a lot of good reasons why it fits in to Chronic Fatigue. Those of you who live and breathe this stuff might have heard me talk about natural killer cells a little bit. ((laughs)) NKs are really broken in Chronic Fatigue Syndrome and natural killer cells are part of your defense that prevents latent viruses from reactivating. And they really, really don’t work well in Chronic Fatigue Syndrome. And our group has done 20 years of work to try and figure out why – and we know why. And we also extend that to say: these natural killer cells that don’t work are closely related to a different cell, cytotoxic T-cells. And they don’t work either and between the two of them, that is your antiviral, latent viral reactivation system. Both of the systems are broken. 

So, enter a virus that infects and affects natural killer cell function and that’s this one. And infects and affects T-cells, cytotoxic T-cells. That’s this one. So we’re kind of keen, we don’t know for sure, I mean this so early in the work, we’ve gone all of three weeks since that paper came out. There’s going to be a lot of work to be done. But it would make a lot of sense, a good hypothesis to construct if this virus is in there mucking up cell function, and that would make a lot of sense to what’s going on. 

It also is a virus that can infect tissues that aren’t white blood cells. And we’ve always thought: something like that has to go on in Chronic Fatigue Syndrome because you all have some neuro-inflammation. Your brain has a low grade level of inflammation. And you have some inflammation in the tissues that make hormones, particularly the hypothalamic-pituitary axis. And this is a virus that has some tropism or infects that type of tissue. So it starts to make the whole picture come together. Now we don’t know enough about this virus’s tropism or what stuff it likes to infect. This is just sort of the first look and some of this may change as we get more sophisticated and look with better ways. But the sense is this virus, if it’s acting like its cousin virus HIV that likes to infect those kinds of tissues, that it’s going to have receptors that let it into other places too. Anyway, I think it fits well and I’m very excited about that fit.

(Thanks to Kim for the transcribing this)

Check out the original video on CFSKnowledgeCenter

Section 4: Retroviruses and A Biomarker

Latent and Active Infections  - When we talk about latent viruses, this is what we’re talking about. The guy on the top is a quiet little white blood cell hanging out doing nothing because no one has asked him, it doesn’t have a job yet. If it becomes activated, it’s because something floated into the system, some antigen, some bug that it’s supposed to respond to. And in our systems we have hundreds of millions of these little quiet cells and each individual cell only knows its one little job. 

Now this one’s for Epstein Barr, that one’s for Staph, and that one is for some other bug. If that bug comes into the system, then that cell is the one that gets activated. And if it had hidden inside it, in its DNA like over there, if it has inside it this little piece of virus fragment, sitting in that DNA, that cell is turned on to make all of its stuff it knows how to make. It got activated. It’s going to make cytokines, it’s going to make interleukin 2, it’s going to make ?? , oh and by the way, it’s going to make that sneaky little virus that was tucked into its DNA too. And that’s what happens. 

Retroviruses are funny because we’re just chock full of them. We have little bits and pieces of retrovirus all in our DNA.

These latent infections just sit around doing nothing until that cell is activated and then boom, they start making virus stuff. Retroviruses are funny because we’re just chock full of them. We have little bits and pieces of retrovirus all in our DNA. Talk about evolution, our great, great, great, great, great, great, great grandfathers got infected with some little piece of something, maybe a chunk from a mouse back then. But it’s not a whole virus. They have just little bits and pieces, of busted up pieces of retrovirus tucked in the DNA. We think it’s an important part of the way that we evolved. That we borrow DNA from other species this way and we transfer things around. If viruses carried little pieces of information into the genome back then. And some of it was bad and that didn’t work out. And some of it was good and it carried on or it was neutral and it carried on. 

Generational Transmission?  - But there are some retroviruses that can be carried generation to generation as a whole and complete virus tucked into that DNA or rather enough DNA to make a whole and complete virus when it’s turned on. And this is one of those retroviruses. It can be transferred generation to generation or what’s called vertical transmission, mother or father to child through the DNA. So we don’t know if there’s 3 or 4% of background. There’s just people who have vertical transmission or if there’s some way that you can infect people back and forth in life. We don’t know that at all, okay? 

But we do know that this virus is one of the ones that is vertically transmitted. We know that from the mouse data. So it can be transmitted vertically. So the question is if you have children, do your children necessarily have it? And the answer is maybe yes or maybe not. First off,

We don’t know if it’s sexually transmitted....We know HIV is, obviously, is a sexually transmitted retrovirus. But, there’s no…you’d think in 25 years, we would have seen massive numbers of spousal pairs. And we have not.

there’s two parents not one. And each only give half of the DNA, yeah, right? So in any given child, there’s only one chance in four that you can pass on any particular piece of DNA on a good day. So you don’t worry too much about kids flat out that way. And then you say: And oh, by the way in their life, they have to come across the thing that activates the virus and turns this whole mess on. And so there’s a whole lot of reasons not to get all worried about…I mean I’m not saying it couldn’t happen to your children…Of course it’s conceivable. But what’s exciting right now is we’re getting this, we’re getting the understanding of it, and we’ll probably, knock on wood, that we will be to the position where we’re actually intervening effectively before it becomes a bigger worry. But, um, I don’t know about kids. I’m saying it is a vertically transmitted virus. 

Sexual Transmission?  - We don’t know if it’s sexually transmitted. I will say that there are sexually transmitted retroviruses. We know HIV is, obviously, is a sexually transmitted retrovirus. But, there’s no…you’d think in 25 years, we would have seen massive numbers of spousal pairs. And we have not. You occasionally do, occasionally we do see a spousal pair. It happens. But almost always those people both had acute infection at the same time at the onset and it’s really unclear if it was transmission between the two of them or if they had some other thing happen that kicked off the whole, the whole thing. And you see household Chronic Fatigue. I mean I do see mother-daughter, father-daughter, father-son, whatever…I’ve seen it. But, in my clinical practice in the 25 years or so, it’s not very common. It doesn’t happen a lot. 

So, the next slide. This virus is not HIV. A lot of people panicked when they heard this. This virus really is not HIV. It’s in the same family, but it’s a distant, distant cousin…very very distant. And it’s not infecting or affecting the same cells. So, it’s not doing the same immunologic thing that HIV does. Okay? 

it’s pretty impressive that out of 101 CFS defined by clinical case definition or a research case definition that they found 99 with virus. And if this is the case, that’s pretty exciting. It’s pretty impressive. And, oh, by the way, we have a biomarker. Not a small deal.

There are also other retroviruses that don’t do anything that we know about. There’s a virus called HTLV-2 that I have studied myself in the past, and many others have, and it’s just sitting around doing nothing. It’s really…it’s vertically transmitted, it even replicates, and it doesn’t cause much in the way of illness. So, that doesn’t necessarily mean that just because you find a retrovirus, it’s definitely the deal. And not every retrovirus is big and bad and ugly. There’s another virus called HTLV-1 that’s vertically transmitted and does cause an illness. And it causes a neurologic illness. And so, we have different bugs, different things. 

HIV is a retrovirus and there’s at least 20 or more drugs directed at HIV. So, will those drugs work to control this virus? That is definitely the big question of the day. And the first thing to say is: some of them probably will. And the second thing to say is, but not all of them…you couldn’t just pick a random one and try it. 

This one’s to show you mouse going to people…that basically it started out way up there as a mouse thing. Mice learned to live with it. They don’t have a receptor that allows this virus to become a big bad deal. So, mice just sit around for generations and generations of mice being a reservoir of virus, but not actually getting sick from the virus. But then the virus shifted and it became capable of jumping from species to human.

Almost All Positives - One Way or the Other - So, this was the study. They had in their freezers samples from people that weren’t from their cohort. So, these were not just Reno samples. There were samples from Florida, from California, from North Carolina, and other places. Everyone in their repository had a Chronic Fatigue diagnosis. The mean age was 55. There was two thirds women. They had this large control sample. They looked…and they looked at these patients, out of 101 patients, and they looked at the DNA, the sequences of the virus in the DNA. It’s really a sophisticated way to look and they found it in 67% and in 3.75% of the 320 controls. 

Now of the negative, these 33 negatives, they went on and looked in other ways. And they found 19 of those had antibody in their plasma, so that was more than half of those negatives. But this is the big number: 30 of the negatives had virus they could identify by taking the serum of those cells, the serum from the plasma, and infecting a cell line and then growing the virus in that cell line. So they could transfer from the plasma, virus to the cell line. Now that has a lot of implications and it’s certainly the reason why, in part, the CDC, the NIH, and others that really care about the blood industry are looking long and hard at this. They found the virus, a transmissible virus, in the plasma and they were able to infect cell lines. So it is suggestive of an infective component, at least in the blood. And then there were other ways, so they worked out that they were able to find 99 of the 101 patients in that way. 

Now think about that for a minute. We define an illness by a bunch of symptoms. Now, I’ll say Dr. Peterson is a really fine doctor, and I’m quite certain that he’s not misdiagnosing Chronic Fatigue Syndrome. He’s really splendid. So, it could be that he has a really clean, tight population of folks in his freezer. But I would say, I think I’m pretty damn good, and I think if I pulled out stuff from my freezer, there might be a couple of MSs in there or something else that evolved down the line. I mean, I’m not sure. But it’s pretty impressive that out of 101 CFS defined by clinical case definition or a research case definition that they found 99 with virus. And if this is the case, that’s pretty exciting. It’s pretty impressive. And, oh, by the way, we have a biomarker. Not a small deal. A biomarker – the virus itself. No better biomarker than something that’s clearly, tightly associated with an illness.

(Thanks again to Kim for transcribing this.)

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Section 5 – Antibodies, What we don’t know, Cancer

Antibodies

[Question from audience, inaudible]

Oh that’s a really good question. She asked: "If there’s antibodies why don’t the antibodies kill it?" That’s a very good question and one that dogs the vaccine-development people in HIV all these years. The reason we don’t have an HIV vaccine yet is that antibodies don’t kill HIV, you need cytotoxic T-cells to kill HIV. So all those vaccines for HIV have been trying to get the cytotoxic T-cell lines all geared up and ready to go and not focus on the antibodies. The antibodies don’t do it. Whereas for other viruses the antibodies are great for it. I mean all those childhood vaccines you got were just trying to build antibodies for all those years. So there are some viruses that just the human body doesn’t make a killing, lethal antibody to attach to that virus.

So we don’t know this virus well enough. I don’t know, there might be an antibody that kills this virus. It’s only been a few years. They haven’t had a chance to look very hard. The other thing disturbing on that other one was only half the people they looked at had antibodies, but they had the virus. So antibodies are probably not going to be our world’s best blood-test for this.

XAND - Judy Mikovits renamed the illness, I’m not sure this is going to stick, but she called it XAND. XMRV Associated Neuroimmune Diseases. The reason why I don’t think it’s going to stick is I don’t think the “M” is going to stick very long. I think as soon as this virus is clearly shown to be a human virus, they are not going to call it a mouse virus any more, and they’re going to rename this virus, and then we’ll be renaming again. So I’m not leaping to embrace the new name, but I will embrace any name that’s not Chronic Fatigue Syndrome! [Applause]




This is also stuff they showed just last week, and this is not published data. And these are not going to be very representative because these are family members of CFS patients, who happen to have MS, fibromyalgia, autism. And in family members of CFS patients who had these other conditions they found XMRV in that family member. So there are lots of questions.

...if you see some negative papers coming out, don’t be discouraged. It’s going to happen. There are going to be some negative papers. People really jump to do this. And the method is not that easy...

This is the first paper. The paper is very exciting. The next step is to validate the paper. The very next step. And this is going to be difficult because what did I tell you about the prostate work? Two of them said yes, and two of them said no. Now if you talk to the guys who said yes, they’ll say the guys that said no didn’t use the same method to look. That’s science! We do this all the time. We get into big quibbles over method. Method, method, method!

Already I have a conference call with the CDC on Monday because they want their samples. The guy at NYU wants their samples. The guy at Hopkins wants their samples. I mean everybody knows that I have a freezer full of samples and my reaction is: Oh my God, what method would you apply? I don’t want to be the one that had the bad method. I don’t want my name on the paper that didn’t use the right tool! So, the first step I think is to get all the people trying to do this together and use the same method. And that’s absolutely necessary. And if you see some negative papers coming out, don’t be discouraged. It’s going to happen. There are going to be some negative papers. People really jump to do this. And the method is not that easy, and getting the right bits and pieces you need together, it’s not: read the paper and then go do it.

Things We Don’t Know 

What cell types are infected? We know for sure that NK-cells are and other white blood cells are. We know that there is some neurotropism [affinity for nervous tissue] from this virus from the mouse studies. But we don’t know every kind of cell type that could be infected and what’s infected in humans.

How is it transmitted? A critical question. Certainly the blood bank industry has jumped right in and are going to try to see if this is a worry there because they have freezers full of samples they can go back and survey for any positive, and then actually have recipients, and they can see if there are any recipients that are positive. So they’ll be able to test that theory I think very quickly and very efficiently.

What is the immune response that controls this virus? You asked that question: would antibodies do it? And the answer is (that's a great question) the antibodies might do it. Cells might do it. It might be that we have to repair these cells and then they can do it. But those are good questions. We don’t know with this virus what the answer is.

Now the other thing about the HIV guys is that they are kind of bored...We’re going to suck some of those guys right into our field now....I think we are going to see a flush of brilliant new people come into our field if this holds up..

But we do have a much better sense of what retroviruses are after the last 20 years of HIV work. We really do. I mean I go to the HIV meetings and I go to the CFS meetings. Let me tell you the difference. Reno, and this is a pretty big meeting last year, I think they had 100 and maybe 200 investigators, and that was the whole world, the Japanese were there, the Europeans were there and pretty much it’s a who’s who of who does this work and there was 200 of us. And the HIV meetings, I’ve been to meetings where 18,000 people came [gasps from audience]. And that’s the kind of brain power that was being directed.

Now the other thing about the HIV guys is that they are kind of bored, don’t have anything to do, patients are doing well, [laughter] science is a little dry, not a lot of grants. Cool! We’re going to suck some of those guys right into our field now. This is going to be really, really good. We’ve been waiting for a flush of brilliant new people, and I think we are going to see a flush of brilliant new people come into our field if this holds up, there’s going to be a lot of good interest. 

Cancer

Does this virus alter the risk for cancer?... My gut reaction is yes probably...

Does this virus alter the risk for cancer? Now it’s a question that has been left unanswered to you and every single one of my patients has asked me this question. Do I have an increased risk of cancer? My gut reaction is yes probably, because the cells that are your cancer-prevention cells are part of what’s broken or partially broken in this illness. So you always hear me talking about anything you can do, [e.g.] antioxidants, to try to help you any way you can to boost up your own tumor-defense systems. And these cells in particular. But here we are 25 years into this illness and we do not to date have a natural history study that is longer than 3 years.

No one has yet answered for you the question that needs to be answered. Part of my motivation to put together these clinics with Hannah, these Chronic Fatigue clinics, is that we were going to use this big common database and if we really can get a bunch of clinics all linked up together using the same database we’re going to have a natural history study finally. Because you have to do it yourself. That’s how it works in this field. We actually don’t have that information for you. 

Can we develop Immune-based therapies? I and [Dr] Mikovits have been working on immune-based therapies for years. We did a really cool one years ago with cell extension. Some of you were in that study and some of you got really big impressive results when we enhanced your cytotoxic T-cells and your natural killer cells. You got good clinical improvement.

(thanks to Garcia for transcribing this)

Section 6: Virus Life Cycle, Immune Modulators (Antivirals)

And here’s the real compelling question: will antivirals work? This is a virus that’s sort of coming in to a white blood cell and it’s hunting for its receptor. And then it’s going to attach to this cell. This is a retrovirus attaching to the cell. Now in this virus, we don’t know what that receptor is yet in human. We actually sort of have an idea from the mouse work, but we don’t know for sure. But there’s an attachment step. And then the virus enters the cell. It fuses to the cell. In HIV there’s these entry inhibitors and fusion inhibitors that prevent that so there are potential therapies if it were the same receptor. I kind of doubt it. I don’t think we’ll be using those particular HIV drugs. 

Then it gets into the cell and when it gets into the cell, it dumps its RNA into the cell. It pokes a little hole and the virus comes in. And then that RNA comes out. And we’re DNA, not RNA. The nucleus of our cells is DNA, so it has to be turned into DNA. And to do that, it uses an enzyme called reverse transcriptase and that turns the (see I knew before that thing before it told me. I am smart). Anyway, it turns RNA into DNA and that is a wonderful target for this virus…the reverse transcriptase inhibitors…because then the DNA can integrate into the cell. Now we have integrase integration inhibitors also…in HIV…integrase inhibitors. But they are fairly selective for HIV. I don’t know that they would be effective in another retrovirus. 

..there are literally thousands of compounds in the pharmaceutical companies’ shelves that they developed for HIV that weren’t as good as things for HIV that approved that might be the very perfect thing for this virus. So, we’re not starting from scratch here with this virus – at all!

And then, when the cell is activated and its DNA starts making stuff like this, it has to be…it makes these great big long proteins and those proteins have to be cleaved into little pieces (see I’m sinking here). And that’s the protease inhibitor line in HIV, the proteases that cleave are inhibited and that prevents that piece from being torn up. And then all these bits and pieces assemble themselves over on the cell wall and they bud off – BOP – and there’s a virus. And that’s how viruses are made.

So, we have entry inhibitors, we have reverse transcriptase inhibitors, we have integrase inhibitors, we have protease inhibitors. And then all those put together is the whole repertoire of drugs that have been developed over the last 20 years or so for HIV. 

But, be it known that there are literally thousands of compounds in the pharmaceutical companies’ shelves that they developed for HIV that weren’t as good as things for HIV that approved that might be the very perfect thing for this virus. So, we’re not starting from scratch here with this virus – at all! The other thing about this virus, and this is just from what Dr. Coffin said at the Chronic Fatigue meeting on Friday (I’m not a retrovirologist as brilliant as these guys) but I can parrot them pretty well. Dr. Coffin said – because this virus doesn’t seem to mutate very much, it’s a great target for vaccine trials. 

And when you ask - what about antibodies? – if we vaccinated people to this virus that already had the virus, we could goose up their immune response to this particular virus. That’s what they’re doing in HIV trials, they vaccinate infected people. So you might suppress the virus with an antiviral and then goose up the immune system with vaccines, so it could really work hard on this virus and then reduce it. So you could start postulating. Isn’t it fun to be able to postulate therapies…I mean, it’s great. I’m loving this. I’m lying awake at night thinking of all these things. It’s like – oooh,we could do this – oooh, we could do that. Good stuff. I know, I know, I’m an immunologist, what can I say? 

Isn’t it fun to be able to postulate therapies…I mean, it’s great. I’m loving this. I’m lying awake at night thinking of all these things. It’s like – oooh,we could do this – oooh, we could do that. Good stuff. I know, I know, I’m an immunologist, what can I say? 

Ampligen  - Of course one of the things I think about is immunomodulators – drugs that would either quiet immune activation or enhance cell function are very appropriate. Okay, so what’s already out there? Well, Ampligen, Ampligen’s an interesting drug. And they actually showed – they had 8 patients that had Ampligen data – that they showed at the CFSAC meeting that Dan showed. And it had a mixed result. In some cases, Ampligen was very effective in suppressing this virus, and in some cases it was not – in those 8 patients. That’s not very many. But Ampligen sounds kind of promising because it’s an antiviral that’s an immunomodulator that enhances natural killer cells and cytotoxic T-cell function. It’s even more intriguing than before in my mind, I think Ampligen’s got some real potential.

Immunovir (Isoprinosine)    - some of my patients are on this medication. It’s only had phase 2 trials, it hasn’t had phase 3 trials. But it’s more or less a nutraceutical, it’s an amino acid. But it is also an NK cell enhancer and a cytotoxic T-cell enhancer that may have some antiviral effect. 

Cell Therapy   -  this cell therapy – I referred to this ex-vivo cell therapy – some of you were in this study – It was in 1993 or…it was 1993. Well we took a lymph node from a patient and we grew the cells in a laboratory and we made literally a transfusion of white blood cells. Max did that. He was busy, busy transfusing my patients with white blood cells – their own white blood cells. But in the test, in the laboratory, we had grown them, fixed sort of what was broken about them, and then we got some very very nice clinical responses in that Phase 1, that study that never got to go to a Phase 2 study for lack of funding. And then finally, this makes cytokines that are either directly antiviral or immune enhancing more interesting.

Neutraceuticals - The nutraceuticals, they have less work done. Omega-3s are anti-inflammatory, the mushroom extracts that the Japanese use to enhance natural killer cell function, but these aren’t studies that had placebo control data and looked promising. CoQ10 at roughly 100 twice a day – that was really anti-fatiguing and enhanced cell functions. TNF inhibitors, we have a couple few patients on TNF inhibitors and I’m seeing some nice responses if they’re cytokines are way wacked out and they’re super revved up. 

That’s a natural killer cell, the little guy killing that target cell. That’s an Epstein Barr virus infected target. And there’s that little white blood cell doing its job. That’s what we’re trying to do. So the white blood cells infected with virus and you want these cells to go in there and kill that cell. So, the other question with this is: okay you’ve got one virus, but what if you’ve got this virus plus a couple of other viruses? What’s the role of all these viruses all together? What about HHV-6, EBV, enteroviruses, and this virus. If we say that all these viruses are doing their work together, it might be necessary to treat more than one virus. It might be necessary to design a study that has the retrovirus piece and a Herpes virus piece because sometimes viruses lend each other machinery to make their infections more potent and damaging.

(Thanks once again to Kim for the transcription)e

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