Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome

[rosie26]

Same here for tests from a lab I don't completely trust - thought it might be due to my immune system being buggered. I'll have more thorough results in week or so, from a better lab.

Be interesting to see what your results show Val.

I remember also having a test for EBV when I was working at the hospital - I had a very sore throat at the time and a doctor on the ward did a test for me and that came back negative also - so I have had two tests and both negative - so I don't know. How reliable are tests.

 

[anciendaze]

Please note that the full text of the referenced paper describes tests for EBV infection which go a great deal beyond common clinical lab results. They also report that tests showed a great deal of latent replication must be taking place. Common assumptions in testing for EBV are based on active infections and antibody response to them. Few labs test for DNA of latent virus in immune cells. This paper specifically reports that certain evidence of RNA, produced by active infections, was absent or reduced. It also shows a crippled response via IFN-gamma. Under these circumstances it is unreasonable to say that it can't apply to you because you don't have unusual EBV results from standard clinical labs.

 

[Soundthealarm21]

Please note that the full text of the referenced paper describes tests for EBV infection which go a great deal beyond common clinical lab results. They also report that tests showed a great deal of latent replication must be taking place. Common assumptions in testing for EBV are based on active infections and antibody response to them. Few labs test for DNA of latent virus in immune cells. This paper specifically reports that certain evidence of RNA, produced by active infections, was absent or reduced. It also shows a crippled response via IFN-gamma. Under these circumstances it is unreasonable to say that it can't apply to you because you don't have unusual EBV results from standard clinical labs.

Do you mean PCR testing?

 

[anciendaze]

Do you mean PCR testing?

PCR testing, both qPCR and RTPCR, is part of the suite of tests used, but only part. They also used multiparameter flow cytometry to count immune cells with multiple markers. Even studies doing clinical flow cytometry have typically been limited to sorting cells by a single marker. (Note the disclaimer at the bottom of the page about the research instrument.) This would prevent them from detecting the specific deficits of polyfunctional immune cells found here. Beyond that they used ELISA and stimulated cell culture immunoassays. It's all there in the text.

This is the kind of battery of modern research techniques which has so often been absent in studies of ME/CFS. I'd say they really examined their early data and were guided by it in choosing that immune challenge with EBNA-1. This is not an example of confirmation bias behind a single favorite hypothesis.

 

[natasa778]

Wondering if there could be links to what was found in MS

... we made the dual virus hypothesis of a possible involvement of both viruses in MS pathogenesis, with the possibility for MSRV of a direct role of effector of pathogenicity, and for EBV of an initial trigger of future MS, years later.

... Thus, the data indicate that the two main links between EBV and MS (IM and high anti-EBNA-1-IgG titers) are paralleled by activation of the potentially neuropathogenic HERV-W/MSRV. These novel findings suggest HERV-W/MSRV activation as the missing link between EBV and MS ...

thread here

Activation of MSRV-Type Endogenous Retroviruses during Infectious Mononucleosis and Epstein-Barr Virus Latency: The Missing Link with Multiple Sclerosis?


In a scenario where EBV is a initial trigger and ERV has a direct role of effector of pathogenicity I guess antivirals like valtrex would not be of much help, at least not long term?

 

[natasa778]

another bit from that MS paper that might be pertinent to ME:

As for the post-infection stages of EBV latency, it is well known that during latency, EBV expresses a limited repertoire of proteins, non-coding RNAs and microRNAs [54]. The virus remains immunologically silent in small numbers of memory B cells, which traffic into inflamed tissues, and are tightly controlled by invariant natural killer T cells [55] and by cytotoxic T lymphocyte cells to prevent lymphoproliferation [56]. Since HERV-W is expressed by a high proportion of B cells (Figure 2B), it is likely that reciprocal interactions occur within these cells during latency, that could play an additional role to the indirect mechanism proposed by Meier and coworkers, by which latent EBV infection could contribute to (neuro)inflammation, through the expression of small non-coding RNAs that bind to Toll-like receptor 3 and potentially other intracellular receptors [56].

 

[anciendaze]

Just a quick thought: we can no longer be sure about inferences that silent virus is restricted to "small numbers of memory B cells". If the virus is capable of exploiting clonal expansion we could be underestimating latent viral load by a large margin. Lytic replication releases hundreds or thousands of virions, but kills the host cell in the process. Replication of DNA of latent virus during clonal expansion could easily result in many millions of infected cells without viral RNA or proteins, or antibodies to these, seen in active infection.

 

[Christopher]

I don't understand.



Would that be why "immune stimulants" sometimes cause crashes?

 

[anciendaze]

Christopher,

You have to be a little more specific on what you mean by "immune stimulants". I suspect you intend this to apply to macrophage activating factors (MAF), but can't be sure. There is also the problem that immune systems have many parts, like the macrophages mentioned, or specific classes of T and B cells. There are many other interpretations.

For example, small doses of antigens can stimulate an immune response; for that matter, this can even apply to low doses of radiation. There was even a trend at one time to bathe in spa waters with small amounts of radioactive material, or to sit in abandoned uranium mines. (I actually knew such people.) This went away when radiation begin to be considered consistently bad for you.

Traditional medicine has vaccines and adjuvants, (which seem to have a bad flavor for many here,) as antigenic immune stimulants. Many hormones stimulate immune response, but that is also hard to pin down, as some suppress response. There is also a problem with differing responses at different levels, leading to paradoxical responses.

The immune system is a tangle of many feedback loops. This means that paradoxical responses -- moving in the opposite direction to the one intended -- are quite likely. Labeling any particular molecule as a stimulant, regardless of the context in which it is used, is a problem.

Other examples of immune stimulants may be nothing more than vitamins with a special marketing spin. Practically any herbal product can also be said to "stimulate the immune system", for marketing purposes, though I don't know how to separate these into different classes. Some mushrooms said to have beneficial properties are in the same families with others known to produce neurotoxins. Even families that are generally safe to eat, like morels, have toxic species. When you realize that low doses of toxins can stimulate a response in the opposite direction you become cautious about generalizations based on a few instances.

See why I have a problem with that question?

 

[Christopher]

Christopher,

You have to be a little more specific on what you mean by "immune stimulants". I suspect you intend this to apply to macrophage activating factors (MAF), but can't be sure. There is also the problem that immune systems have many parts, like the macrophages mentioned, or specific classes of T and B cells. There are many other interpretations.

For example, small doses of antigens can stimulate an immune response; for that matter, this can even apply to low doses of radiation. There was even a trend at one time to bathe in spa waters with small amounts of radioactive material, or to sit in abandoned uranium mines. (I actually knew such people.) This went away when radiation begin to be considered consistently bad for you.

Traditional medicine has vaccines and adjuvants, (which seem to have a bad flavor for many here,) as antigenic immune stimulants. Many hormones stimulate immune response, but that is also hard to pin down, as some suppress response. There is also a problem with differing responses at different levels, leading to paradoxical responses.

The immune system is a tangle of many feedback loops. This means that paradoxical responses -- moving in the opposite direction to the one intended -- are quite likely. Labeling any particular molecule as a stimulant, regardless of the context in which it is used, is a problem.

Other examples of immune stimulants may be nothing more than vitamins with a special marketing spin. Practically any herbal product can also be said to "stimulate the immune system", for marketing purposes, though I don't know how to separate these into different classes. Some mushrooms said to have beneficial properties are in the same families with others known to produce neurotoxins. Even families that are generally safe to eat, like morels, have toxic species. When you realize that low doses of toxins can stimulate a response in the opposite direction you become cautious about generalizations based on a few instances.

See why I have a problem with that question?

Yea, I understand. Seems like there's lots of opportunity for the immune system to get confused, as it's so complicated.

So with this paper, they're saying that since EBV can replicate latently in B cells, EBV load can rise over time when the immune system is stimulated and B cells start replicating, so we have lots of EBV-infected B cells. Does the EBV hinder the function of the B cell then that it's hanging out in?

If this property is true of EBV in general, what is the difference for CFS patients? Are our immune systems being stimulated so much that we have lots more EBV-infected B cells than controls whose B cells don't replicate as much?

Would antivirals not be totally effective, because they only stop lytic replication rather than latent? What a conundrum, you need your immune system to function, but when it does, EBV hitches a ride and gums up the works.

I wonder if people improve by mold and toxin avoidance because those substances also stimulate the immune system and further the EBV load. Avoiding toxins probably gives the immune system a chance to calm down.

I know I had the best few months of my life when I was living near the ocean for a summer - totally calm, no allergies, no ADD, no anxiety. As soon as I moved back to a major city, they all came back.

I don't like what I'm starting to realize about this whole thing. Is this why "smarter" (lots of hormones) people seem to be affected more by these types of problems? Can meditation help by "balancing" hormones. Hm.

 

[anciendaze]

Yea, I understand. Seems like there's lots of opportunity for the immune system to get confused, as it's so complicated.

So with this paper, they're saying that since EBV can replicate latently in B cells, EBV load can rise over time when the immune system is stimulated and B cells start replicating, so we have lots of EBV-infected B cells. Does the EBV hinder the function of the B cell then that it's hanging out in?

We need to see several other things about cells infected with EBV. Right now we see evidence that latent replication is taking place, but we don't know much about viral loads in patients because standard tests depend on responses that this paper shows to be weakened or unreliable. Something is impairing response, but a great deal of the story is missing. We see that certain classes of cells are depleted. Could this be the entire impact of infection, destroying cells that produce a response that threatens the virus? Or, are there more subtle types of impairment in surviving cells? I don't know.

At this point I feel the need to say that my emphasis on latent replication was not the major part of the authors' intent. They were primarily talking about specific deficits they observed. My own inference was that errors in measures of viral load meant that a possibility we had earlier decided was off the table suddenly became plausible again.

If this property is true of EBV in general, what is the difference for CFS patients? Are our immune systems being stimulated so much that we have lots more EBV-infected B cells than controls whose B cells don't replicate as much?

EBV in general can do this trick of latent replication, though we really don't know how important it is in most people, who are able to keep latent EBV under control.

Again, we don't have reliable measures of total viral load for EBV, let alone how much results from latent replication. It should be possible to develop such an assay, but no such test is currently in use.
It is quite possible the EBV in ME/CFS patients is different. It would be easy to damage or silence genes responsible for active, lytic replication.

Would antivirals not be totally effective, because they only stop lytic replication rather than latent? What a conundrum, you need your immune system to function, but when it does, EBV hitches a ride and gums up the works.

There are no good specific antivirals targeting EBV. The general herpes antivirals now available largely interfere with DNA polymerase, which is apparently also responsible for latent replication. They do not require lytic activity, but lytic activity has been the measure by which we determine if there is infection. If the doctor thinks infection is gone, treatment stops. Treatment would leave the viral DNA present, but prevent more replication. You would then have to wait for the body to clear itself of infected cells by maintaining these antivirals until infected cells are replaced. This fits the scattered results from Dr. A. Martin Lerner's use of antivirals. It requires long-term administration of antivirals, and results are slow to appear. If the infection has reached bone marrow, I don't even know if the replacement cells would be free of infection.

I wonder if people improve by mold and toxin avoidance because those substances also stimulate the immune system and further the EBV load. Avoiding toxins probably gives the immune system a chance to calm down.

I know I had the best few months of my life when I was living near the ocean for a summer - totally calm, no allergies, no ADD, no anxiety. As soon as I moved back to a major city, they all came back.

I don't like what I'm starting to realize about this whole thing. Is this why "smarter" (lots of hormones) people seem to be affected more by these types of problems? Can meditation help by "balancing" hormones. Hm.

From what I've experienced, and what others have reported, you might be right about symptoms disappearing at the seashore. This is not a general solution. Some people I know would have to live in a plastic bubble, and it would have to be a special kind of plastic.

We've been seeing evidence that immune response was confused and misdirected in the past. This paper gives some solid backing to that idea, with quantitative data. While I have doubts about some treatments suppressing immune response to the disease instead of the disease itself, I don't think it would hurt any of us to reduce loads of common viruses in the herpes group.

 

[alex3619]

Antivirals are fantastic at treating acute viremic infections if the right drug is used for the specific pathogen. This kind of EBV infection is not viremic. We do not currently have any good drugs for this. If a virus is only slowly replicating, and is widespread in millions of cells that can divide and lead to even more infected cells, then there is no current good strategy to deal with it. One line of research currently being done is combining antivirals with other factors. Its still a long way from being shown to be effective. In the meantime antivirals should stop a viral infection from going viremic, but thats about it.

 

[beaverfury]

Antivirals are fantastic at treating acute viremic infections if the right drug is used for the specific pathogen. This kind of EBV infection is not viremic. We do not currently have any good drugs for this. If a virus is only slowly replicating, and is widespread in millions of cells that can divide and lead to even more infected cells, then there is no current good strategy to deal with it. One line of research currently being done is combining antivirals with other factors. Its still a long way from being shown to be effective. In the meantime antivirals should stop a viral infection from going viremic, but thats about it.

Any theoretical models in the pipeline?

Could they create a synthetic virus to impart DNA into the EBV and disrupt it's replication? Kind of infecting the infection.

 

[heapsreal]

Something that will improve nk function should help control ebv??

 

[Christopher]

Antivirals are fantastic at treating acute viremic infections if the right drug is used for the specific pathogen. This kind of EBV infection is not viremic. We do not currently have any good drugs for this. If a virus is only slowly replicating, and is widespread in millions of cells that can divide and lead to even more infected cells, then there is no current good strategy to deal with it. One line of research currently being done is combining antivirals with other factors. Its still a long way from being shown to be effective. In the meantime antivirals should stop a viral infection from going viremic, but thats about it.

So why would antivirals help some patients? Also, @anciendaze said that antivirals do help stop latent replication.

When I take Valtrex, I get more flu-like symptoms and less neurological symptoms.

 

[alex3619]

Antivirals slow viremia, slow the spread of the virus through a lytic lifecycle. Hence its less visible to the immune system. Over time it might reduce the tissue viral load. We still do not know for sure what will reduce these viruses enough to end ME, if such a thing is even possible. It is entirely probable these viruses are for life. The issue is whether or not they are producing symptoms.

Antivirals have minimal impact on slowly replicating latent infections. Some, yes, but you have to keep taking the antiviral forever. These kinds of viruses are not fully cleared by the immune system. There is talk of provoking the virus, of making it fully active, so that antivirals can have a full impact. I do not know how far the research along these lines has gone.

Nearly the entire population has latent herpes viruses. Most are not sick. However these viruses have additional life cycles. Latent viruses are sometimes active, but not in the way seen in acute viremia.

If these drugs worked properly then one course of antivirals would eliminate the virus. This is one of several reasons why I think many doctors presume EBV cannot be involved in ME. The second is they confuse post viral fatigue (which everybody gets at some point) with CFS, and CFS with ME. Post viral fatigue has a several month recovery phase, up to five years. ME does not. The last issue is that a virus like EBV comes and goes. We do not remain in viremia, which is acute lytic viral infection. Since doctors are not very well informed, in general, on the other lifecycles, they do not realize this is not the end of the story. Yet they should, as shingles and cold sores (as examples) clearly show these viruses persist. One issue is that most of this information on alternate viral lifecycles is far too recent for it to be even known about when most doctors were going through medical school. So doctors usually presume, unless they are watching the science closely, that a viral infection is either about fully latent viruses or actively replicating in a lytic lifecycle.

 

[alex3619]

When I take Valtrex, I get more flu-like symptoms and less neurological symptoms.

This may be an interesting combination of symptoms. More flu-like probably means more cytokines. Less neurological may indeed mean less viral infection, though possibly also less targeting of the nervous system by your immune system. If you have elevated serum titres that drop with the Valtrex, then it would show the Valtrex is stopping the virus from going viremic. In some of us that can literally be life saving, but it will not eradicate most herpes viruses completely.

 

[natasa778]

This may be an interesting combination of symptoms. More flu-like probably means more cytokines. Less neurological may indeed mean less viral infection, though possibly also less targeting of the nervous system by your immune system. If you have elevated serum titres that drop with the Valtrex, then it would show the Valtrex is stopping the virus from going viremic. In some of us that can literally be life saving, but it will not eradicate most herpes viruses completely.

This could be linked to the possible effects of valrex (and acyclovir?) on interferon activation!? I do not have details right now, but there was quite a bit of discussion and posting on this possibility in the past. (searching for IDO - interferon pathways and valacycolvir should bring up some results!)

Also interesting in the light of recent findings from MS researchers. I just started a thread on it, but here again:


Latent EBV infection in B cells and autoimmune disease

...
Humans and EBV have evolved together for thousands of years, according to Marc S. Horwitz, PhD, of the University of British Columbia in Vancouver.

"The way the virus has learned to survive is to infect us and stay hidden inside a subset of cells for the remainder of our lives," Horwitz said in an interview.

But the cells this virus adapted to live in, B cells, are a poor host in some ways, he said. This is because B cells turn over rapidly and often, unlike many other tissues in the body.

"So the strategy EBV has developed to keep its host B cell alive but latent and hidden from attack by the immune system is by constantly poking the immune system's low level interferon response, which is akin to keeping the immune system on the edge of its seat and ready to pounce," said Horwitz, who is co-leader of the university's infection, inflammation, and immunity program.

In that hyperalert state, when the immune system detects a new threat its response could be excessive, which could push the individual over the edge into autoimmunity, he explained.

The T-Cell Connection

Many epidemiologic studies have found a strong familial component in autoimmune diseases. In a healthy host, EBV infection is tightly controlled by a subset of cytotoxic CD8+ cells, which destroy the infected cells. As Pender continued his research, he then suggested that this genetic component could be an inherited deficiency of CD8+ cells. ...

full article
http://www.medpagetoday.com/Rheumatology/GeneralRheumatology/43797

 

[anciendaze]

I'm not going to comment on specific medications and particular patients, but I will offer a caution on interpreting results.

First, as stated above, there is no antiviral specific to EBV, treatment therefore has to affect many different common viruses. Second, none of the drugs labeled for a particular indication is likely to apply solely to that problem. As a wild example, there was research showing that lithium salts, indicated to control mania, also reduced HIV loads. (Off-label use is very common in practice, though it is generally downplayed, because nobody wants to admit that doctors experiment on patients all the time.) Third, those flu-like symptoms are typically caused by cytokines that stimulate inflammation; when part of the immune system wakes up, this may increase even though the pathogen load is going down. The classic example is the Jarisch-Herxheimer reaction. (In the context of viral disease, I've seen this when a doctor was pleased that a patient developed shingles, because this showed the immune system was starting to work. The patient wasn't nearly as thrilled. Shingles is caused by VZV, another herpes-type virus.)

If you are talking about viremia, you are talking almost entirely about the results of lytic replication, which releases large numbers of virions into the bloodstream. Viremia actually means virions in the blood. Virus hidden in immune cells in the blood is generally not counted as viremia.

 

[anciendaze]

Query: the one person who I feel sure really had ME/CFS and was cured by antiviral therapy was Dr. A. Martin Lerner himself. Does anyone know how another prominent activist, say Leonard Jason, recovered?