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Dr Martin Lerner's Abortive Infection Theory of ME/CFS — Unifying Herpesvirus & Enterovirus ME/CFS?

Discussion in 'Latest ME/CFS Research' started by Hip, Nov 8, 2017.

  1. pattismith

    pattismith Senior Member

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    Thank you for answering Hip, sorry to ask you so much. I always presume your brain is working so much better than mine...:)

    My question would be: Antiviral drugs N°5 would produce something mimicing a kind of abortive infection, so it may be interesting to test antibodies in patients after a course with this kind of anti-viral drug...To see if we can observe the same pattern...:thumbdown:
     
  2. Hip

    Hip Senior Member

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    Sounds plausible in principle, but I don't really understand enough about abortive infections to know whether it would work in practice.



    Some time ago, I was pondering on whether the reverse approach might work: to develop a drug that converts non-permissive cells into permissive ones, so that the abortive viral infection in these cells can start replicating and produce virions, resulting in a fully-fledged productive infection in the tissues, which the immune system should then attack and destroy, as per normal.

    In the case of enterovirus infections, when enterovirus enters cells in the body that are dividing cells (like liver cells, which are always multiplying and replicating themselves via cell division), the virus forms a normal productive infection, creating thousands of new virions in each cell.

    However, when enterovirus enters non-dividing cells, the virus is not able to make many new virions, and so instead may set up a chronic non-cytolytic enterovirus infection in these non-dividing cells (as explained earlier, a non-cytolytic infection is a sort of abortive infection).

    The reason non-dividing cells are non-permissive for enterovirus is because non-dividing cells lack a factor (called hnRNPC1) which is crucial for successful viral replication and production of new virions (more details about this factor here).

    This hnRNPC1 factor appears only during times of cell division and replication (cell mitosis), so you don't get any hnRNPC1 in non-dividing cells. Thus I wondered if it might be possible to develop a drug which stimulates the production of hnRNPC1 in all cells, including non-dividing cells, which might then convert non-cytolytic infections into productive infections, which would be cleared by the immune system.



    Incidentally, it occurred to me that this issue of non-cytolytic enterovirus infections only occurring in non-dividing cells might explain why ME/CFS rarely occurs in anyone younger than around 10 years old (the "twin peaks" study showed that ME/CFS before the age of around 10 is pretty rare — see Figure 1).

    I think the reason why young children rarely get ME/CFS might be due to the fact that the bodies of young children are rapidly growing, so the cells in their body will be constantly undergoing cell division, making it hard for enterovirus to create any non-cytolytic infections. As children grow older, their rate of growth slows, and cell division slows down and eventually stops in many organs. So as children grow into adults, you now you have more non-dividing cells in the adult body, which enterovirus may infect and produce the non-cytolytic infections linked to ME/CFS.
     
    Last edited: Nov 13, 2017
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  3. Gingergrrl

    Gingergrrl Senior Member

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    I am happy to help and thank you for thinking about my case and proposing different theories which are very interesting to me. I hope they will help others down the line, too.

    The mold was the final trigger but I was exposed to it from the end of 2012 until we finally moved out in 2015. The mold was minor in the beginning but I was exposed to toxic levels from at least mid 2013 to 2015 (in retrospect, but did not know it at the time). I've never heard "mingle-mangle" before but it is a perfect description of my illness!

    This is a great question and I think it is correct but am not sure without finding my records. I tested positive for autoimmunity in Feb 2016 (and in additional tests later in 2016) but I am not certain when the EBV IgM titer finally stopped being positive like it was for 2-3 yrs prior. And I have never tested it again, and am assuming it is negative now, but do not know this for a fact.

    I agree with all of this but I am not sure that my autoimmunity is only mold triggered vs. also being viral triggered. I think it is probably a combination of both mold and viral triggers in a big mingle-mangle ;)

    I know the evidence is limited on all of this but I feel optimistic that I will continue to improve and won't hit the six month mark for Rituximab until approx Feb 1, 2018. It has already exceeded my expectations (along with the IVIG).
     
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  4. Wonkmonk

    Wonkmonk Senior Member

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    I really hope looking thoroughly at cases like yours can finally help doctors and scientists put the puzzle together.

    I do believe that Dr Lerner's theory could be right for a subset of cases, and I might be one of them.

    I have observed one funny thing. I react badly to the following foods:
    - Garlic
    - Potatos with peel and skin (without peel/skin there is no problem)
    - Ready-to-eat tomato sauce (no problem with fresh tomatos)
    - Hot chili

    The interesting thing is, these are definitely no food allergies, because there are no allergy symptoms and I can tolerate tomatos and potatos in other form. There is also no gastro-intestinal problems whatsoever, so I also don't believe it's a food intolerance plus I never had a food intolerance to those (or any) foods before.

    The bad reaction is quite similar to what I experienced during the initial worsening/herxheimer reaction after starting Valacyclovir: Headache, general worsening of fatigue, heart palpitations etc.

    So I was wondering what might cause these reactions and I found that each of these foods contains a chemical which studies have found to induce apoptosis, e.g. in cancer cells and/or virally infected cells, plus they all have broad spectrum anti-viral activity includung against herpes viruses.

    These chemicals are:
    - Garlic: Allicin
    - Potato skin and peel: Solanine and Chaconine
    - Unripe tomatos: Tomatine
    - Chili: Capsaicine

    What makes me confident that these chemicals might be to blame is that solanine is present in potato skin and peel, but not in the rest of the potato, and I only react negatively to potatos WITH skin/peel. With respect to tomatos, ripe fresh tomatos don't contain much tomatine, but unripe tomatos do contain significant amounts of tomatine (that's why they aren't edible), and manufacturers of ready-to-eat tomato products also have some amount of unripe tomatos in their products. I only react negatively to these products and not to ripe fresh tomatos.

    If Dr Lerner is right, these chemicals might induce apoptosis in infected non-permissive cells and that is causing the same symptoms as Valacyclovir does in the beginning.

    That leads me to another unsolved question about Dr Lerner's theory: Where does the initial worsening/herxheimer reaction come from when you start Valacyclovir? It doesn't kill the virus, just stops it from replicating, so technically it can't be a real Herx/die off reaction. Could it be possible that Valacyclovir induces apoptosis in (some?) infected non-permissive cells and that causes the initial worsening?

    Sorry, this was a bit long now and I acknowledge it's a weird theory with no real evidence, but that's how I try to make sense of it and it would be consistent with Dr Lerner's theory.

    I am wondering if anyone has similar reactions to these foods...
     
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  5. pattismith

    pattismith Senior Member

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    Given the fact that CFS/ME patients are at higher risk of developping non Hodgkin lymphomas,
    it may be that ZEBRA could be an accurate biomarker of an EBV abortive lytic infection (even in the absence of lymphoma)... maybe a useful marker for CFS/ME?


    2012 May 23.
    An Epstein-Barr Virus (EBV) mutant with enhanced BZLF1 expression causes lymphomas with abortive lytic EBV infection in a humanized mouse model.

    Abstract
    Immunosuppressed patients are at risk for developing Epstein-Barr Virus (EBV)-positive lymphomas that express the major EBV oncoprotein, LMP1.
    Although increasing evidence suggests that a small number of lytically infected cells may promote EBV-positive lymphomas, the impact of enhanced lytic gene expression on the ability of EBV to induce lymphomas is unclear. Here we have used immune-deficient mice, engrafted with human fetal hematopoietic stem cells and thymus and liver tissue, to compare lymphoma formation following infection with wild-type (WT) EBV versus infection with a "superlytic" (SL) mutant with enhanced BZLF1 gene (Z = Zebra protein) expression.
    The same proportions (2/6) of the WT and SL virus-infected animals developed B-cell lymphomas by day 60 postinfection; the remainder of the animals had persistent tumor-free viral latency. In contrast, all WT and SL virus-infected animals treated with the OKT3 anti-CD3 antibody (which inhibits T-cell function) developed lymphomas by day 29. Lymphomas in OKT3-treated animals (in contrast to lymphomas in the untreated animals) contained many LMP1-expressing cells. The SL virus-infected lymphomas in both OKT3-treated and untreated animals contained many more Z-expressing cells (up to 30%) than the WT virus-infected lymphomas, but did not express late viral proteins and thus had an abortive lytic form of EBV infection. LMP1 and BMRF1 (an early lytic viral protein) were never coexpressed in the same cell, suggesting that LMP1 expression is incompatible with lytic viral reactivation. These results show that the SL mutant induces an "abortive" lytic infection in humanized mice that is compatible with continued cell growth and at least partially resistant to T-cell killing.


    2017 Sep 5
    Lytic EBV infection investigated by detection of Soluble Epstein-Barr virus ZEBRA in the serum of patients with PTLD.

    Abstract
    The ZEBRA protein (encoded by the BZLF1 gene), is the major transcription factor of EBV, expressed upon EBV lytic cycle activation. Several studies highlighted the critical role of EBV lytic infection as a risk factor for lymphoproliferative disorders like post-transplant lymphoproliferative disease (PTLD). Here, we use an antigen-capture ELISA assay specifically designed to detecting the circulating soluble ZEBRA (sZEBRA) in serum samples (threshold value determined at 40ng/mL). We retrospectively investigated a population of 66 transplanted patients comprising 35 PTLD. All the samples from a control population (30 EBV-seronegative subjects and 25 immunocompetent individuals with EBV serological reactivation), classified as sZEBRA < 40ng/mL were assigned as negative. At PTLD diagnosis, EBV genome (quantified by qPCR with EBV DNA>200 copies/mL) and sZEBRA were detectable in 51% and 60% of cases, respectively. In the patients who developed a pathologically-confirmed PTLD, the mean sZEBRA value in cases, was 399 ng/mL +/- 141 versus 53ng/mL +/- 7 in patients who did not (p  < 0,001). This is the first report relating to the detection of the circulating ZEBRA in serum specimens, as well as the first analysis dealing with the lytic cycle of EBV in PTLD patients with this new biomarker.
     
  6. Hip

    Hip Senior Member

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    @pattismith, I read that Zebra is a protein that switched between EBV latency and viral reactivation. I can't see how this could be specifically connected to abortive EBV infections.
     
  7. Gingergrrl

    Gingergrrl Senior Member

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    Thanks @Wonkmonk and I would be thrilled if some aspect of my case contributed to helping doctors and scientists figure out this puzzle.

    That is interesting and I have no problem with garlic, potato skins, or tomato sauce but I do not tolerate spicy foods of any kind (life-long). Just to clarify, when my MCAS was out of control in 2015, I reached the point that all I count ingest was water with dextrose and salt. But in remission, I can eat anything but still avoid the foods that bothered me life-long and avoid food dyes.
     
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  8. bspg

    bspg Plant Queen

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    This thread is very interesting. Thanks to @Hip for creating it! :D


    Yay! @Gingergrrl finally has a name for her illness:

    "some kind of CFS plus autoimmunity mingle-mangle"

    :rofl::rofl::rofl:
     
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  9. Gingergrrl

    Gingergrrl Senior Member

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    Thank you @bspg (and @Wonkmonk) and my illness is now officially "some kind of CFS plus autoimmunity mingle-mangle due to mold exposure"... I actually like it and it has a nice ring to it LOL :rofl:
     
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  10. Wonkmonk

    Wonkmonk Senior Member

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    @Gingergrrl Hehehe...I might have discovered a new disease here :p

    In other news I am going to try something new: Dr Goldstein proposed 40 years ago that Cimetidine can rapidly cure some cases of EBV infectious mononucleosis:

    http://annals.org/aim/article-abstract/700598/cimetidine-ranitidine-epstein-barr-virus-infection

    I am aware this author is highly controversial and presents no evidence except his own experience, but Dr Lerner also recommends Cimetidine to improve response to Valtrex. In Dr Golstein's cases (which took no Valtrex), the mechanism is unclear. Dr Lerner proposes that Cimetidine works by increasing Valtrex plasma levels (which is supported by evidence). So this seems worth trying.

    If it works, it would be another indication (though not proof of course) that my CFS is caused by EBV according to Dr Lerner's theory.
     
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  11. pattismith

    pattismith Senior Member

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    Just to make a warning on the use of Cimetidine. Most of the time a safe drug, but myopathy can occur in rare cases

    upload_2017-11-16_8-10-39.png
     
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  12. Wonkmonk

    Wonkmonk Senior Member

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    @pattismith Thanks for pointing this out, Patty. It is always important to know all possible risks, but after researching a bit on Google, it seems to me that these cases were exceptionally rare and causal relation with Cimetidine wasn't established. It also seemed reversible after stopping the drug in a significant part of the known cases.

    So in total, although this drug - like all others - cannot be regarded as 100% safe, I think the risk-reward profile of trying it still seems favorable to me.
     
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  13. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Cimetidine like zantac ive read works by reducing T suppressor cells which increases T cell activity.

    There is some research showing it is effective against varicella virus aka shingles.
     
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  14. Wonkmonk

    Wonkmonk Senior Member

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    @heapsreal Someone else (I don't know who) posted here that it somehow prevents EBV from entering the cells. Sadly I don't remember the post or the thread.
     
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  15. ash0787

    ash0787 Senior Member

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    remind us how we know there are consistent 'enterovirus' in me/cfs patients ? doesn't it only show in biopsy ?
     
  16. Hip

    Hip Senior Member

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    Chronic enterovirus infection is found in muscle tissue or stomach tissue biopsies of ME/CFS patients (numerous studies on ME/CFS patients from the 1970s onwards have shown this); but you can also easily detect chronic enterovirus infections by blood test if you use an antibody test based on a neutralization assay. Neutralization assays are sensitive, and will detect enterovirus, whereas other forms of antibody testing (such as ELISA and CFT) are insensitive. PCR blood tests are also not sensitive enough to reliably detect chronic enterovirus infections.

    ARUP lab provides a sensitive antibody test based on a neutralization that Dr Chia uses to routinely detect chronic active enterovirus infections in his ME/CFS patients.
     
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  17. Wonkmonk

    Wonkmonk Senior Member

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    Has Dr Lerner actually found EBV or other herpes virus in his heart biopsies of CFS patients? Or has any other CFS doctor in any organ or tissue?
     
  18. Hip

    Hip Senior Member

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    I Google searched for biopsy evidence of abortive herpesvirus infections in the heart or other tissues of ME/CFS patients, but could not find anything.
     
  19. Gingergrrl

    Gingergrrl Senior Member

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    Hey, you never know... ;)

    I learned of this a few years ago from a friend from this board. I never tried Cimetidine but I did try Zantac (both for EBV and later for MCAS as an H2 blocker) but it never helped me in either case.
     
  20. pattismith

    pattismith Senior Member

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    Dr Lerner in this old paper says:

    "We have observed that ALL CFS patients have abnormal oscillating T-wave flattenings and T-wave inversions at Holter monitoring [22]."

    he thought that this was a sign of myocyte lysis, but did he ruled out other causes for inverted T waves?

    in this wiki page , it is clearly stated that:

    "An ECG in a person with a potassium level of 1.1 meq/l showing the classical changes of ST segment depression, inverted T waves, large U waves, and a slightly prolonged PR interval".

    and that "Causes of hypokalemia include diarrhea, medications like furosemide and steroids, dialysis, diabetes insipidus, hyperaldosteronism, hypomagnesemia, and not enough intake in the diet.[1]"

    I wonder if CFS/ME patients may have a special sensitivity to low/border line kalemia that could explain these cardiac signs, as well as others known hypokalemia symptoms:


    "Usually symptoms of low potassium are mild. At times the effects of low potassium can be vague. There may be more than one symptom involving the gastrointestinal (GI) tract, kidneys, muscles, heart, and nerves.

    • Weakness, tiredness, or cramping in arm or leg muscles, sometimes severe enough to cause inability to move arms or legs due to weakness (much like a paralysis)
    • Tingling or numbness
    • Nausea or vomiting
    • Abdominal cramping, bloating
    • Constipation
    • Palpitations (feeling your heart beat irregularly)
    • Passing large amounts of urine or feeling thirsty most of the time
    • Fainting due to low blood pressure
    • Abnormal psychological behavior: depression, psychosis, delirium, confusion, or hallucinations."
     
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