The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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new XMRV research (talks about prostate cancer but mentions EBV promoting XMRV

Discussion in 'XMRV Research and Replication Studies' started by taniaaust1, Jan 30, 2011.

  1. taniaaust1

    taniaaust1 Senior Member

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    "NF-{kappa}B Activation Stimulates Transcription and Replication of Xenotropic Murine Leukemia Virus-Related Virus in Human B-lineage and Prostate Carcinoma Cells.
    Sakakibara S, Sakakibara K, Tosato G.

    Laboratory of Cellular Oncology, and Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA."

    Seems the NCI and NIH is doing some good research http://www.ncbi.nlm.nih.gov/pubmed/21270144

    Very confuses to a non scientific person such as myself but i still got something out of it and having had mono, found it interesting.

    **now im going to look up what NF-kB is.....as im interested what else activates that and what its to do with seeing it promotes XMRV**
     
  2. taniaaust1

    taniaaust1 Senior Member

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    for anyone wondering too, from the normal wikipedia on NF-kB

    "NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.[1][2][3][4][5] NF-κB plays a key role in regulating the immune response to infection (kappa light chains are critical components of immunoglobulins). On the converse, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.[6]
    "
     
  3. Mark

    Mark Former CEO

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    TNF-alpha:

    http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha

    Tumor necrosis factor (TNF, cachexin or cachectin and formerly known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.
    The primary role of TNF is in the regulation of immune cells. TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, including major depression[1], Alzheimer's disease[2] and cancer.[3]
     
  4. Mark

    Mark Former CEO

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    More about NF-kB:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140602/

    The NF-κB transcription factor is a vital regulator of cellular processes involved in immune response, cellular proliferation, differentiation, and apoptosis (6, 38, 47, 53).

    Constitutive activation of NF-κB is also thought to contribute to multiple pathophysiological conditions such as rheumatoid arthritis (55), inflammatory bowel disease (60), and AIDS (22) and, with ever increasing evidence, cancer (1, 5, 33, 48).
    In mammals, the NF-κB family consists of RelA (from here on referred to as p65), c-Rel, and RelB, as well as p105 and p100 and their processed forms, p50 and p52, respectively (31). Each subunit contains a Rel homology domain (RHD) specifying DNA binding, protein dimerization, and nuclear localization. In addition, p65, c-Rel, and RelB contain transactivation domains (TAD) located at the carboxy terminus. Although in vitro most NF-κB subunits possess the ability to homo- or heterodimerize, in vivo, NF-κB primarily exists as a p50/p65 heterodimer.
     
  5. Mark

    Mark Former CEO

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    Long Terminal Repeats: The Retroviral Promoter - Stanford Tutorial:
    http://www.stanford.edu/group/nolan/tutorials/retcl_3_ltrs.html

    The above appears to describe what the NCI have now shown is also true of the XMRV Long Terminal Repeat.

     
  6. Cort

    Cort Phoenix Rising Founder

    That would mean inflammation would spark XMRV replication - a good finding for CFS and particularly good that NF-kB is involved because NF-kB has been implicated in quite a few different areas in CFS before.

    Azithromycins effectiveness in some patients may be due to its NF-kb altering capabilities

    http://www.aboutmecfs.org/Trt/TrtAzithromycin.aspx

    Its also been suggested to play a major role in the upregulation of the IFN isoform (100 kDA) that appears to lead to the RNase L problems in CFS and the PKR enzyme, which is often upregulated in CFS - turns NF-kB on.. This suggests that NF-kB activation could play a role in the RNase L problems in CFS as well.

    http://aboutmecfs.org/Rsrch/2-5OASRNaseLBackgroundCFS.aspx
     
  7. Cort

    Cort Phoenix Rising Founder

    Maes

    Maybe the most significant connection, though, is with Dr. Maes - he believes NF-kB plays a key role in producing the inflammation and the 'psychosomatic' symptoms in ME/CFS and he has documented this in several studies.

    http://www.ediver.be/ediver/latest%20news/Chronic%20fatigue%20syndrome%20-%20review%20-%20inflammation.pdf

    Purpose of review
     
  8. Cort

    Cort Phoenix Rising Founder

    Maes II

    Here's the biggie from Maes. To bad its in a very small journal that's hard to get. He was even able to associate increased NF-kB levels with symptom severity.

    http://www.ncbi.nlm.nih.gov/pubmed/17693979

    One of my requests for Mary Schweitzer was to get Dr. Maes to the April Workshop. I hope they can.
     
  9. Mark

    Mark Former CEO

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    So...to attempt a translation of the NCI/NIH abstract...

    XMRV's LTR contains two sites to which NF-kB (immune regulator) binds.

    If you knock out the first of these NF-kB binding sites - denoted kB-1 - then XMRV is inhibited from replicating as it otherwise would do in response to TNFα (inflammatory cytokine and immune regulator) and EBV LMP1.

    When grown in all these cell lines - prostate cancer and B-lineage cells - the mutated XMRV, with the kB-1 site impaired, replicated less efficiently.

    [Note: EBV LMP1 (Epstein-Barr virus (EBV) latent membrane protein-1) "plays a critical role" for for EBV-induced B-cell transformation and in the lytic cycle of virus production. - http://jvi.asm.org/cgi/content/full/79/7/4415]

    This shows that TNFα (inflammatory cytokine) and EBV LMP1 (Epstein-Barr virus) promote XMRV to replicate in prostate cancer cells and B-cells, by using the κB-1+ site.

    Thus: Inflammation, EBV infection, and anything else that activates the immune regulator NF-κB, causes XMRV to replicate in prostate cancer and B-cells.
     
  10. Mark

    Mark Former CEO

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    Hmm...so then: the kB-1 site of XMRV is exploiting the immune regulation function in order to replicate itself. NF-kB is intended to promote an immune response to infection or inflammation - but it also promotes XMRV to replicate. Could this perhaps be the mechanism that we have been calling "auto-immune"? Is it in fact XMRV that causes the immune system to get locked into a cycle, by provoking an immune cascade? How does the body respond to this XMRV replication it's provoking?

    This feels like a really solid jigsaw piece fitting in perfectly and linking up two (or three, or four) big sections of a puzzle...
     
  11. leaves

    leaves Senior Member

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  12. Cort

    Cort Phoenix Rising Founder

    Thanks for clarifying that Mark. Isn't that a tricky little devil....

    This suggests to me that XMRV could be activated by any other pathogen that activates NF-kB....it might not be XMRV activating them - it could be them activating XMRV! As you point out we don't know what happens when XMRV then starts replicating - that might be another link in the immune cascade.

    A patient of Dr DeMeirleir's reported that hormones do not appear to be a key trigger for XMRV; if that's true then maybe it is inflammation - from a pathogen, from gut problems, from methylation problems, etc.

    Then you have NK-kB apparently helping to trigger RNase L problems in CFS -- a very interesting conjunction occurring there as well.

    Other pathogens also exploit immune activation as well, I believe. I believe EBV replicates when B-cells are activated. I imagine other people know of other pathogens as well that do that.
     
  13. Mark

    Mark Former CEO

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    EBV, HTLV, HIV, Hepatitis B and C, influenza virus, all promote NF-kB activation.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC199181/

    It seems not unlikely that XMRV also promotes NK-kB activation, but I'm not sure which other viruses exploit NK-kB itself for their own replication, like XMRV does.

    "This activation may serve several functions: to promote viral replication, prevent virus-induced apoptosis, and mediate the immune response to the invading pathogen."

    "Transcriptional regulators of the NF-kB/IkB family promote the expression of well over 100 target genes, the majority of which participate in the host immune response (1). These proteins include a multitude of cytokines and chemokines, receptors required for immune recognition, proteins involved in antigen presentation, and adhesion receptors involved in transmigration across blood vessels walls. Because of this extensive role in immune action, NF-kB has been termed the central mediator of the immune response. Gene knockout and other studies establish roles for NF-kB in the ontogeny of the immune system but also demonstrate that NF-kB participates at multiple steps during oncogenesis (2) and the regulation of programmed cell death"


    Actually, if I remember correctly, this is where I originally came in to this forum, when I first posted with the observation that a virus that could hide and only come out when your immune system was under stress from another invader, would be occupying a cunning little niche...
     
  14. Cort

    Cort Phoenix Rising Founder

    I didn't know such an innocuous name hid such a key factor......NF-kB is a major player in autoimmune disorders and cancer as well.

    http://www.abcam.com/index.html?pageconfig=resource&rid=11255&pid=10629

    Given that I wonder why Maes's paper got buried in Neuroendocrine letters when it found evidence of upregulation of such a key immune factor.

    Herpesviruses

    This paper suggests though that herpesviruses do better when NF-KB production is suppressed not increased. I'm sure this is an evolving field, though.

     
  15. Mark

    Mark Former CEO

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    Exactly, and this appears to me like a crucial cause-and-effect question answered...

    Raising then the next question, as you rightly say, as to whether this process drives a vicious cycle, or whether XMRV just responds to immune activation. Perhaps the answer is both - that there are circumstances where the process can become runaway - if the body notices XMRV replication, or its effects, and responds with more immune activation...

    ...could this be the severe case, where additional co-infections which are similarly parasitic on the immune response are adding their own persistent effects in to the mix? The variety of 'states' of ME/CFS, and their apparent relationship to persistent co-infections, seems to suggest an answer...perhaps the immune system can stabilise in a state where the co-infections are also driving their own cycle of immune activation, together with XMRV - and ordinary infections become chronic?...

    I'm imagining a diagram with a series of cause and effect arrows where you add both EBV and XMRV and get that vicious circle...
     
  16. Mark

    Mark Former CEO

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    I think that's fine and just narrows down what it means that herpesvirus activate NF-kB: the NF-kB is getting activated in order to suppress them: it's an immune response, rather than the herpesviruses 'intending' (!) to switch on NF-kB...

    The quote above:
    "This activation may serve several functions: to promote viral replication, prevent virus-induced apoptosis, and mediate the immune response to the invading pathogen."
    ...I almost added that 'mediate the immune response' sounded most likely to me - all these viruses cause the immune regulator to be activated...and they don't generally like it...figures...:)

    In terms of treatment this is the Catch-22 when you have co-infections: when the body's fighting them, XMRV is replicating; stop the body from fighting the other infections, and XMRV replication stops but the co-infections start back up...somebody posted something very much like that experience just the other day, sounds a familiar story...
     
  17. Gemini

    Gemini Senior Member

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    Mark,

    Do you think it's possible to develop an animal model--infected with XMRV and co-infections--to observe this and develop treatments?
     
  18. Cort

    Cort Phoenix Rising Founder

    The animal model idea is interesting...that is always a big deal in medical research and some researchers are stressing out lab rodents through exercise - and putting them into a state where they resemble CFS....that is their animal model for CFS as I remember. I hope to do a writeup on this....

    I would think that would be a great step..instead of exercise them into CFS - infect them into it :)
     
  19. Gemini

    Gemini Senior Member

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    Cort,

    Agree. Can Mary S. get animal models on the April Workshop agenda?
    Possibly as a follow-up to the first XMRV animal model study? Also,
    am I correct that a small animal XMRV model is now possible--
    thought I saw something about it recently on PubMed?

    Edit update:

    J Virol. 2011 Feb;85(3):1205-13. Epub 2010 Nov 17.
    Early Events in Retrovirus XMRV Infection of the Wild-Derived Mouse Mus pahari.
    These data support the use of Mus pahari as a model for XMRV pathogenesis and as a platform for vaccine and drug development against this potential human pathogen

    http://www.ncbi.nlm.nih.gov/pubmed/21084477
     
  20. taniaaust1

    taniaaust1 Senior Member

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    That's very interesting.

    I agree this area would be a good area to be followed up more in some way. I'd never heard of Dr Maes before, kind of exciting to hear that he's linked it with symptom severity (and then its been linked with XMRV).
    ........

    Thanks Mark for deciphering what that was saying some, helped me understand it a little more rather then being like chinese to me.
    ....

    I hate that idea.. more like they'd then be studying over training syndrome some body builders and athletes get rather then CFS/ME
     

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