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NIH NCI study shows Epstein Barr enhances XMRV replication

Discussion in 'XMRV Research and Replication Studies' started by ixchelkali, Mar 18, 2011.

  1. ixchelkali

    ixchelkali Senior Member

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    [SIZE=-1]Journal of Virology, April 2011, p. 3179-3186, Vol. 85, No. 7[/SIZE]
    [SIZE=-1]0022-538X/11/$012.00+0 doi:10.1128/JVI.02333-10[/SIZE]
    [SIZE=-1]American Society for Microbiology. All Rights Reserved.[/SIZE]
    NF-[​IMG]B Activation Stimulates Transcription and Replication of Retrovirus XMRV in Human B-Lineage and Prostate Carcinoma Cells[​IMG]

    Shuhei Sakakibara,1* Kaori Sakakibara,2 and Giovanna Tosato1

    Laboratory of Cellular Oncology,1 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

    Received 8 November 2010/ Accepted 20 January 2011

    Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-[​IMG]B activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-[​IMG]), which activates NF-[​IMG]B, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-[​IMG] and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-[​IMG]B activator, increased long terminal repeat (LTR)-dependent XMRV transcription. We identified two NF-[​IMG]B binding sites (designated [​IMG]B-1 and [​IMG]B-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-[​IMG]B component p65/RelA. Mutation of the [​IMG]B-1 site, but not the [​IMG]B-2 site, impaired responsiveness to TNF-[​IMG] and LMP1 in reporter assays. A mutant XMRV with a mutation at the [​IMG]B-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145, and PC-3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4, and the Burkitt's lymphoma cell line BJAB. These results demonstrate that TNF-[​IMG] and EBV LMP1 enhance XMRV replication in prostate carcinoma and B-lineage cells through the [​IMG]B-1 site in the XMRV LTR, suggesting that inflammation, EBV infection, and other conditions leading to NF-[​IMG]B activation may promote XMRV spread in humans.
     
  2. eric_s

    eric_s Senior Member

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    There was already some discussion about that study earlier here, looks like now it was finally printed.
     
  3. ixchelkali

    ixchelkali Senior Member

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    Thanks, eric_s. Since it was dated April 2011 I thought it was new. Of course, when you have no short term memory to speak of, everything is new! ;)
     
  4. Riley

    Riley Senior Member

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    Is there a link to the previous discussion? I thought this was going to be big news.
     
  5. ixchelkali

    ixchelkali Senior Member

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    Oh, good, I'm not the only one.;) There's a link in Eric's post above, on the word "here."
     
  6. Bob

    Bob

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  7. omerbasket

    omerbasket Senior Member

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    I've read the entire study, and I think that this is very interesting.
    There are studies that shows that NF-kappa-B is raised in ME/CFS, as well as in Prostate Cancer, Fibromyalgia and Irritable Bowel Syndrome:
    http://www.ncbi.nlm.nih.gov/pubmed/17693979

    http://www.ncbi.nlm.nih.gov/pubmed/17693978

    http://informahealthcare.com/doi/abs/10.1080/03009740510026715

    http://www.ncbi.nlm.nih.gov/pubmed/20460401

    http://www.ncbi.nlm.nih.gov/pubmed/19301309

    http://www.ncbi.nlm.nih.gov/pubmed/20032425

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1794118/

    We all know about the EBV connection. Besides that, a professor that studies Fibromyalgia once told me that there is an increased prevalence of Fibromyalgia in people with Crohn's Disease (or the other way around). Crohn's Disease is an autoimmune disease, and one of the best treatments for Crohn's Disease is a class of drugs named "ANTI-TNF-alpha" - they inhibit TNF-alpha. In this study we have seen that TNF-alpha causes, likely because of activation of NF-kappa-B, XMRV to replicate quicker.
    So - we have TNF-alpha which inhibition of causes in many cases remission in Crohn's Disease, we have a larger number of Fibromyalgia patients within the patients with Crohn's Disease (than in the other populations), and we have a possible connection between fibromyalgia and a retrovirus that's replication would be inhibited if you use the same ANTI-TNF-alpha medicines that help Crohn's patients. So perhaps they have the same cause?
    Some would say - "but corticosteroids help patients with Crohn's, and they increase the replication of XMRV in vitro". That's correct - But what they also do is decrease the level of inflammation - and perhaps the effect of the corticosteroids an the virus (i.e helping it replicate) is less important than their effect on the inflammation (decreasing the level of inflammation, and perhaps therefore inhibiting replication by XMRV, perhaps more than the corticosteroids induced its replication).

    And, the connection to EBV is very important, and it might help to explain how outbreaks of ME/CFS occurs when there is only casual contact between people - perhaps they harbor XMRV, then get infected by EBV and then the XMRV goes out of control.
    It would be interesting to know if other viruses connected to ME/CFS, like CMV and HHV-6 also help XMRV to replicated - by this mechanism (of NF-kappa-B) or by another mechanism.

    Also, the Silverman's study in which they found that IL-8 is induced by XMRV is interesting, since raised levels of IL-8 are also connected to ME/CFS, Prostate Cancer, Fibromyalgia and Irritable Bowel Syndrome (although there is one Klimas study im which she found that IL-8 was REDUCED in patients with CFS... Pretty odd, because, for example, the WPI and Kenny De-Merleir found it allevated - when De-Merleir found it elevated in ME/CFS patients that are positive for XMRV):
    http://www.tcrt.org/OpenAccess/LToE_TCRT_3_5_411.pdf

    http://www.ncbi.nlm.nih.gov/pubmed/20407431

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC540195/

    http://www.ncbi.nlm.nih.gov/pubmed/11477278

    http://forums.aboutmecfs.org/attachment.php?attachmentid=3848&d=1284150125
     
  8. Esther12

    Esther12 Senior Member

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    It's so weird that there seems to be all these reasons that XMRV would fit in well as a potential cause of CFS... but most now think it's likely just contamination. If XMRV (or similar) was in 8% of the population, but needed to be triggered/other factors to cause illness, that's the only way I could see CFS being largely caused by a single virus.

    Maybe EBV has this affect on a number of viruses? Maybe XMRV will work out for CFS, and all those negative studies will have gotten something wrong? Maybe someone's playing a joke on us.
     
  9. omerbasket

    omerbasket Senior Member

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    Or maybe some of the scientists involved have an ego which is too big in order to reproduce other's methods, exactly as they were done.

    By the way, I think it's very possible that XMRV needs something more in order to become pathogenic (it's probably very likely), but the question is: If you take XMRV (or other HMRV) off of the equation, could you still have ME/CFS?
    I think that due to many things (it being a retrovirus; MLVs-induced diseases in animals; the very large percantages in which it's found in ME/CFS patients, against the much much smaller percentages in the healthy population; and more) it's most reasonable that without XMRV or another HMRV you won't have ME/CFS, but that is not proven yet.

    Now, if XMRV (HMRV) would be proven to be a pathogen that is neccessary for the development of ME/CFS, it still doesn't say that it's sufficient for that. I mean - do wee know for sure that HIV does not need something else in order to become pathogenic? But if you take HIV off of the equation, you don't have AIDS. However, finding things that helps XMRV be pathogenic might help finding therputic ways other than those that deal with XMRV, in order to help ME/CFS patients. It's just that if XMRV is neccessary in order for a person to have ME/CFS, I think it would be wiser to concentrate on dealing with XMRV at first.
     

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