Tuesday, 23 June 2015

HERVs and human autoimmune diseases

Is HERV activation a trigger for the development of MS? #MSBlog #MSResearch

"The following study provides in silico evidence that human endogenous retroviruses (HERVs) may play a role in MS and other associated autoimmune diseases. Specific HERV loci, or positions in our genomes, where these HERVs are integrated into our genome, are linked with MS, type 1 diabetes and rheumatoid arthritis (RA). Whether the linkage to these HERV loci are due to the HERVs or another gene, or regulatory element, in the genome close by is a moot point. However, there is other in vivo (within the body) and pathological evidence that HERVs are transcriptionally active in autoimmune diseases and the active HERV products may trigger the so called innate immune system to provide a danger signal that something is amiss in the nervous system, pancreas or joints. This danger signal may be what is required to trigger autoimmune cells to attack self and cause the disease-specific organ damage. This is why treatments that suppress HERV activation may work in these diseases and underpins our trial of raltegravir in MS. Interestingly, herpes viruses, in particular EBV, are known to transactivate HERVs and causes them to emerge from the genome. Therefore, drugs that block EBV activity may also suppress HERV activity. The so called dual viral hypothesis of MS is not a new concept and has been around for many years. I have discussed the EBV-HERV-MS link many times on this blog, therefore, for the regular readers there is noting new here."
"Who knows may be we will get an answer to viral and dual-viral hypotheses of MS in the next 10-20 years."


Epub: Nexø et al. Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci. Immunol Res. 2015 Jun 20.

Background: Autoimmune diseases encompass a plethora of conditions in which the immune system attacks its own tissue, identifying them as foreign. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian manner. 

Objective: In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. 

Results: We found that at least one human endogenous retroviral locus was associated with each of the three diseases. Although there was a significant overlap, most loci only occurred in one of the studied disease. Remarkably, within each disease, there was a statistical interaction (synergy) between two loci. Additional synergy between retroviral loci and human lymphocyte antigens is reported for multiple sclerosis. 

Conclusion: We speculate the possibility that recombinants or mixed viral particles are formed and that the resulting viruses stimulate the innate immune system, thereby initiating the autoimmune response.

CoI: I am the chief investigator of an investigator-led study testing the anti-HIV drug raltegravir in MS. This trial has been generously funded by Merck and sponsored by QMUL. 

28 comments:

  1. This is interesting with regards to your study, or is this as the mouse has stated, term paper research, stating somethting you pretty much already know
    Does this lend anymore weight to your theory regarding Raltegravir, and when oh when will we know the results
    I'm pretty sure you have no investors to satisfy so why the wait?

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    1. Investors get to hear the results begore publication as there are no invesyors publication will be when the results are announced.

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  2. MS research is nowhere near where we hoped it'd be.

    Guess we have to just accept our fates.

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    1. Well it's a lot further on than it was even 5 years ago.

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  3. It's time for a paradigm change in MS, and so more and more paper like this are welcome

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    1. Yep, I also believe that the EBV is the right horse to bet on BUT 10 years are too long......

      we need 5 years only and then off you go for the Nobel prize.

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    2. Maybe EBV is the answer but there is no vaccine and no proven therapy. If we want to get rid of EBV and have a drug the first port of call should be infectious mono and not MS. Remember the Charcot part 1 may fail because raltegravir is not the right drug.

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    3. Then team up with someone who works on EBV vaccine or mono treatment - you should achieve quite a lot in 5 years once the hypothesis is right.

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    4. Isn't there anti ebv specific treatments already being trialled?
      Isn't EBV being linked to a number of cancers and being classed as one of the oncovirus types such as hpv?
      What bewilders me is how for 50 years we've known Ebv is an issue yet no one has examined this further, I know many cancer researchers are looking at it.
      But if this is the cause, does it mean treating it will help or is it already too late? How do you suppose this relates to RRMS vs ppms?
      And how does immunosuppressants work when Ebv mono etc are fought by strengthening the immune system? I have spoken to a doctor with Ms who himself claims immunosuppression is not the way to go and one needs a healthy strong immune system to fight Ms

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    5. Sorry for the numbered replies but isn't there a current trial in nasopharyngeal cancer looking at an ebv vaccine MVA-EBNA1/LMP2? To try to stop the reoccurrence of this cancer in people previously treated?
      So basically chemo followed by vaccine or other maintenance type effect

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    6. Team up... pretty sure profg has done this numerous times but the funders have not been interested.... if you have non believing referees there is not much you can do.
      We spent years trying to get studies on progression off the ground in the late 1990s early 2000s and the referees were not interested.......the concept was too early and there was not enough buy in that ms was more than autoimmunity. It wasnt until the mid 2000s that the idea of ms being more than autoimmunity started to take hold.

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    7. Kris, I also had a doctor once who claimed that it's better to improve our immune system than to lower it.

      IF the viral hypothesis is true than indeed one would need a strong immune system to fight off the viruses.

      Mice what do you think about that?

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    8. Matt Perry would probably ask and I will ask how do you explain the efficacy of HSCT. No immune response, no anti viral immune response but no worse MS or is the virus in the immune response. Is it in the B cells but B cell numbers go crazy after alemtuzumab and why has it been so hard to find live virus.

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    9. Whatever virus is involved one would assume ablation be It full of partial would eradicate such, is it that the newer cells are then naive to myelin etc so the B cells are then no longer harmful

      Let's be honest after so long are we really close to a cure and proper treatments?

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  4. I think we're on the right track, here... Speaking go myself:
    EBV age 12
    Corneal herpes age 19
    EBV (again!) age 30
    First symptoms of MS age 30
    MS flare coinciding with HSV flare age 44.

    I have no doubt they're all linked.

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  5. Dear Dr Giovannoni,

    This is very interesting; could you please point me to the documentation for the software used to create this model? I would like to learn more about this.

    Aidan

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  6. To add, I am one of those convinced of the ebv link, but does that lead us to treatment avenues or merely give us a cause as to why the malfunctioning of the immune system started?
    And for those with Ms its too late?

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  7. If this is the case, then how/why do induction therapies show such efficacy? What do they dungeon a herv perspective? Interesting stuff!

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    1. Good question Its all in the Bs and the EBV reservoir however theGs need to answer but the have not been particularly forthcoming

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  8. Would this not suggest strengthening the immune system would be better than weakening it to help
    There's ALOT of touted ways to lower ebv levels and or increase cd8 T cells by boosting the immune system, would this not help?
    Also does stress lower cd8 T cell levels?

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    1. Prof. Pender thinks like you (more or less)

      http://multiple-sclerosis-research.blogspot.com/2014/06/deficiency-in-cd8-t-cells-in-msa-reason.html

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    2. This is the theory behind Ldn I think?
      Also why NAC and other supplements seem to work according to a blog I read regarding fighting ebv
      Would blood tests of cd8 and nk levels be beneficial at onset? Correcting these might help?

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  9. FYI, a study linking ALS to HERVs.

    http://www.nih.gov/news/health/sep2015/ninds-30.htm

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    1. Very interesting.
      They ask themselves if antiviral therapy could be the solution.
      Prof G. & Pender intuition about viral activity in CNS causing damages and troubles acquires more and more credit.

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    2. Im told ProfG down under already has a trial planned.

      http://stm.sciencemag.org/content/7/307/307ra153

      Human endogenous retrovirus-K contributes to motor neuron disease
      Li W et al.

      A large number of viral sequences are present in the human genome but remain silent. However, under pathological conditions, these viruses can get expressed. Li et al. now report that one such virus, human endogenous retrovirus-K, is expressed in neurons of a subpopulation of patients with amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease. The envelope protein of this virus causes degeneration of neurons, and transgenic animals expressing this protein develop an ALS-like syndrome caused by nucleolar dysfunction in motor neurons. Reactivation of the virus is regulated by the transcription factor TDP-43. Thus, therapeutic approaches against this virus could potentially alter the course of the disease.

      Will this explain the us of raltegovir in Charcot 1?

      I should have asked him when bumping into him in Sheffield today (200miles North of London)...how odd was that.

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