Alternatives to EBV

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Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis. Engdahl E, Gustafsson R, Huang J, Biström M, Lima Bomfim I, Stridh P, Khademi M, Brenner N, Butt J, Michel A, Jons D, Hortlund M, Alonso-Magdalena L, Hedström AK, Flamand L, Ihira M, Yoshikawa T, Andersen O, Hillert J, Alfredsson L, Waterboer T, Sundström P, Olsson T, Kockum I, Fogdell-Hahn A. Front Immunol. 2019 Nov 26;10:2715. doi: 10.3389/fimmu.2019.02715.

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) aetiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8,742 people with MS and 7,215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9 × 10-22), and increased risk of future MS (OR = 2.22, p = 2 × 10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS aetiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

What is the aetiological triggerof MS. Is it EBV, is it something else, is it EBV and something else. HHV6 has been around as a candidate since the 1990s and appears to be more common

Human herpesvirus 6 (HHV-6) is the common collective name for Human betaherpesvirus 6A (HHV-6A) and Human beta herpesvirus 6B (HHV-6B). These closely related viruses are two of the nine herpesviruses known to have humans as their main target and host. HHV-6 has been reported to transactivate EBV. Individuals are at a 10-fold less risk of MS if they are seronegative for EBV. However, among individuals who are positive, those that acquire EBV infection later in life are at a 3-fold greater risk for MS.

77% of humans are exposed to HHV-6B by the age of two and the prevalence of HHV-6 in adults is assumed to be over 90%. After the primary infection, the HHV-6 DNA appears briefly in the serum (and spinal fluid) and then a small amount of virus establishes latency. HHV-6 active infections can persist in the brain tissue long after all traces of the virus have disappeared from the blood,hence the interest in MS.

HHV-6 may activate EBV so both viruses could be involved. This will be a case of if an anti-viral is developed that tackles HHV-6 will it change the risk of developing MS

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  • Are there any anti virals in development that stop ebv or HHV=6B? If so, will they be cheap enough to do trials that for once prove or disapprove the above hypothesis?I have been coming to this blog for last 5 years talk about the black Swan etc. Yet the research is at a stand still while Ms becomes a pandemic. What is the point in reporting this if nothing is going to be done about it? The virus theory cannot be the single cause otherwise large percentage of human race should develop MS. Genetics cannot be the single cause of MS as it effects all races and gender. Lack of vitamin d cannot be a single cause of MS as it would mean all people living in the North develop MS. Put all the research papers into cloud data lake. The date can be any format word excel pdf etc. Run unsupervised Machine learning algorythms to discover the link. A new antibiotic has been just discovered that works against super bugs by AI. Or tell me where I can get hold of ms research papers from a site that I can download for free. So I can run machine learning models against the data. I find the lack of progress amazing with such rapid advances in computer and automation of biological assays.

    • “I find the lack of progress amazing with such rapid advances in computer and automation of biological assays.”

      I wholeheartedly agree with you. My friend was diagnosed with MS in the mid 80s and was asked by the neuro at the time whether she had had glandular fever (EBV) as this was likely a risk factor / possible cause. 35 years later nothing has happened.

      I now view MS research as an industry. The approach has been expand or die. So we have huge numbers of MS researchers around the world and neuro prescribing MS drugs which run into the tens of billions of $ each year. You will notice that most neuros specialising in MS get paid by pharma to be on steering committees / provide consultancy input etc. They declare this on the second page of slide presentations (often naming 10-15 companies) but never declare the amount received!

      I’m still waiting for the Black Swan. If EBV is the cause / drive of the disease a vaccine would prevent the disease and possibly put it into remission for those with the disease. Is a vaccine/ antiviral likely to come to market? I don’t think so:

      – tens/hundreds of billions wiped off the share value of pharma companies who sell MS drugs:
      – thousands of MS researchers out of a job;
      = neuros / MSologists who would no longer be able to supplement their salaries with payments for service given to pharma companies;
      – no more international conferences around the world where researchers / neuros dish out prizes and work out how the gravy train can bev kept on the tracks.

      In 2020 we should have answers by now, but no one will publish a definitive papers showing the central role of EBV and pharma won’t allow an antiviral to take out the cash cows they have developed.

      Even Prof G acknowledges that relapses / focal inflammation is not the real MS (it’s likely a virus in the brain).

      Money drives this show and it will take a brave soul to expose this scandal.

    • If the above sounds critical let me add balance by offering a possible way out. Have you approached the makers of Brincidofovir to give you supply on compassionate basis to see if it stops MS in its tracks? Then recruit barts patients in advanced stages of MS and ask volunteers to help run the trial to reduce cost. In 5 years you will have the answer. And we can all stop wasting time by running around in circles like headless chickens, is it ebv or hhv-6 activating ebv, etc.
      With just 200 barts patients. You can end this never ending saga of the black Swan.

      • What makes you think you know best? No machine can ever learn what Prof G and MD know. You need to go back to your neuro. If barts team would of responded to you. The reason they are silent they do not agree and if I was honest their being kind because you have MS.

        • That’s not what I’m saying. AI will come up with links trolling through massive amount of data. You can easily upload entire medical knowledge to cloud data store. And machine learning will trowl through the entire data set and come up with links. You still need to be expert to dismiss the coincidental links and recognise links that actually point to a new discovery. I know it sounds amazing and crazy. But this where technology is at. How do I know? Its my area of speciality. Just set up a similar system at a manufacturing company to improve their production processing.

    • Valaciclovir was studied a long time ago to treat MS (https://www.ncbi.nlm.nih.gov/pubmed/15957509). The study showed a trend towards reduced relapses, but this was not statically significant and didn’t show on the MRI scans. Another study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772668/pdf/1005-09.pdf) showed that the half life of EBV infected B-lymphocytes in valaciclovir treatment is 11 months. They calculated that treatment for 11.3 years could provide eradication. The former study ran for only 2 years (just over 2 half-lives), so it’s hardly surprising that the results didn’t reach statistical significance. Aciclovir, Valaciclovir, Penciclovir and Famciclovir all have actions against the human herpes viruses like EBV (HHV4) and HHV6.
      Michael Pender genetically altered T-cells to target EBV infected B-cells of those with progressive MS and found that when the treatment worked well, they improved clinically. This is in stark contrast to expensive drugs that slow the progress of disease, but don’t result in clinical improvement. https://insight.jci.org/articles/view/124714/pdf
      I wonder why nobody has done a study combining B-cell depleting agents with long term thymidine kinase blocking agents? CARE-MS 1 and 2 only used Aciclovir for 2 months.

  • Could we widen EBV as the cause of other ailments? What causes other autoimmune issues and allergies? Something must trigger autoimmunity. If we could prove out that EBV was a wider problem, could that drive research?

    • It is best known as the cause of infectious mononucleosis (“mono” or “glandular fever”). It is also associated with various non-malignant, premalignant, and malignant Epstein–Barr virus-associated lymphoproliferative diseases such as Burkitt lymphoma, hemophagocytic lymphohistiocytosis,[2] and Hodgkin’s lymphoma; non-lymphoid malignancies such as gastric cancer and nasopharyngeal carcinoma; and conditions associated with human immunodeficiency virus such as hairy leukoplakia and central nervous system lymphomas.[3][4] The virus is also associated with the childhood disorders of Alice in Wonderland syndrome[5] and acute cerebellar ataxia[6] and, based on some evidence, higher risks of developing certain autoimmune diseases,[7] especially dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome,[8][9] and multiple sclerosis.[10][11][12] About 200,000 cancer cases per year are thought to be attributable to EBV.[1

      https://en.wikipedia.org/wiki/Epstein%E2%80%93Barr_virus

  • HHV-6 may activate EBV so both viruses could be involved. This will be a case of if an anti-viral is developed that tackles HHV-6 will it change the risk of developing MS

    From the same family

    They used an antiviral drug called acyclovir, which blocks viral DNA amplification. They administered the drug to mouse models that were subjected to hyper-thermic stress to mimic fever. Study data show this prevented HSV reactivation and the death of neurons.

    Although further studies are required, Sawtell said this finding holds promise that current antivirals may impact the outcomes of long term HSV latency and reactivation in the nervous system.

    https://medicalxpress.com/news/2020-03-biological-link-reactivated-hsv-neurological.html

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