Sunday, 8 March 2015

Is there a specific variant of EBV associated with MS?

It is time the MS community takes the EBV hypothesis seriously? #MSResearch #MSBlog

"I am jealous; this is a study we were meant to do several years ago. With new deep sequencing technologies you get low frequency DNA sequencing reads from viruses present in peripheral blood including EBV. These viral sequences are typically filtered out and ignored with geneticists analyse genomic DNA data. We had a collaboration with colleagues in the UK to analyse EBV sequence data from MSers, disease controls and healthy people. Unfortunately, the person leading on this left our group and the project was never completed."

"The study below suggests that a specific genetic variation in one of the genes from EBV is associated with MS. Could a specific subtype of EBV be causing MS? This is not such way-off or out-of-field hypothesis. Most viruses that cause systemic infections and rarely cause a disease of the central nervous system, as a delayed or complication of infection, have a variant or variants that evolve to infect the brain. Examples of this are are the JC virus (PML), measles (subacute sclerosing panencephalitis or SSPE), rubella (panencephalitis)  and herpes simplex virus (encephalitis). Why would EBV be any different? What we haven't be able to establish with any confidence is whether or not the EBV we find in the brains of MSers is there by accident or driving the MS disease process. You need to remember that EBV infects B-cells and lives in B-cells; therefore any disease that involves B-cells will have a small number of EBV-infected B cells in the target organ that is found there by chance. MS maybe no different. The EBV hypothesis of MS, i.e. that EBV is the cause of MS, is not driven by biological or experimental data, but by epidemiological studies. For example, if you are not infected with EBV the chances of you getting MS are close to zero. In comparison if you have been infected with EBV, in particular if you have symptomatic EBV infection or infectious mononucleosis or glandular fever, the chances of you getting MS soar. Unfortunately, the epidemiological data are not good enough to prove, or disprove, causation. This is why this study's findings are so tantalising and need to be confirmed."

"What next? I suggest the International MS genetics consortium (IMSGC) take on the task of trying to replicate this study's findings. Why the IMSGC? The IMSGC have the necessary samples in the freezer and have in depth data on the MSers and their family members to analyse associations and new hypotheses in detail. For example, they can address vertical transmission (mother-to-child) and horizontal transmission (person-to-person) patterns and associate them with age of onset, latitude, country of birth and residence, etc. It is very likely that if EBV causes MS it will interact with some human genes to trigger the disease. The IMSCG have acquired large amount of genomic data already to fast-track analyses of this nature. Finally, if the IMSCG take up the challenge of replicating this study it will be much cheaper that starting from scratch. The other thing is speed; the IMSGC have time and resources on their side."

"I have one reservation about this study that could potentially be addressed by a pathological study. The peripheral blood compartment may not be the best compartment to look for MS-specific EBV variants. The best place to look is in the brain of MSers. Therefore in parallel to the proposed IMSGC  replication studies I would urge funders to put out a specific call for MS investigators to tackle the CNS vs peripheral compartment EBV hypothesis."


"I often use the virus HTLV-1 as an analogy when discussing the viral hypothesis of MS. It is an interesting virus as it can be transmitted vertically and horizontally and rarely causes a disease in infected subjects that is not too dissimilar to PPMS, called tropical spastic paraparesis or HTLV-1 associated myelopathy (HAM). I discuss this here to illustrate the transmission patterns."

Epub: Mechelli et al. Epstein-Barr virus genetic variants are associated with multiple sclerosis. Neurology. 2015 Mar 4. 

OBJECTIVE: We analyzed the Epstein-Barr nuclear antigen 2 (EBNA2) gene, which contains the most variable region of the viral genome, in MSers and control subjects to verify whether virus genetic variants are involved in disease development.

METHODS: A seminested PCR approach and Sanger sequencing were used to analyze EBNA2 in 53 patients and 38 matched healthy donors (HDs). High-throughput sequencing by Illumina MiSeq was also applied in a subgroup of donors (17 MSers and 17 HDs). MSers underwent gadolinium-enhanced MRI and human leucocyte antigen typing.

RESULTS: MS risk significantly correlated with an excess of 1.2 allele (odds ratio [OR] = 5.13; 95% confidence interval [CI] 1.84-14.32; p = 0.016) and underrepresentation of 1.3B allele (OR = 0.23; 95% CI 0.08-0.51; p = 0.0006). We identified new genetic variants, mostly 1.2 allele- and MS-associated (especially amino acid variation at position 245; OR = 9.4; 95% CI 1.19-78.72; p = 0.0123). In all cases, the consensus sequence from deep sequencing confirmed Sanger sequencing (including the cosegregation of newly identified variants with known EBNA2 alleles) and showed that the extent of genotype intraindividual variability was higher than expected: rare EBNA2 variants were detected in all HDs and MSers (range 1-17 and 3-19, respectively). EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features.

CONCLUSIONS: Our study unveils a strong association between Epstein-Barr virus genomic variants and MS, reinforcing the idea that Epstein-Barr virus contributes to disease development.

7 comments:

  1. Prof G, could rituximab and ocrelizumab be working via killing EBV infected B cells?

    ReplyDelete
  2. Hi
    Not sure if you guys saw my previous post regarding a chap who contracted hiv after Ms and once treated with HAART had no issues with MS as far as I'm aware
    He even stopped beta interferon for awhile with no issues
    This was on another forum, supports your hypothesis even more

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    Replies
    1. stopped beta interferon for a while?

      did he have to go back on it?

      Delete
  3. Hey Team G.

    I know it's relative guess work until the trials are done, but in terms of your best guess/hypothesis, is your working assumption that eradicating EBV/suprressing HERVs would "cure" MS for those that already have it. Or do you see it more as a preventative measure (i.e. vaccinate kids to stop MS from ever developing)?

    Thanks!

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    Replies
    1. This is something the same as what I wanted to ask. If your chances of developing MS are nigh on zero if you are never infected with EBV, why not develop a vaccine for EBV? Not that this may help those of us who have already developed MS. ???

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  4. Why not give progressive ms patients anti ebv anti herv treatment. I'm sure most would be more than happy to try an evidence based experimental treatment with great potential.

    ReplyDelete

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