Wednesday, 11 June 2014

Clinic Speak: JCV prevalence rates in MSers

Is PML an example of evolution in action? #ClinicSpeak #MSBlog #MSResearch

"The following study shows confirms that about 57% of MSers are JC virus seropositive and are therefore at risk of developing PML as a complication of natalizumab treatment. This figure does increase with age; MSers who are JCV seronegative can get exposed to wild-type JC virus in the environment. When you get infected with the JC virus it does not cause and identifiable infection; we think the infection is asymptomatic or very mild. Once infected the virus persists in the body. I use the term persist and not latent, because JCV does not have a latency programme that allows it to hibernate in the body. To persist it has to be replicating and living somewhere in the body. At present we think this is occurring in the kidney and possibly the tonsils and bone marrow. The fact that it is a persistent virus means that it may be druggable, i.e. targeted by a drug  that can stop it replicating. If it is druggable then we may in the future be able to treat people who are JCV positive with a drug and clear the virus. This would then reduce, or even eliminate, the risk of PML. I am aware of several Pharma companies working on the virus at the moment with this aim in mind."

"When and how does PML develop? We don't know. What we do know is that is a slow process and takes months to years to occur. The virus has to acquire several mutations in its binding, or surface protein, that allows it to stick to glial cells in the brain. In addition, the PML strains have mutations in  the so called regulatory regions of  their genomes. All these mutations must take time to occur and there must be a compartment in the body where the mutant PML strain is being selected. We have not identified this compartment yet, but I hypothesise that it must be in the central nervous system. Why? The mutant viruses will almost certainly need its target cells to bind so as to acquire a selection advantage over so called wild-type virus. These cells, astrocytes and oligodenrocytes, are only present in the central nervous system. This may be why PML is so common on natalizumab and not other therapies; natalizumab is the only drug that stops immune surveillance of the CNS substantially and allows the evolution and virus free reign at producing a PML-disease causing strain. A functioning immune system is too clever for the virus and prevents the virus evolving. This theory also explains why a high titre, or antibody index, of antibody against JCV is an important risk factor for developing PML. As the virus replicates and mutates viral particles will leak out of the CNS into the periphery and will stimulate the immune system to produce more antibody. This is what we call an immunological booster and is not too dissimilar to the booster response we see when we give people booster vaccinations. This is why I am beginning to use a rising anti-JCV titre in my decision making."

"I hope  this all makes sense to you. I have tried to represent it a simple cartoon."


Bozic et al. Anti-JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial.Eur J Neurol. 2014 Feb;21(2):299-304.

BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of JC virus (JCV) infection due to combined host and viral factors. Anti-JCV antibodies provide a means to assess JCV exposure and stratify PML risk. The reported seroprevalence of anti-JCV antibodies varies from 39% to 91% depending on assay methodology and population studied. A two-step anti-JCV antibody assay (STRATIFY JCV™; Focus Diagnostics, Cypress, CA, USA) detected anti-JCV antibodies in approximately 55% of MSers. This study describes the prevalence of anti-JCV antibodies in a large, multinational MS population.


METHODS: This cross-sectional epidemiology study was designed to enroll a minimum of 2000 MSers with an MS diagnosis of any type, irrespective of treatment, from Europe, Canada and Australia. Anti-JCV antibody prevalence was determined by STRATIFY JCV; the effects of demographic and disease characteristics were evaluated.

RESULTS: A total of 7724 MSers from 10 countries participated in the study. Overall anti-JCV antibody prevalence was 57.1% (95% confidence interval 56.0%-58.2%). Seroprevalence was significantly associated with increasing age, gender and country of current residence (P < 0.0001). No significant differences in anti-JCV antibody prevalence were associated with MS disease characteristics, including duration and type of MS and number and duration of MS therapies.

CONCLUSIONS: Overall seroprevalence of anti-JCV antibodies in MSers from Europe, Canada and Australia was consistent with previous studies using the STRATIFY JCV assay. Anti-JCV prevalence differed significantly by age, gender and country, but no geographical pattern was evident. Disease and treatment type were not associated with differences in anti-JCV antibody status.

3 comments:

  1. "Is PML an example of evolution in action?"

    A good question which can be asked for quite every virus.
    I have read an interesting article some time ago.

    Unfortunatly it's only availible in german:

    http://www.scinexx.mobi/dossier-517-1.html

    Translated with google translate:

    https://translate.google.de/translate?hl=de&sl=de&tl=en&u=http%3A%2F%2Fwww.scinexx.mobi%2Fdossier-517-1.html

    ReplyDelete
  2. Which pharma is working on a JCV treatment (assuming it is druggable)?

    ReplyDelete
    Replies
    1. I can only guess, but I would have thought any company that has drugs that can trigger PML
      anti-CD20?, anti-CD49d? would have an interest.

      Delete

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