Friday, 13 June 2014

Neutralizing antibody to JC virus

Could neutralizing anti-JC virus antibodies prevent PML? #MSBlog #MSResearch

"The study below has developed and assay to look an antibodies in MSers that can neutralise the receptor protein on the surface of JC virus, the virus that causes PML. I note they are focused on the wild-type virus protein called VP1. This may not be relevant to the strain that causes PML as this protein is mutated in the PML strains and as a result the mutant loses its ability to bind to sialic acid a receptor on many cells. It is feasible that neutralizing antibodies to wild-type virus will not be able to neutralise the mutant strains and allow them to escape and cause PML. Neutralizing anti-viral antibodies are interesting story and has been well-developed in the field of HIV. Without an animal model of JCV infection and PML it will be difficult to study this in detail. This is an example of how animal research could potentially provide insights that are directly relevant to human disease."

Diotti et al. Cloning of the first human anti-JCPyV/VP1 neutralizing monoclonal antibody: epitope definition and implications in risk stratification of patients under natalizumab therapy. Antiviral Res. 2014 Jun 5. pii: S0166-3542(14)00157-0.

Background: JC virus (JCPyV) has gained novel clinical importance as cause of progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease recently associated to immunomodulatory drugs, such as natalizumab used in MS. Little is known about the mechanisms leading to PML, and this makes the need of PML risk stratification among natalizumab-treated patients very compelling. Clinical and laboratory-based risk-stratification markers have been proposed, one of these is represented by the JCPyV-seropositive status, which includes about 54% of MS patients. 

Objective: We recently proposed to investigate the possible protective role of neutralizing humoral immune response in preventing JCPyV reactivation. 

Methods & Results: In this proof-of-concept study, by cloning the first human monoclonal antibody (GRE1) directed against a neutralizing epitope on JCPyV/VP1, we optimized a robust anti-JCPyV neutralization assay. This allowed us to evaluate the neutralizing activity in JCPyV-positive sera from MSers, demonstrating the lack of correlation between the level of anti-JCPyV antibody and anti-JCPyV neutralizing activity. 

Conclusions: Relevant consequences may derive from future clinical studies induced by these findings; indeed the study of the serum anti-JCPyV neutralizing activity could allow not only a better risk stratification of the patients during natalizumab treatment, but also a better understanding of the pathophysiological mechanisms leading to PML, highlighting the contribution of peripheral versus central nervous system JCPyV reactivation. Noteworthy, the availability of GRE1 could allow the design of novel immunoprophylactic strategies during the immunomodulatory treatment.

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