Methods for the detection of jc polyoma virus

Abstract

Methods and compositions for determining whether a subject is at risk for PML, including subjects being treated with immunosuppressants, by determining whether the subject harbors a JCV variant with reduced binding for sialic acid relative to a normal JCV, are presented. Furthermore, combinations of JCV-VP1 sequence variations that are associated with PML and that can be used as a basis of an assay for identifying subjects susceptible to PML, subjects with PML (e.g., early stage PML), or subjects at risk of developing PML in response to an immunosuppressive treatment are provided.

Description

RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) from U.S. provisional application Ser. No. 61 / 150,310 entitled “Methods for the Detection of JC Polyoma Virus” filed Feb. 5, 2009, the disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention relates to methods for the detection of the human JC polyomavirus virus, diagnosis of progressive multifocal leukoencephalopathy (PML), and the development of therapeutics for PML.BACKGROUND OF THE INVENTION[0003]JC polyomavirus (JCV) infection in humans can cause a demyelinating disease of the central nervous system, progressive multifocal leukoencephalopathy (PML). However, JCV infection usually does not result in PML in healthy subjects. JCV infection is prevalent in many human populations without causing widespread PML. PML typically only develops in JCV-infected subjects that also have a weakened immune system. Subjects that are immuno-compromised due to a disease ...

AI Technical Summary

Benefits of technology

[0011]Aspects of the invention are based, at least in part, on the discovery that certain types of mutations in the JCV capsid protein are associated with the conversion of an asymptomatic form of JCV infection into a PML-associated form of JCV. According to aspects of the invention, without committing to any particular mechanism, mutations that disrupt the ability of a JCV particle to bind to or interact with sialic acid can result in the virus no longer being contained in the peripheral compartment of a subject and result in the virus obtaining freer passage to the CNS, a site of PML disease. In some embodiments, these mutations allow virus to achieve that by avoiding “trapping” on certain glycoproteins and glycolipid pseudoreceptors expressed in peripheral organs and cells, including but not limited to immune cells and red blood cells. Additionally, as some of these sites are targets on normal host immune response (antibody and T-cell) these mutations may allow virus evading recognition by the immune system, particularly in subjects with weakened immune systems.

[0013]In some embodiments, aspects of the invention relate to determining whether a subject has been exposed to an infection by any JCV variant. In some aspects, infection by a wild-type JCV variant may increase the risk profile for PML since PML associated mutations may arise from the wild-type JCV, even though these may be rare events. Accordingly, in some embodiments, a subject may be tested for the presence of one or more indicia of JCV infection (e.g., detection of viral proteins or nucleic acid, or indirectly via the detection of an immune response to a JCV infection, e.g., in the form of serum antibodies to JCV viral proteins). It should be appreciated that indicia of any JCV infection (e.g., wild-type or variant) may be evaluated. If a subject has already been exposed to a JCV infection, then the subject may be identified as having a higher risk profile than a non-infected subject. Accordingly, a JCV-infected subject that is being treated with an immunosuppressive agent, may be evaluated for specific JCV mutations or may be monitored more frequently than a non-infected subject.

Problems solved by technology

While infection by JCV is asymptomatic in most subjects, infection may result in serious conditions (like PML) and even death in some subjects.

However, since publicly available PML sequences were obtained from CSF or brain tissues of PML patients whereas non-PML sequences were obtained from the urine of healthy subjects, just based on the analysis of Genebank samples it could not unequivocally be demonstrated whether these amino acid variants were produced via a viral mutation in the patients or represented one or more rare viral variants that occur in all JCV clades and are enriched (e.g., positively selected) in PML cases as being more likely to be causing PML.

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