Screening for JC Virus Variants May Aid PML Detection in Multiple Sclerosis Patients

Prompt detection of the neurotropic variant of the John Cunningham virus in blood may be a critical step in the prevention of the development of severe progressive multifocal leukoencephalopathy in patients with multiple sclerosis, research published in the European Journal of Neurology indicates.

Recently, several cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients taking a broad range of therapies for multiple sclerosis (MS), including natalizumab (Tysabri), fingolimod (Gilenya), and dimethyl fumarate (Tecfidera). Since its market reintroduction in 2006 through December 2014, there have been 514 confirmed cases of PML in patients taking natalizumab. In this study, Maria Inmaculada Dominguez-Mozo, PhD, of Hospital Clinico San Carlos in Madrid, and colleagues analyzed data from patients taking natalizumab to better understand the mechanism behind John Cunningham virus (JCV) conversion and PML infection.

The study included 100 MS patients who were on natalizumab for at least 3 months (3-39 months). Peripheral blood mononuclear cells, serum, and urine samples were collected from all patients at baseline (without treatment) and quarterly thereafter (after treatment onset). Cerebrospinal fluid (CSF) samples were collected only in patients suspected of having PML.

CLINICAL CHART: Multiple Sclerosis Treatments

Dependent on the level of JCV excretion in urine, patients were divided into three groups: continual (34%), intermittent (52%), and absent (14%). The viral load in the continual group was significantly higher at different treatment points compared to the intermittent group. JCV DNA was detected in the blood and/or serum of 23% of patients. Four of those patients had simultaneous positive indications in the blood and serum, 2 of whom went on to develop confirmed PML.

In the 2 patients with confirmed PML, JCV was only detected in both blood and serum at PML diagnosis. The same pathogenic neurotropic variant was identified in the blood, serum, and CSF samples of the non-severe PML patient (P1004), in contrast to the 4 neurotropic variants identified in the patient with severe PML (P89).

“In these two PML patients the persistence of JCV and the number of neurotropic viral variants in PBMCs, serum and CSF, at PML diagnosis, were associated with the symptoms and aftermath of this disease,” the authors wrote. Patient P89, a carrier of the DR&-DQ2 haplotype and who had a persistent JCV viral load, suffered from a severe case of PML with worse outcomes than P1004. Three of the 4 neurotropic variants detected in P89 had more binding sites for more transcription factors than the variant detected in P1004. “These transcription factors are in the PBMCs and glia cells and allow a higher rate of viral replication, resulting in a more severe case of PML,” they wrote.

“These results point to the usefulness of screening for the neurotropic variant in PBMCs throughout the course of natalizumab treatment. This work also suggests that the number and quantity of neurotropic variants are related to the severity of PML,” the authors concluded. 


  1. Domínguez-mozo MI, García-montojo M, Arias-leal A, et al. Monitoring the John Cunningham virus throughout natalizumab treatment in multiple sclerosis patients. Eur J Neurol. 2015; doi:10.1111/ene.12834.