Monitoring the John Cunningham virus throughout natalizumab treatment in multiple sclerosis patients

Abstract

The detection of the neurotropic variant in blood during natalizumab treatment could be critical in the prevention of the development of severe PML, since this variant appears simultaneously with the clinical symptoms of PML and mutates quickly.

High cumulative JC virus seroconversion rate during long‐term use of natalizumab

“…JCV DNA positive) but tested seronegative initially, since JCV DNA status of our patients was not available. Recently, the results of some small studies suggested that patients can have viraemia without anti-JCV antibodies [5][6][7] more often than initially described by Rudick et al [19], who concluded that this was a rare condition. Less likely though, these patients can also exist in the seronegative group in which the patients stayed seronegative during follow-up.…”

“…By this mechanism, natalizumab prevents leukocytes migrating into the central nervous system and thereby suppresses the inflammatory reaction in patients with multiple sclerosis (MS). In addition, it has been reported that seronegative patients can be JCV DNA positive, suggesting that seroconversion can also be caused by reactivation of the virus already present in a patient [5][6][7]. This is a rare but potentially life-threatening opportunistic infection of the brain caused by reactivation and replication of the John Cunningham virus (JCV).…”

“…However, patients who are initially tested seronegative can be infected with the JCV and seroconvert during natalizumab treatment resulting in an increased risk of developing PML. In addition, it has been reported that seronegative patients can be JCV DNA positive, suggesting that seroconversion can also be caused by reactivation of the virus already present in a patient [5][6][7]. Initially, Gorelik et al [8] reported annual seroconversion rates of about 2% in RRMS patients treated for 48 weeks with natalizumab with a follow-up of 5 years.…”

Natalizumab-treated patients at high risk for PML persistently excrete JC polyomavirus

“…Intermittent excretion made the measure of urinary JCV of little diagnostic benefit, leaving it largely ignored in the approach to mitigating PML risk. Given that appropriate interrogation of the urine reveals a consistent signal that likely represents encapsidated virus, that the viral load is high and strongly correlated with high antibody titer, and the fact that the level of viruria increases with progression to PML (Delbue et al 2015; Bellizzi et al 2013; Domínguez-Mozo et al 2015) suggest urinary JCV has clinical value. Active JCV infection in the urine can often be detected prior to JCV antibodies (Laroni et al 2012; Lanzillo et al 2014), directing attention to those patients that may already be heading down the path to neurotropic JCV.…”

Exploring the role of NCCR variation on JC polyomavirus expression from dual reporter minicircles

“…Analysis of numerous PML NCCR sequences has shown their great variability with repeats, deletions, and point mutations [ 24 , 31 – 37 ] ( Fig 1 ). In addition to the inter-compartment variability within patients, wide intra-compartment variability has been observed [ 34 , 36 , 38 – 44 ]. These rearranged NCCRs ( rr -NCCR) present a modified pattern of binding sites for cell-specific transcription factors, thus highly suggesting that they could play a major role in cell-type specificity, and JCV replication within the brain [ 11 ].…”