Diagnostic Value of JC Polyomavirus Viruria, Viremia, Serostatus and microRNA Expression in Multiple Sclerosis Patients Undergoing Immunosuppressive Treatment.

Carla Prezioso,Marco Ciotti,Sara Passerini,Dolores Limongi,Gabriele Brazzini,Doriana Landi,Carolina Gabri Nicoletti,Antonella Conte,Maria Antonella Zingaropoli,Anna Teresa Palamara,Girolama Alessandra Marfia,Claudio Maria Mastroianni,Valeria Pietropaolo,Marco Iannetta,Francesca Piacentini,Ugo Moens,Alfonso Grimaldi,Maria Rosa Ciardi,Marta Altieri

doi:10.3390/jcm11020347

Abstract

Markers of JC polyomavirus (JCPyV) activity can be used to evaluate the risk of progressive multifocal leukoencephalopathy (PML) in treated multiple sclerosis (MS) patients. The presence of JCPyV DNA and microRNA (miR-J1-5p), the anti-JCV index and the sequence of the non-coding control region (NCCR) in urine and plasma were determined in 42 MS subjects before treatment (T0), 6 months (T6) and 12 months (T12) after natalizumab, ocrelizumab, fingolimod or dimethyl-fumarate administration and in 25 healthy controls (HC). The number of MS patients with viruria increased from 43% at T0 to 100% at T12, whereas it remained similar for the HC group (35–40%). Viremia first occurred 6 months after treatment in MS patients and increased after 12 months, whereas it was absent in HC. The viral load in urine and plasma from the MS cohort increased over time, mostly pronounced in natalizumab-treated patients, whereas it persisted in HC. The archetypal NCCR was detected in all positive urine, whereas mutations were observed in plasma-derived NCCRs resulting in a more neurotropic variant. The prevalence and miR-J1-5p copy number in MS urine and plasma dropped after treatment, whereas they remained similar in HC specimens. Viruria and miR-J1-5p expression did not correlate with anti-JCV index. In conclusion, analyzing JCPyV DNA and miR-J1-5p levels may allow monitoring JCPyV activity and predicting MS patients at risk of developing PML.

Highlights

The arsenal of medications to treat multiple sclerosis (MS) has been enriched by a variety of drugs with differing mechanisms of action
Viral DNA with a viral load mean value of 5.5 × copies/mL was detected in 6/19 urine specimens from patients to be given ocrelizumab and in 10/19 urine samples with a JC viral load mean value of 5 × copies/mL obtained from patients to be treated with natalizumab
Analysis of qPCR performed on urine samples showed a further increase in mean of viral load that was of 6 × 104 copies/mL in patients treated with ocrelizumab, of 8.5 × 106 copies/mL in patients treated with natalizumab and of 1.5 × 105 copies/mL and 1.0 × 105 copies/mL in patients treated with fingolimod and DMF, respectively (Table 1)

Summary

Introduction

The arsenal of medications to treat multiple sclerosis (MS) has been enriched by a variety of drugs with differing mechanisms of action. To date, 13 disease-modifying therapies (DMTs) for treatment of relapsing-remitting MS (RRMS) have been approved by the Food and Drug Administration (FDA), changing the scenery for RRMS patients’. These drugs allow long periods of disease activity-free remission [2], they are correlated with a higher risk of side effects. Several DMTs have been associated with progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system (CNS) caused by a lytic infection sustained by JC polyomavirus (JCPyV), a circular double-stranded DNA virus with a restricted cellular tropism [3]. Natalizumab (Tysabri® ) is one of the most effective therapies for the treatment of active RRMS [6] and, regardless its efficacy, long-term use (mostly more than 18 months) is associated with increased risk of PML [7]

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