Monitoring the John Cunningham virus throughout natalizumab treatment in multiple sclerosis patients M. I. Dom  ınguez-Mozo a , M. Garc  ıa-Montojo a , A. Arias-Leal a ,  A. Garc  ıa-Mart  ınez a , J. L. Santiago b , I. Casanova a , V. Gal  an a , R. Arroyo a , M. Fern andez-Arquero b and R. Alvarez-Lafuente a a Department of Neurology, Instituto de Investigaci  on Sanitaria del Hospital Cl  ınico San Carlos (IdISSC), Hospital Cl  ınico San Carlos, Madrid; and b Department of Immunology, Instituto de Investigaci  on Sanitaria del Hospital Cl  ınico San Carlos (IdISSC), Hospital Cl  ınico San Carlos, Madrid, Spain Keywords: JC virus, multiple sclerosis, natalizumab, progressive multifocal leukoencephalopathy Received 9 March 2015 Accepted 4 August 2015 European Journal of Neurology 2016, 23: 182–189 doi:10.1111/ene.12834 Background and purpose: Progressive multifocal leukoencephalopathy (PML) cases have arisen amongst multiple sclerosis patients treated with natalizumab. Our objective was to gain a better understanding of the mechanisms that underlie the John Cunningham virus (JCV) infection which causes PML. Methods: A study was made of (i) the quarterly JCV DNA levels in periph- eral blood mononuclear cells (PBMCs), serum and urine samples in 100 multi- ple sclerosis patients during their natalizumab treatment (3–39 months), (ii) the association between human leukocyte antigen (HLA) class II and the pre- vious viral detection and (iii) the identification of the JCV variants in those patients suspected of having PML. Results: (i) JCV DNA in PBMCs and/or serum was detected in 23% of our cohort. Patients with an intermittent JCV excretion in urine had a significant increase of the viral load and prevalence in this compartment during natal- izumab treatment. (ii) The frequency of the DRB1*07/DQA1*02:01/ DQB1*02:02 haplotype tended to be higher in patients with detectable versus undetectable JCV DNA in PBMCs (P corrected = 0.108). (iii) The variants in PBMCs and serum of the non-PML patient matched the archetype. In the patient with non-fatal PML, the archetype and the same neurotropic variant in PBMCs, serum and cerebrospinal fluid was identified at the time PML was diagnosed, whereas in the patient with a worse PML prognosis, four neu- rotropic variants in the three previous compartments were found by the PML diagnosis. Conclusions: The detection of the neurotropic variant in blood during natal- izumab treatment could be critical in the prevention of the development of severe PML, since this variant appears simultaneously with the clinical symp- toms of PML and mutates quickly. Introduction Natalizumab is used for the treatment of multiple sclerosis (MS). It is a humanized monoclonal antibody that binds the very late antigen 4 (VLA-4). VLA-4 mediates cell migration and infiltration in immune signaling [1]. Since its reintroduction in 2006 up to December 2014, 514 confirmed cases of progressive multifocal leukoencephalopathy (PML) in MS patients worldwide (http://www.biogenidec.com) have been reported. PML is a severe demyelinating disease caused by infection by the John Cunningham virus (JCV) in the central nervous system. Currently, there is no specific antiviral drug against this virus [1]. The JCV genome is a circular double-stranded DNA molecule with a non-coding control regulatory region (NCCR) which determines the viral variant Correspondence: M. I. Dom  ınguez-Mozo, Unidad de Investigaci  on Experimental (Planta -1, laboratorios 3 y6), Hospital Cl  ınico San Carlos, C/ Profesor Mart  ın Lagos s/n, 28040 Madrid, Spain (tel.: +34 91 3303000/7437; fax: +34 91 3303457; e-mail: mariadomomd@gmail.com). © 2015 EAN 182 ORIGINALARTICLE EUROPEANJOURNALOFNEUROLOGY