Ricerc@Sapienza

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease induced by reactivation of Polyomavirus JC (JCPyV). Modulation of normal immune functions, as during longterm administration of disease-modifying therapies (DMTs) for Multiple Sclerosis (MS) treatment, plays a central role in JCPyV reactivation and PML development. The variability of JCPyV seroprevalence coupled with the intermittent nature of JCPyV infection, raises questions regarding the predictive value of assays currently used to assess PML risk. A risk stratification algorithm, applicable only for natalizumab (NZT) administration, has not led to a PML incidence reduction. Actually, other candidates such as L-selectin (CD62L) expression, T-cell response to JCPyV reactivation and JCPyV-DNA detection in blood (viremia) have been proposed. Recent studies signify the potential of JCPyV microRNAs (miRNAs) as biomarkers of JCPyV infection as they can be detected in plasma, urine and cerebrospinal fluid (CSF) of both JCPyV seropositive and seronegative healthy individuals and immunosuppressed patients. JCPyV encodes for two mature miRNAs, jcv-miR-J1-5p (5p-miRNA) and jcv-miR-J1-3p (3p-miRNA), that appear late in infection to downregulate early viral gene expression and target host factors aiding virus to escape immune elimination. The biomarker potential of miRNAs in blood has been studied for NTZ-associated PML, but studies in course of other DMTs are still lacking. In this project, we will characterize JCPyV miRNAs expression in plasma and urine of NTZ-treated MS patients as well as in patients treated with fingolimod (F), dimethyl fumarate (DF), ocrelizumab (OCRE), and in healthy controls (HCs) to evaluate the utility of these miRNAs in PML risk assessment. Moreover, a COS-7 cell-based model will be used to study and monitor miR-J1-5p expression during viral replication.