JCPyV miR-J1-5p in Urine of Natalizumab-Treated Multiple Sclerosis Patients.

Simone Agostini,Roberta Mancuso,Andrea Saul Costa,Domenico Caputo,Mario Clerici

doi:10.3390/v13030468

Simone Agostini, Roberta Mancuso + Show 3 more

Open Access

https://doi.org/10.3390/v13030468

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Journal: Viruses	Publication Date: Mar 12, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Don Carlo Gnocchi Foundation, University of Milan

Abstract

The use of Natalizumab in Multiple Sclerosis (MS) can cause the reactivation of the polyomavirus JC (JCPyV); this may result in the development of progressive multifocal leukoencephalopathy (PML), a rare and usually lethal disease. JCPyV infection is highly prevalent in worldwide population, but the detection of anti-JCPyV antibodies is not sufficient to identify JCPyV infection, as PML can develop even in patients with negative JCPyV serology. Better comprehension of the JCPyV biology could allow a better understanding of JCPyV infection and reactivation, possibly reducing the risk of developing PML. Here, we investigated whether JCPyV miR-J1-5p—a miRNA that down-regulates the early phase viral protein T-antigen and promotes viral latency—could be detected and quantified by digital droplet PCR (ddPCR) in urine of 25 Natalizumab-treated MS patients. A 24-month study was designed: baseline, before the first dose of Natalizumab, and after 1 (T1), 12 (T12) and 24 months (T24) of therapy. miR-J1-5p was detected in urine of 7/25 MS patients (28%); detection was possible in three cases at T24, in two cases at T12, in one case at T1 and T12, and in the last case at baseline and T1. Two of these patients were seronegative for JCPyV Ab, and viral DNA was never found in either urine or blood. To note, only in one case miR-J1-5p was detected before initiation of Natalizumab. These results suggest that the measurement of miR-J1-5p in urine, could be a biomarker to monitor JCPyV infection and to better identify the possible risk of developing PML in Natalizumab-treated MS patients.

Highlights

The Polyomavirus JC (JCPyV), isolated for the first time in 1971 [1], is a ubiquitous human neurotropic virus belonging the family Polyomaviridiae
In the attempt to identify more reliable markers for JCPyV infection and reactivation, we monitored miR-J1-5p expression—an unambiguous signal of infection compared to antibodies—in urine of JCV infected relapsing remitting MS (RRMS) patients treated with Natalizumab for a 24month period
Therapy was well tolerated by all 25 RRMS patients (20 females and 5 males, mean age: 36.12 ± 8.60 years)

Summary

Introduction

The Polyomavirus JC (JCPyV), isolated for the first time in 1971 [1], is a ubiquitous human neurotropic virus belonging the family Polyomaviridiae. The miRNAs of human polyomaviruses (SV40, JCPyV and BKPyV) show a partial, shared sequence identity. JCPyV expresses a pri-miRNA (pri-miR-J1) that, is processed by Drosha-DGCR8 microprocessor [8], in a pre-miRNA (pre-miRJ-1). JCPyV expresses a pri-miRNA (pri-miR-J1) that, is processed by Drosha-DGC2Rof810 microprocessor [8], in a pre-miRNA (pre-miRJ-1). JCPyV-specific antibodies are not sufficient for the diagnosis of JCPyV infection [32] This whole issue is further complicated by the observation that miR-J1-5p and -3p are expressed in PML, but they can be observed in MS patients without PML and even in healthy controls [34,35]. In the attempt to identify more reliable markers for JCPyV infection and reactivation, we monitored miR-J1-5p expression—an unambiguous signal of infection compared to antibodies—in urine of JCV infected RRMS patients treated with Natalizumab for a 24month period

Study Population and Specimens

Data Analysis

Results