Human polyomavirus JC monitoring and noncoding control region analysis in dynamic cohorts of individuals affected by multiple sclerosis under treatment with natalizumab: An observational study

Abstract

Progressive multifocal leukoencephalopathy (PML) onset, caused by Polyomavirus JC (JCPyV) in patients affected by multiple sclerosis (MS) during natalizumab treatment, raised concerns about the safety profile of this agent. Therefore, the aims of this study were the JCPyV reactivation monitoring and the noncoding control region (NCCR) and viral protein 1 (VP1) analysis in patients affected by MS and treated with natalizumab.We performed JCPyV-specific quantitative PCR of biological samples collected at moment of recruitment (t0) and every 4 months (t1, t2, t3) for 1 year. Subsequently, analysis of NCCR and VP1 rearrangements was carried out. Moreover a 2-step virus-like particle-based enzyme-linked immunosorbed assay was performed at t0 and t3, to detect specific anti-JC virus antibodies in serum of the enrolled subjects. Data were analyzed using chi-square test. Results showed a significant association between JC viruria and JCPyVantibodies after 1 year of natalizumab (p=0.04).Moreover, sequences isolated from peripheral blood mononuclear cells (PBMCs) of 2 patients with JCPyVantibody at t0 and t3, showed a NCCR Type IIR with a duplication of a 98bp unit and a 66bp insert, resulting in a boxB deletion and 37 T to G transversion into the Spi-B binding site. In all patients, a prevalence of genotypes 1A and 1B, the predominant JCPyV genotypes in Europe, was observed. In conclusion, it could be important to understand whether the specific inflammatory scenario of multiple sclerosis could affect JCPyV reactivation from latency, in particular from kidneys. Moreover, for a more accurate PML risk stratification, testing JC viruria seems to be useful to identify patients who harbor JCPyV but with an undetectable JCPyV-specific humoral immune response. In these patients, it may also be important to study the JCPyV NCCR rearrangement: in particular, Spi-B expression in PBMCs could play a crucial role in JCPyV replication and NCCR rearrangement.