Studio della riattivazione del Polyomavirus umano JC durante il trattamento con anticorpi monoclonali: analisi di fattori virali e dell'ospite.

Polyomavirus JC (JCV) reactivation causing progressive multifocal leukoencephalopathy (PML) is a main concern during biological therapies. We investigated JCV reactivation in the blood (PBMC and plasma samples) and urine of immunomediated diseases and relapsing-remitting subtype of multiple sclerosis (RRMS) patients after a long-term treatment with infliximab and natalizumab, respectively. Although JCV DNAemia occurred transiently, an higher JCV prevalence was detected in PBMC of patients treated with both mAbs than that observed in the diseases and healthy control groups. However, the viral load in the positive samples was low and did not significantly differ among them. All the patients, treated and untreated, exhibited an high prevalence of JCV in urine samples, with a range of viral load higher than that in the blood, as commonly reported in the literature. In order to monitor the risk of the viral reactivation, influenced by these mAbs treatment, we studied the possible JCV non-coding control region (NCCR) evolution. All positive samples sequenced exhibited the NCCR archetype structure; of note, several infliximab samples showed few point mutations in some cellular transcriptional factor binding sites on the viral NCCR. Moreover, we focused on the viral-host factor interaction during JCV reactivation. In particular, we analysed the possible effect of the mAb therapy on features related to the immunity response by exploiting the viremia of persistent widespread Torquetenovirus (TTV) as marker of immune functional status. A positive correlation between TTV viral load and number of mAb infusions performed was observed. Finally, we investigated whether infliximab and natalizumab treatment exerted some effect on microRNAs (miRNAs) expression level. We examined the expression level of four main miRNAs miR146-a, miR-150, miR-155, miR-223, potential players of the innate and adaptive immunity. Collectively, our results confirmed that infliximab treatment led to a down-regulation of miRNAs highly expressed in rheumatic patients, with miRNA-146a levels under that of healthy controls. Instead, no significant variations were detected among patients treated or not with natalizumab. Although these results derived from relatively small groups of patients, the infliximab and natalizumab long-term treatment, did not seem to exert foremost effects on the possible JCV reactivation. Further investigations should be performed in order to assess the real risk of a long-term mAbs treatment, to identify the possible factor(s) and shed light on the mechanism(s) implicated in the JCV molecular evolution and PML development.