JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

Abstract

Objective: To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS).

Methods: We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon β-1a monotherapy >36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides.

Results: JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging-detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34(+) cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4(+) and CD8(+) T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4(+) T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34(+) (p = 0.05) and B cells (p = 0.03).

Interpretation: Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34(+) cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.

© 2014 American Neurological Association.

Figures

Figure 1

Frequency of JCV DNA detection by PCR in PBMC subpopulations and plasma of all MS patients. No significant differences were found between natalizumab and interferon β-1a treated patients.

Figure 2

Measurement of JC viral load in blood mononuclear cell subpopulations of all MS patients. JC viral load was higher in CD34+ cells compared to B cells (p=0.006), T cells (p=0.004) and polymorphonuclear (PMN) cells (p=0.002). Viral load was also higher in monocytes (Mono) compared to T cells (p=0.005) and PMN (p=0.004). JC viral load was significantly higher in CD34+ and monocytes, compared to other PBMC subpopulations, when only natalizumab-treated MS patients were included in this analysis.