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JC polyomavirus expression and bell-shaped regulation of its SF2/ASF suppressor during the follow-up of multiple sclerosis patients treated with natalizumab

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Abstract

Natalizumab is effective against multiple sclerosis (MS), but is associated with progressive multifocal leukoencephalopathy (PML), fatal disease caused by the JCV polyomavirus. The SF2/ASF (splicing factor2/alternative splicing factor) inhibits JCV in glial cells. We wondered about SF2/ASF modulation in the blood of natalizumab-treated patients and if this could influence JCV reactivation. Therefore, we performed a longitudinal study of MS patients under natalizumab, in comparison to patients under fingolimod and to healthy blood donors. Blood samples were collected at time intervals. The expression of SF2/ASF and the presence and expression of JCV in PBMC were analyzed. A bell-shaped regulation of SF2/ASF was observed in patients treated with natalizumab, increased in the first year of therapy, and reduced in the second one, while slightly changed, if any, in patients under fingolimod. Notably, SF2/ASF was up-regulated, during the first year, only in JCV DNA-positive patients, or with high anti-JCV antibody response; the expression of the JCV T-Ag protein in circulating B cells was inversely related to SF2/ASF protein expression. The SF2/ASF reduction, parallel to JCV activation, during the second year of therapy with natalizumab, but not with fingolimod, may help explain the increased risk of PML after the second year of treatment with natalizumab, but not with fingolimod. We propose that SF2/ASF has a protective role against JCV reactivation in MS patients. This study suggests new markers of disease behavior and, possibly, help in re-evaluations of therapy protocols.

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Notes

  1. 685 cases (682 MS, 3 CD), as of September 7, 2016 (http://chefarztfrau.de/?page_id=716, accessed October 19, 2016). At the time of writing, three PML cases were reported in Natalizumab-naïve Fingolimod-treated patients, with doubts for diagnosis and/or treatments (Faulkner 2015).

  2. For two patients the JCV DNA could not be evaluated, for scarcity of the samples.

  3. The other two patients were anti-JCV antibody-negative, but the JCV DNA could not be evaluated.

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Acknowledgments

The authors wish to thank all patients and volunteers whose participation enabled this study, and E. Gomes, Immunohematology & Transfusion Unit, Asl1 Sassari, for providing samples of healthy volunteers. The study was supported in part by grants from CARITRO 2013 and grant CRP-59781, RAS LR-2012. EU was supported by a research fellowship of CARITRO 2013. Author contributions: EU and AD conceived and designed the study. EU, CP, MC, GI performed the experiments. SL and GA provided blood samples and related medical records of MS patients. AD, EU, GI analyzed the data. EU and GI performed the statistical analysis. AD, CS, GPS, SL and GA contributed reagents/materials/analysis tools. AD and EU wrote the manuscript. Potential conflicts of interest: nothing to report.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, I-07100, Sassari, Italy

    Elena Uleri, Gabriele Ibba, Claudia Piu, Maurizio Caocci, Caterina Serra & Antonina Dolei

  2. Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, I-07100, Sassari, Italy

    Stefania Leoni, Giannina Arru & GianPietro Sechi

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  1. Elena Uleri
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  2. Gabriele Ibba
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  9. Antonina Dolei
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Correspondence to Antonina Dolei.

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Uleri, E., Ibba, G., Piu, C. et al. JC polyomavirus expression and bell-shaped regulation of its SF2/ASF suppressor during the follow-up of multiple sclerosis patients treated with natalizumab. J. Neurovirol. 23, 226–238 (2017). https://doi.org/10.1007/s13365-016-0492-x

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