JC polyomavirus expression and bell-shaped regulation of its SF2/ASF suppressor during the follow-up of multiple sclerosis patients treated with natalizumab.
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.
Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, I-07100, Sassari, Italy.
Elena
E
Uleri
Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, I-07100, Sassari, Italy.
Gabriele
G
Ibba
Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, I-07100, Sassari, Italy.
Claudia
C
Piu
Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, I-07100, Sassari, Italy.
Maurizio
M
Caocci
Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, I-07100, Sassari, Italy.
Stefania
S
Leoni
Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, I-07100, Sassari, Italy.
Giannina
G
Arru
Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, I-07100, Sassari, Italy.
Caterina
C
Serra
Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, I-07100, Sassari, Italy.
GianPietro
G
Sechi
Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43B, I-07100, Sassari, Italy. doleivir@uniss.it.
Antonina
0000-0001-5815-5310
A
Dolei
D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007577:JC Virus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D007968:Leukoencephalopathy, Progressive Multifocal / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D000069442:Natalizumab / Q000627:therapeutic use*; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology / Q000821:virology; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D014775:Virus Activation / Q000187:drug effects
D000914:Antibodies, Viral; D007155:Immunologic Factors; D000069442:Natalizumab; C000595779:SRSF1 protein, human; D000068103:Serine-Arginine Splicing Factors; D000068876:Fingolimod Hydrochloride
B lymphocytes; Fingolimod; JCV; Multiple sclerosis; Natalizumab; Progressive multifocal leukoencephalopathy; SF2/ASF; T-antigen