Host cell virus entry mechanisms enhance anti-JCV-antibody switch in natalizumab-treated multiple sclerosis patients.
J Neurovirol
; 22(6): 736-746, 2016 12.
Article
em En
| MEDLINE
| ID: mdl-27170332
Estimating the individual risk for the development of progressive multifocal leukoencephalopathy (PML) in anti-John Cunningham virus (JCV) antibody-negative patients with multiple sclerosis (MS) treated with natalizumab is a major challenge. A serological conversion occurring under treatment from anti-JCV antibody-negative to positive status may significantly increase this risk. We investigated changes in peripheral blood cells' gene expression induced by natalizumab treatment in anti-JCV antibody-negative MS patients and tested blood transcriptional profile that characterizes patients predisposed to antibody switch under natalizumab treatment. After 3 years of natalizumab treatment, 24.6 % of anti-JCV antibody-negative MS patients switched to become anti-JCV antibody-positive (JCV switchers). Natalizumab induced 946 and 1186 significantly differentiating genes in JCV switchers and non-switchers, respectively. In JCV switchers, the signature was enriched by over-expression of genes associated with the first stages of viral entry to host cells including macropinocytosis (p = 1.82E-06), virus entry via endocytosis (p = 1.60E-06), clathrin-mediated endocytosis (p = 1.13E-04), and caveolar-mediated endocytosis (p = 4.50E-04) pathways. Further analysis to identify pre-existing transcriptional differences that characterize future JCV switchers prior to treatment initiation also demonstrated a transcriptional signature enriched by similar viral entry mechanisms. These findings, verified in an additional independent cohort of natalizumab-treated patients, could lead to future identification of patients that remain anti-JCV antibody-negative thus allowing safe continuation of treatment, as well as the development of future targeted therapeutic interventions to reduce the risk of PML.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucoencefalopatia Multifocal Progressiva
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Vírus JC
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Interações Hospedeiro-Patógeno
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Natalizumab
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Soroconversão
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Fatores Imunológicos
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Esclerose Múltipla
Tipo de estudo:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
J Neurovirol
Assunto da revista:
NEUROLOGIA
/
VIROLOGIA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Israel