title: Host cell virus entry mechanisms enhance anti-JCV-antibody switch in natalizumab-treated multiple sclerosis patients.
abstract: 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.
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, 52621, Israel. Anat.Achiron@sheba.health.gov.il.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Anat.Achiron@sheba.health.gov.il.
authors.forename: Anat
authors.initials: A
authors.lastname: Achiron
authors.affiliation: Functional Genomics and Neurogenomics, Sheba Medical Center, Tel Hashomer, 52621, Israel.
authors.forename: Gadi
authors.initials: G
authors.lastname: Miron
authors.affiliation: Functional Genomics and Neurogenomics, Sheba Medical Center, Tel Hashomer, 52621, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Zilkha-Falb
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, 52621, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Magalashvili
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, 52621, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Dolev
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, 52621, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Stern
authors.affiliation: Functional Genomics and Neurogenomics, Sheba Medical Center, Tel Hashomer, 52621, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Gurevich
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000096:biosynthesis; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016023:Integrins / Q000235:genetics / Q000276:immunology; D007577:JC Virus / Q000276:immunology* / Q000472:pathogenicity; D007968:Leukoencephalopathy, Progressive Multifocal / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008297:Male; D009103:Multiple Sclerosis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000821:virology; D000069442:Natalizumab / Q000627:therapeutic use*; D010873:Pinocytosis / Q000187:drug effects; D011446:Prospective Studies; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D012307:Risk Factors; D000069078:Seroconversion / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000914:Antibodies, Viral; D007155:Immunologic Factors; D016023:Integrins; D000069442:Natalizumab; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell
keywords: Gene expression profiling; JCV; Multiple sclerosis; Natalizumab