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.

Interaction of the viral infectious agents in the development and exacerbation of the multiple sclerosis

“…JCV enters host cells by attaching to particular receptors, including integrin molecules, the seroto-nin receptors, very late antigen-4 (VLA-4), followed by increased proliferation of B cells that cause JCV to enter the brain. However, some patients are susceptible to PML, while others are resistant; mechanisms such as differential reactivity of the patient's immune system and variation in the virus-host interaction have been suggested [45]. In light of this, it appears necessary to positively evaluate anti-JCV antibody serum as a significant risk factor for PML development before deciding the treatment course for MS patients, despite the fact that natalizumab has a very effective treatment response in RRMS patients [46].…”