JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis
Spyridon Chalkias MD
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorXin Dang PhD
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorEvelyn Bord BS
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorMarion C. Stein MD
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorR. Philip Kinkel MD
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorJacob A. Sloane MD
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorMaureen Donnelly RN
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorCarolina Ionete MD
Department of Neurology, University of Massachusetts Memorial Medical Center, Worcester
Search for more papers by this authorMaria K. Houtchens MD
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Search for more papers by this authorGuy J. Buckle MD, MPH
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Search for more papers by this authorStephanie Batson BS
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorCorresponding Author
Igor J. Koralnik MD
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Address correspondence to Dr Koralnik, Chief, Division of NeuroVirology, Director, HIV/Neurology Center, Beth Israel Deaconess Medical Center, Professor of Neurology, Harvard Medical School, E/CLS–1005, 330 Brookline Ave, Boston, MA, 02215. E-mail: [email protected]Search for more papers by this authorSpyridon Chalkias MD
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorXin Dang PhD
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorEvelyn Bord BS
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorMarion C. Stein MD
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorR. Philip Kinkel MD
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorJacob A. Sloane MD
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorMaureen Donnelly RN
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorCarolina Ionete MD
Department of Neurology, University of Massachusetts Memorial Medical Center, Worcester
Search for more papers by this authorMaria K. Houtchens MD
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Search for more papers by this authorGuy J. Buckle MD, MPH
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Search for more papers by this authorStephanie Batson BS
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Search for more papers by this authorCorresponding Author
Igor J. Koralnik MD
Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Address correspondence to Dr Koralnik, Chief, Division of NeuroVirology, Director, HIV/Neurology Center, Beth Israel Deaconess Medical Center, Professor of Neurology, Harvard Medical School, E/CLS–1005, 330 Brookline Ave, Boston, MA, 02215. E-mail: [email protected]Search for more papers by this authorAbstract
Objective
To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS).
Methods
We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon β-1a monotherapy >36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides.
Results
JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging–detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34+ cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4+ and CD8+ T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4+ T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34+ (p = 0.05) and B cells (p = 0.03).
Interpretation
Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34+ cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4+ T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment. ANN NEUROL 2014;75:925–934
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