JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab

Elliot Frohman, Maria Chiara Monaco, Gina Remington, Caroline Ryschkewitsch, Peter N. Jensen, Kory Johnson, Molly Perkins, Julia Liebner, Benjamin Greenberg, Nancy L Monson, Teresa C. Frohman, Daniel Douek, Eugene O. Major

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

IMPORTANCE Infection with JC virus (JCV) may lead to development of demyelinating progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) who are treated with natalizumab. OBJECTIVE To determine whether mononuclear cells in circulation from MS patients treated with natalizumab harbor JCV DNA. DESIGN, SETTING, AND PARTICIPANTS In this prospective investigation, we enrolled 49 MS patients from the Clinical Center for Multiple Sclerosis at The University of Texas Southwestern Medical Center and 18 healthy volunteers.We drew 120-mL blood samples from 26 MS patients at baseline and at approximately 3-month intervals to 10 months during the course of natalizumab infusions. One blood sample was drawn from 23 MS patients receiving natalizumab for more than 24 months and from 18 healthy volunteers. INTERVENTIONS Natalizumab treatment of MS. MAIN OUTCOMES AND MEASURES The blood sampleswere separated using flow cytometry into CD34+, CD19+, and CD3+ cell subsets; DNA templates were prepared using quantitative polymerase chain reaction for JCV DNA identification. Plasma samples were tested for anti-JCV antibodies by enzyme-linked immunosorbent assays performed at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological and Communicative Diseases and Stroke. RESULTS Thirteen of the 26 patients (50%) with baseline and follow-up blood samples had detectable viral DNA in at least 1 cell compartment at 1 or more points. Ten of the 23 patients (44%) receiving treatment for more than 24 months and 3 of the 18 healthy volunteers (17%) also had detectable viral DNA in 1 or more cell compartment. Fifteen of the 49 MS patients (31%) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24%) in CD19+ cells. Only 1 of 18 healthy volunteers were viremic in CD34+ cells and none in CD19+ cells. Nine patients and 1 healthy volunteer were viremic but had seronegative test results for JCV antibodies. CONCLUSIONS AND RELEVANCE JC virus DNA was detectable within cell compartments of natalizumab-treated MS patients after treatment inception and longer. JC virus DNA may harbor in CD34+ cells in bone marrow that mobilize into the peripheral circulation at high concentrations. Latently infected cells initiate differentiation to CD19+ cells that favors growth of JCV. These data link the mechanism of natalizumab treatment with progressive multifocal leukoencephalopathy.

Original languageEnglish (US)
Pages (from-to)596-602
Number of pages7
JournalJAMA Neurology
Volume71
Issue number5
DOIs
StatePublished - 2014

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JC Virus
Multiple Sclerosis
Healthy Volunteers
DNA
Progressive Multifocal Leukoencephalopathy
Viral DNA
Natalizumab
Virus
Cells
Molecular Medicine
Antibodies
Therapeutics
Neurosciences
Bone Marrow Cells
Cell Differentiation
Flow Cytometry
Enzyme-Linked Immunosorbent Assay
Stroke
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Frohman, E., Monaco, M. C., Remington, G., Ryschkewitsch, C., Jensen, P. N., Johnson, K., ... Major, E. O. (2014). JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. JAMA Neurology, 71(5), 596-602. https://doi.org/10.1001/jamaneurol.2014.63

JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. / Frohman, Elliot; Monaco, Maria Chiara; Remington, Gina; Ryschkewitsch, Caroline; Jensen, Peter N.; Johnson, Kory; Perkins, Molly; Liebner, Julia; Greenberg, Benjamin; Monson, Nancy L; Frohman, Teresa C.; Douek, Daniel; Major, Eugene O.

In: JAMA Neurology, Vol. 71, No. 5, 2014, p. 596-602.

Research output: Contribution to journalArticle

Frohman, E, Monaco, MC, Remington, G, Ryschkewitsch, C, Jensen, PN, Johnson, K, Perkins, M, Liebner, J, Greenberg, B, Monson, NL, Frohman, TC, Douek, D & Major, EO 2014, 'JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab', JAMA Neurology, vol. 71, no. 5, pp. 596-602. https://doi.org/10.1001/jamaneurol.2014.63
Frohman, Elliot ; Monaco, Maria Chiara ; Remington, Gina ; Ryschkewitsch, Caroline ; Jensen, Peter N. ; Johnson, Kory ; Perkins, Molly ; Liebner, Julia ; Greenberg, Benjamin ; Monson, Nancy L ; Frohman, Teresa C. ; Douek, Daniel ; Major, Eugene O. / JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. In: JAMA Neurology. 2014 ; Vol. 71, No. 5. pp. 596-602.
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abstract = "IMPORTANCE Infection with JC virus (JCV) may lead to development of demyelinating progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) who are treated with natalizumab. OBJECTIVE To determine whether mononuclear cells in circulation from MS patients treated with natalizumab harbor JCV DNA. DESIGN, SETTING, AND PARTICIPANTS In this prospective investigation, we enrolled 49 MS patients from the Clinical Center for Multiple Sclerosis at The University of Texas Southwestern Medical Center and 18 healthy volunteers.We drew 120-mL blood samples from 26 MS patients at baseline and at approximately 3-month intervals to 10 months during the course of natalizumab infusions. One blood sample was drawn from 23 MS patients receiving natalizumab for more than 24 months and from 18 healthy volunteers. INTERVENTIONS Natalizumab treatment of MS. MAIN OUTCOMES AND MEASURES The blood sampleswere separated using flow cytometry into CD34+, CD19+, and CD3+ cell subsets; DNA templates were prepared using quantitative polymerase chain reaction for JCV DNA identification. Plasma samples were tested for anti-JCV antibodies by enzyme-linked immunosorbent assays performed at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological and Communicative Diseases and Stroke. RESULTS Thirteen of the 26 patients (50{\%}) with baseline and follow-up blood samples had detectable viral DNA in at least 1 cell compartment at 1 or more points. Ten of the 23 patients (44{\%}) receiving treatment for more than 24 months and 3 of the 18 healthy volunteers (17{\%}) also had detectable viral DNA in 1 or more cell compartment. Fifteen of the 49 MS patients (31{\%}) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24{\%}) in CD19+ cells. Only 1 of 18 healthy volunteers were viremic in CD34+ cells and none in CD19+ cells. Nine patients and 1 healthy volunteer were viremic but had seronegative test results for JCV antibodies. CONCLUSIONS AND RELEVANCE JC virus DNA was detectable within cell compartments of natalizumab-treated MS patients after treatment inception and longer. JC virus DNA may harbor in CD34+ cells in bone marrow that mobilize into the peripheral circulation at high concentrations. Latently infected cells initiate differentiation to CD19+ cells that favors growth of JCV. These data link the mechanism of natalizumab treatment with progressive multifocal leukoencephalopathy.",
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T1 - JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab

AU - Frohman, Elliot

AU - Monaco, Maria Chiara

AU - Remington, Gina

AU - Ryschkewitsch, Caroline

AU - Jensen, Peter N.

AU - Johnson, Kory

AU - Perkins, Molly

AU - Liebner, Julia

AU - Greenberg, Benjamin

AU - Monson, Nancy L

AU - Frohman, Teresa C.

AU - Douek, Daniel

AU - Major, Eugene O.

PY - 2014

Y1 - 2014

N2 - IMPORTANCE Infection with JC virus (JCV) may lead to development of demyelinating progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) who are treated with natalizumab. OBJECTIVE To determine whether mononuclear cells in circulation from MS patients treated with natalizumab harbor JCV DNA. DESIGN, SETTING, AND PARTICIPANTS In this prospective investigation, we enrolled 49 MS patients from the Clinical Center for Multiple Sclerosis at The University of Texas Southwestern Medical Center and 18 healthy volunteers.We drew 120-mL blood samples from 26 MS patients at baseline and at approximately 3-month intervals to 10 months during the course of natalizumab infusions. One blood sample was drawn from 23 MS patients receiving natalizumab for more than 24 months and from 18 healthy volunteers. INTERVENTIONS Natalizumab treatment of MS. MAIN OUTCOMES AND MEASURES The blood sampleswere separated using flow cytometry into CD34+, CD19+, and CD3+ cell subsets; DNA templates were prepared using quantitative polymerase chain reaction for JCV DNA identification. Plasma samples were tested for anti-JCV antibodies by enzyme-linked immunosorbent assays performed at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological and Communicative Diseases and Stroke. RESULTS Thirteen of the 26 patients (50%) with baseline and follow-up blood samples had detectable viral DNA in at least 1 cell compartment at 1 or more points. Ten of the 23 patients (44%) receiving treatment for more than 24 months and 3 of the 18 healthy volunteers (17%) also had detectable viral DNA in 1 or more cell compartment. Fifteen of the 49 MS patients (31%) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24%) in CD19+ cells. Only 1 of 18 healthy volunteers were viremic in CD34+ cells and none in CD19+ cells. Nine patients and 1 healthy volunteer were viremic but had seronegative test results for JCV antibodies. CONCLUSIONS AND RELEVANCE JC virus DNA was detectable within cell compartments of natalizumab-treated MS patients after treatment inception and longer. JC virus DNA may harbor in CD34+ cells in bone marrow that mobilize into the peripheral circulation at high concentrations. Latently infected cells initiate differentiation to CD19+ cells that favors growth of JCV. These data link the mechanism of natalizumab treatment with progressive multifocal leukoencephalopathy.

AB - IMPORTANCE Infection with JC virus (JCV) may lead to development of demyelinating progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) who are treated with natalizumab. OBJECTIVE To determine whether mononuclear cells in circulation from MS patients treated with natalizumab harbor JCV DNA. DESIGN, SETTING, AND PARTICIPANTS In this prospective investigation, we enrolled 49 MS patients from the Clinical Center for Multiple Sclerosis at The University of Texas Southwestern Medical Center and 18 healthy volunteers.We drew 120-mL blood samples from 26 MS patients at baseline and at approximately 3-month intervals to 10 months during the course of natalizumab infusions. One blood sample was drawn from 23 MS patients receiving natalizumab for more than 24 months and from 18 healthy volunteers. INTERVENTIONS Natalizumab treatment of MS. MAIN OUTCOMES AND MEASURES The blood sampleswere separated using flow cytometry into CD34+, CD19+, and CD3+ cell subsets; DNA templates were prepared using quantitative polymerase chain reaction for JCV DNA identification. Plasma samples were tested for anti-JCV antibodies by enzyme-linked immunosorbent assays performed at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological and Communicative Diseases and Stroke. RESULTS Thirteen of the 26 patients (50%) with baseline and follow-up blood samples had detectable viral DNA in at least 1 cell compartment at 1 or more points. Ten of the 23 patients (44%) receiving treatment for more than 24 months and 3 of the 18 healthy volunteers (17%) also had detectable viral DNA in 1 or more cell compartment. Fifteen of the 49 MS patients (31%) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24%) in CD19+ cells. Only 1 of 18 healthy volunteers were viremic in CD34+ cells and none in CD19+ cells. Nine patients and 1 healthy volunteer were viremic but had seronegative test results for JCV antibodies. CONCLUSIONS AND RELEVANCE JC virus DNA was detectable within cell compartments of natalizumab-treated MS patients after treatment inception and longer. JC virus DNA may harbor in CD34+ cells in bone marrow that mobilize into the peripheral circulation at high concentrations. Latently infected cells initiate differentiation to CD19+ cells that favors growth of JCV. These data link the mechanism of natalizumab treatment with progressive multifocal leukoencephalopathy.

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