We have described a novel clinical entity caused by JC virus (JCV) infection of cortical pyramidal neurons in an immunosuppressed individual. This patient presented with lesions restricted to the hemispheric gray matter on MRI, developed aphasia, progressive cognitive dysfunction and seizures and had a rapid fatal outcome. We called this disease JCV encephalopathy (JCVE), since it is distinct from Progressive Multifocal Leukoencephalopathy (PML), caused by JCV infection of glial cells. Post mortem histological evaluation demonstrated for the first time a productive and lytic infection of cortical pyramidal neurons by JCV. We have analyzed the full length sequence of a molecular clone of JCV obtained from the brain of this patient, JCVCPN1, which revealed an archetype-like regulatory region (RR), and a novel 143 bp deletion in the Agnoprotein gene. The CPN mutant was subsequently found in the neurons or cerebrospinal fluid of three other patients with PML. We hypothesize that changes in JCV sequence are responsible for the specific infection of cortical pyramidal neurons in this patient. However, whether JCVCPN1 growth in neurons is made possible by its RR, the novel Agnoprotein deletion, or both, remains unclear. Furthermore, we postulate that JCV infection of cortical neurons may also occur in other individuals, including in PML patients with demyelinating lesions located at the gray white- junction or within the gray matter. Finally, we hypothesize that other pyramidal neurons, located in the hippocampus may also be infected by JCV variants, which could lead to the development of seizures. To test these hypotheses, we will pursue the following set of Specific Aims:
Aim 1) Characterize the host cell range of JCVCPN1 in vitro Aim 2) Determine the contributions of the Agnoprotein deletion and archetype-like RR to the phenotype of JCVCPN1 in vitro Aim 3) Characterize the prevalence of JCV infection of cortical pyramidal neurons in archival samples from PML patients and identify the CPN1 mutation using immunohistochemistry and laser capture microdissection Aim 4) Investigate JCV infection of hippocampal pyramidal neurons in immunosuppressed individuals and in patients with hippocampal sclerosis or intractable epilepsy

Public Health Relevance

JC virus infects glial cells and typically causes a disease of the white matter of the brain, called Progressive Multifocal Leukoencephalopathy. We have described a novel clinical entity caused by a JC virus variant infecting cortical pyramidal neurons. We called this disease, restricted to the gray matter of the brain, JCV encephalopathy (JCVE). We will characterize the pathogenesis of this unique JC virus variant in vitro and define the prevalence of JCV infection of pyramidal neurons in immunosuppressed individuals. We will also investigate the role of JCV infection of hippocampal neurons in immunocompetent people with intractable seizures or elderly subjects with hippocampal sclerosis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Wong, May
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Beth Israel Deaconess Medical Center
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