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Center for Aging and Developmental Biology,
Program in Neurosciences, and Departments of
Neurology (Child Neurology Division),
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Microbiology and Immunology,
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Pediatrics, and
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Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642;
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Center for Neurologic and Neurodegenerative Disease, University of Nebraska Medical Center, Omaha, NE 68198;
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Department of Pediatrics (Child Neurology Division), Children’s Memorial Hospital, Chicago, IL 60614;
Chemocentryx, San Carlos, CA 94074; and
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Department of Laboratory Medicine and Pathology (Neuropathology Division), University of Medicine and Dentistry of New Jersey, Newark, NJ 07103
HIV-1 infection of the brain results in chronic inflammation, contributing to the neuropathogenesis of HIV-1 associated neurologic disease. HIV-1-infected mononuclear phagocytes (MP) present in inflammatory infiltrates produce neurotoxins that mediate inflammation, dysfunction, and neuronal apoptosis. Neurologic disease is correlated with the relative number of MP in and around inflammatory infiltrates and not viral burden. It is unclear whether these cells also play a neuroprotective role. We show that the chemokine, fractalkine (FKN), is markedly up-regulated in neurons and neuropil in brain tissue from pediatric patients with HIV-1 encephalitis (HIVE) compared with those without HIVE, or that were HIV-1 seronegative. FKN receptors are expressed on both neurons and microglia in patients with HIVE. These receptors are localized to cytoplasmic structures which are characterized by a vesicular appearance in neurons which may be in cell-to-cell contact with MPs. FKN colocalizes with glutamate in these neurons. Similar findings are observed in brain tissue from an adult patient with HIVE. FKN is able to potently induce the migration of primary human monocytes across an endothelial cell/primary human fetal astrocyte trans-well bilayer, and is neuroprotective to cultured neurons when coadministered with either the HIV-1 neurotoxin platelet activating factor (PAF) or the regulatory HIV-1 gene product Tat. Thus focal inflammation in brain tissue with HIVE may up-regulate neuronal FKN levels, which in turn may be a neuroimmune modulator recruiting peripheral macrophages into the brain, and in a paracrine fashion protecting glutamatergic neurons.
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