Neuronal fractalkine expression in HIV-1 encephalitis: Roles for macrophage recruitment and neuroprotection in the central nervous system

HIV-1 infection of the brain results in chronic inflammation, contributing to the neuropathogenesis of HIV-1 associated neurologic disease. HIV-l-infe cted mononuclear phagocytes (MP) present in inflammatory infiltrates produc e neurotoxins that mediate inflammation, dysfunction, and neuronal apoptosi s, Neurologic disease is correlated with the relative number of Mr in and a round inflammatory infiltrates and not viral burden. It is unclear whether these cells also play a neuroprotective role. We show that the chemokine, f ractalkine (FKN), is markedly up-regulated in neurons and neuropil in brain tissue from pediatric patients with HIV-1 encephalitis (HIVE) compared wit h those without HIVE, or that were HIV-1 seronegative, FKN receptors are ex pressed on both neurons and microglia in patients with HIVE, These receptor s are localized to cytoplasmic structures which are characterized by a vesi cular appearance in neurons which may be in cell-to-cell contact with MPs, FKN colocalizes with glutamate in these neurons, Similar findings are obser ved in brain tissue from an adult patient with HIVE. FKN is able to potentl y induce the migration of primary human monocytes across an endothelial cel l/primary human fetal astrocyte trans-well bilayer, and is neuroprotective to cultured neurons when coadministered with either the HIV-1 neurotoxin pl atelet activating factor (PAF) or the regulatory HIV-I gene product Tat, Th us focal inflammation in brain tissue with HIVE may up-regulate neuronal FK N levels, which in turn may be a neuroimmune modulator recruiting periphera l macrophages into the brain, and in a paracrine fashion protecting glutama tergic neurons.