Abstract
HIV-1 infection of the developing central nervous system (CNS) results in a primary encephalopathy that is clinically devastating. Although it is established that HIV-1 productively infects brain microglia and macrophages, the mechanism(s) for neuronal dysfunction remain controversial. We have recently demonstrated that cocultures of HIV-1-infected monocytes and primary human fetal astrocytes secrete high, but variable levels of the cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) relative to control uninfected monocyte plus astrocyte cocultures.1,2 Additionally, cocultures of HIV-1-infected monocytes and primary human fetal astrocytes secrete high levels of plateletactivating factor (PAF) (unpublished results). Both conditioned media from these cocultures and exogenous TNF-a, PAF, but not IL-lβ are neurotoxic to primary ultures of human fetal neurons.1,2 TNF-a-induced neurotoxicity is dosedependent and can be blocked in part by AMPA receptor antagonists.3 Studies suggest that the time course for this neurotoxicity is subacute, and occurs between 24-48 hours in this cell culture system. Furthermore, PAF-induced neurotoxicity is dose-dependent and can be blocked in part by NMDA receptor antagonists.Other studies demonstrate that TNF-a and PAF down-regulate the expression f neurotransmitter receptors such as the dopamine D2 receptor, which may be dysfunctional in neuroAIDS. Taken together, these data suggest that TNF-a and PAF, produced by interactions between HIV-1-infected monocytes and astrocytes, may act as two candidate neurotoxins to produce neuronal dysfunction and death. Because these neurotoxins act in part through glutamate receptor systems, glutamate receptor antagonists may be useful in the pharmacotherapy of HIV-1-mediated encephalopathy.
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Gelbard, H.A., Dzenko, K.A., Wang, L., Talley, A., James, H., Epstein, L. (1995). HIV-1-Derived Neurotoxic Factors: Effects on Human Neuronal Cultures. In: Major, E.O., Levy, J.A., Schoenberg, D. (eds) Technical Advances in AIDS Research in the Human Nervous System. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1949-2_5
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DOI: https://doi.org/10.1007/978-1-4615-1949-2_5
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