HIV-1-Associated Dementia: A Metabolic Encephalopathy Fueled By Viral Replication in Mononuclear Phagocytes
Howard F. Gendelman,
University of Nebraska Medical Center
HIV-1-associated dementia (HAD) is a dreaded complication of progressive viral infection. It is associated with HIV-1-induced immunosuppression and productive replication in brain tissue. HIV neuropathogenesis revolves around infection and immune activation of brain mononuclear phagocytes (MPs) (perivascular and brain macrophages and microglia). These cells in conjunction with astroglia secrete neurotoxins producing neuronal injury. The mechanisms for neuronal death are mediated principally through HIV-1-infected MPs (1-5). How this occurs, however, remains poorly understood. To determine the cause of neuronal demise in HAD, novel techniques in neurobiology, virology, cellular immunology, and neurochemistry were developed. Quantitative tests for neuronal function included those utilizing ELISA, lactate dehydrogenase (LDH), calcium imaging, electrophysiology, neuronal apoptosis, glutamate receptor regulation, and reverse phase-high performance liquid chromatography (RP-HPLC). These assays were developed in order to uncover potential immune regulatory mechanisms for HAD-related neuronal injury. Our studies demonstrated that viral and cellular secretory products from immune-activated HIV-1-infected macrophages produce profound neurotoxicity in hippocampal and cortical neurons through both apoptosis and necrotic mechanisms. The intracellular signaling pathways, the identity of the specific immune neurotoxic factors, and their mechanisms for MP activation will be discussed.
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