Expert Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: Vol. 7; Issue 27; 2 December 2005 Abstract
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Possible mechanisms in neuronal injury and apoptosis in HIV-D

Tracy Fischer-Smith and Jay Rappaport

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Figure 1. Possible mechanisms in neuronal injury and apoptosis in HIV-D. Neuronal injury is likely to occur indirectly through factors secreted by infected and/or activated macrophages/microglia and astrocytes. For example, the cytokines TNF-a, IL-6 and IL-1b can act in an autocrine or paracrine manner to further augment cytokine and chemokine production, as well as production of virus through induction of nuclear factors that can act on the viral long terminal repeat (Fig. 2). Additionally, cytokines can promote production of metabolites, such as iNOS, that may cause neuronal injury or loss. Chemokines, including SDF-1a/b, MIP-1b, RANTES and MCP-1 may recruit additional macrophages into the CNS. SDF-1a/b can directly promote neuronal injury. Astrocytes might further contribute to the to the influx of monocytes/macrophages through upregulation of VCAM-1 and ICAM-1 in response to cytokines and Tat. TRAIL may contribute directly to neuronal apoptosis. Virus and shed viral proteins, including gp120 and Tat, promote additional cytokine and chemokine production, as well as act directly on neurons to promote neuronal injury and apoptosis. TNF-a, which is produced by both activated macrophages and astrocytes, can impair astrocyte uptake of excess glutamate and is directly neurotoxic. Additional glutamate allows excess influx of Ca²⁺, triggering a variety of potentially harmful enzymes, as well as formation of free radicals and additional release of glutamate. This release subsequently over stimulates NMDA receptors on neighbouring neurons, initiating further injury. Abbreviations: AA, arachidonic acid; CNS, central nervous system; HIV-D, human immunodeficiency virus type 1 (HIV-1)-associated dementia; ICAM, intercellular cell adhesion molecule; IL, interleukin; iNOS, inducible nitric oxide synthase; MCP, monocyte chemoattractant protein; M-CSF, macrophage colony-stimulating factor; MIP, macrophage inflammatory protein; NMDA, N-methyl-D-aspartate; RANTES, ‘regulated on activation, normal T-cell expressed and secreted’; SDF, stromal-cell-derived factor; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; QA, quinolinic acid; VCAM, vascular cell adhesion molecule.

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