UPDATE ON CURRENT MODELS OF HIV-RELATED NEURONAL INJURY - PLATELET-ACTIVATING-FACTOR, ARACHIDONIC-ACID AND NITRIC-OXIDE

This review aims to summarize recent work related to the pathogenesis and possible treatment of neuronal injury in the acquired immunodefici ency syndrome (AIDS), especially with reference to potential neurotoxi c substances released by HIV-infected or gp120-stimulated macrophages/ microglia. Approximately a third of adults and half of children with A IDS eventually suffer from neurological manifestations, including dysf unction of cognition, movement, and sensation. Among the various patho logies reported in brains of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for a ll intents and purposes not infected by human immunodeficiency virus t ype 1 (HIV-1). This paper reviews recent evidence suggesting that at l east part of the neuronal injury observed in the brains of AIDS patien ts is related to excessive influx of Ca2+ after the release of potenti ally noxious substances from HIV-infected or gp120-stimulated macropha ges/microglia. There is growing support for the existence of HIV- or i mmune-related toxins that lead indirectly to the injury or demise of n eurons via a potentially complex web of interactions between macrophag es (or microglia), astrocytes, and neurons. HIV-infected monocytoid ce lls (macrophages, microglia or monocytes), especially after interactin g with astrocytes, secrete substances that potentially contribute to n eurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, i.e. arachidonic acid and its metabolites, as wel l as platelet-activating factor. Other candidate toxins include nitric oxide (NO), superoxide anion (O-2.(-)), and the N-methyl-D-aspartate (NMDA) agonist, cysteine. Similarly, macrophages activated by HIV-1 en velope protein gp120 also appear its factors can lead to increased glu tamate release or decreased glutamate re-uptake. In addition, interfer on-gamma (IFN-gamma) stimulation of macrophages induces release of the NMDA-like agonist, quinolinate. HIV-infected or gp120-stimulated macr ophages also produce cytokines, including TNF-alpha and IL1-beta which contribute to astrocytosis. A final common pathway for neuronal susce ptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain and several neurodegenerative dise ases, possibly including Huntington's disease, Parkinson's disease, an d amyotrophic lateral sclerosis. This mechanism involves the activatio n of voltage-dependent Ca2+ channels and NMDA receptor-operated channe ls with resultant generation of free radicals, and therefore offers ho pe for future pharmacological intervention.