NEURONAL INJURY ASSOCIATED WITH HIV-1 - APPROACHES TO TREATMENT

Mounting evidence suggests that cognitive dysfunction developing as a result of HIV-q infection is mediated at least in part by generation o f excitotoxins and free radicals in the brain. This syndrome is curren tly designated HIV-1-associated cognitive/motor complex, was originall y termed the AIDS Dementia Complex, and for simplicity, is called AIDS dementia in this review. Recently, brains of patients with AIDS have been shown to manifest neuronal injury and apoptotic-like cell death. How can HIV-1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the virus? Experiments from several diff erent laboratories have lent support to the existence of HIV-and immun e-related toxins in a variety of in vitro and in vivo paradigms. In on e recently defined pathway to neuronal injury, HIV-infected macrophage s and microglia, or immune-activated macrophages and astrocytes (activ ated by the shed HIV-1 envelope protein, gp120, or other viral protein s and cytokines), appear to secrete excitants and neurotoxins. These s ubstances may include arachidonic acid, platelet-activating factor, fr ee radicals (NO. and O-2(.-)), glutamate, quinolinate, cysteine, amine s, and as yet unidentified factors emanating from stimulated macrophag es and reactive astrocytes. A final common pathway for neuronal suscep tibility is operative, similar to that observed in stroke and several neurodegenerative diseases. This mechanism involves excessive activati on of N-methyl-D-aspartate (NMDA) receptor-operated channels, with res ultant excessive influx of Ca2+ and the generation of free radicals, l eading to neuronal damage. With the very recent development of clinica lly tolerated NMDA antagonists, there is hope for future pharmacologic al intervention.