KYNURENINE PATHWAY INHIBITION REDUCES NEUROTOXICITY OF HIV-1-INFECTEDMACROPHAGES

The AIDS dementia complex (ADC) is a consequence of excessive immune a ctivation driven at least in part by systemic HIV infection and probab ly brain infection. Quinolinic acid (QUIN) is a neurotoxic tryptophan metabolite produced by macrophages in response to stimulation with cyt okines or infection with HIV-1. Consequently it has been implicated in ADC pathogenesis. However, macrophages infected with HIV-1 synthesize numerous neurotoxic substances. Therefore we conducted experiments us ing human fetal brain tissue to determine the relative importance of Q UIN as a neurotoxin in ADC. Human macrophages were infected with HIV-1 in vitro using a viral isolate from a demented patient. 6-Chloro-n-tr yptophan, an inhibitor of QUIN biosynthesis, was added to half the mac rophage cultures to block formation of QUIN. Supernatants containing Q UIN (SQ(pos)) or in which QUIN biosynthesis had been inhibited (SQ(neg )) were then added to human fetal brain aggregate cultures. Toxicity w as evaluated using lactate dehydrogenase efflux, trypan blue exclusion , immunohistochemistry, image analysis, and electron microscopy. Each technique showed a reduction of toxicity in SQ(neg)-treated cultures. These studies confirm the significance of QUIN as a neurotoxin in ADC and suggest that neuroprotective strategies may have a place in the tr eatment of this disease.