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Kynurenine pathway inhibition reduces neurotoxicity of HIV-1-infected macrophages

From the Centre for Immunology (S.J. Kerr, L.A. Pemberton, and Dr. Brew), and the Departments of Neurology and HIV Medicine (Dr. Brew), St Vincent's Hospital, Darlinghurst; the School of Biological Sciences (Dr. Armati) and the Mass Spectrometry Analytical Facility (B. Tattam), Department of Pharmacy, University of Sydney; and the Biomedical Mass Spectrometry Unit (Dr. Smythe), University of New South Wales, Australia.

Address correspondence and reprint requests to Mr. Stephen J. Kerr, Centre for Immunology, St Vincent's Hospital, Darlinghurst, NSW, 2010 Australia.

The AIDS dementia complex (ADC) is a consequence of excessive immune activation driven at least in part by systemic HIV infection and probably brain infection. Quinolinic acid (QUIN) is a neurotoxic tryptophan metabolite produced by macrophages in response to stimulation with cytokines 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 using human fetal brain tissue to determine the relative importance of QUIN as a neurotoxin in ADC. Human macrophages were infected with HIV-1 in vitro using a viral isolate from a demented patient. 6-Chloro-D-tryptophan, an inhibitor of QUIN biosynthesis, was added to half the macrophage cultures to block formation of QUIN. Supernatants containing QUIN (SQ_pos) or in which QUIN biosynthesis had been inhibited (SQ_neg) were then added to human fetal brain aggregate cultures. Toxicity was 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 treatment of this disease.

Supported by a Commonwealth AIDS Research Grant.

Received April 14, 1997. Accepted in final form June 18, 1997.

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