Brew BJ, Corbeil J, Pemberton L, Heyes M, Evans L, Penny R, Cooper DA; International Conference on AIDS.

Int Conf AIDS. 1992 Jul 19-24; 8: Th67 (abstract no. ThB 1511).

Centre for Immunology, St. Vincent's Hospital, Sydney, Australia.

OBJECTIVES: Quinolinic acid (QUIN), an excitotoxin acting through the N Methyl D Aspartate receptor, has been found to be markedly elevated in the cerebrospinal fluid of patients with AIDS dementia complex (ADC), raising the possibility of its importance in the pathogenesis of ADC. The cellular origin of QUIN and its relationship to HIV-1 infection and cytokines are unknown but at least one cytokine, gamma interferon, can "switch on" the first enzyme in QUIN synthesis. We tested the hypothesis that HIV infected and activated macrophages could produce QUIN. METHODS: Human macrophages were isolated from peripheral blood mononuclear cells and grown in serum-free conditions. The production of QUIN by resting macrophages was compared with the production by macrophages infected with various strains of HIV-1 including those from patients with severe ADC. To substantiate that QUIN was produced by the kynurenine pathway, [13C6]-tryptophan was added to the media and assay for [13C6]-QUIN was undertaken by gas chromatography-mass spectrometry. Next, macrophages were activated by gamma interferon and QUIN assayed. Lastly, two populations of macrophages were infected one with cytomegalovirus (CMV) and the other with human herpes virus type 6 (HHV-6). Supernatants for QUIN analysis were taken at 24, 36, 48 and 60 hours. RESULTS: Resting macrophages did not produce QUIN. HIV-1 infected macrophages produced up to 20,000 nM of QUIN and there was no significant difference in QUIN production by HIV-1 isolated from patients with ADC versus those without. [13C6]-QUIN was detected in the supernatants from macrophages that had had [13C6]-tryptophan added to the medium. Gamma interferon activated macrophages produced concentrations of QUIN similar to those infected with HIV-1. QUIN production by HHV-6 infected macrophages peaked at 900 nM and CMV infected macrophages had negligible production. CONCLUSIONS: QUIN is produced by macrophages that have been infected by HIV-1, by macrophages activated by gamma interferon and by macrophages infected with HHV-6. There is, however, differential production with the highest levels resulting from infection with HIV-1 and gamma interferon activation. HIV-1 infected macrophages produce QUIN in concentrations that are far in excess of the known several hundred-fold nanomolar neurotoxic concentrations. The mechanism at least in part is probably related to gamma interferon production by inflammatory cells. These results further support a role for QUIN in the pathogenesis of AIDS dementia complex.

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Dementia Complex
• Acquired Immunodeficiency Syndrome
• Cytokines
• HIV-1
• Humans
• Interferon Type II
• Interferon-gamma, Recombinant
• Kynurenine
• Macrophages
• Neurotoxins
• Quinolinic Acid
• Simian Acquired Immunodeficiency Syndrome
• Tryptophan
• Tryptophan Oxygenase

Other ID:

• 92400089

UI: 102197802

From Meeting Abstracts