CSF quinolinic acid levels are determined by local HIV infection: cross-sectional analysis and modelling of dynamics following antiretroviral therapy

Abstract

Quinolinic acid (QUIN) is a product of tryptophan metabolism that can act as an endogenous brain excitotoxin when released by activated macrophages. Previous studies have shown correlations between increased CSF QUIN levels and the presence of the AIDS dementia complex (ADC), a neurodegenerative condition complicating late-stage human immunodeficiency virus type 1 (HIV) infection in some patients. CSF QUIN is putatively one of the important molecular mediators of the brain injury in this clinical setting and, more generally, serves as a marker of local macrophage activation. This study was undertaken to examine the relationship of CSF QUIN concentrations to local HIV infection and to define the effects of antiretroviral drug treatment on CSF QUIN using two complementary approaches. The first was an exploratory cross-sectional analysis of a clinically heterogeneous sample of 62 HIV-infected subjects, examining correlations of CSF QUIN levels with CSF and plasma HIV RNA levels and other salient parameters of infection. The second involved longitudinal observations of a subset of 20 of these subjects who initiated new antiretroviral therapy regimens. In addition to descriptive analysis, we used kinetic modelling of QUIN decay in relation to that of HIV RNA to assess further the relationship between CSF QUIN and infection in the dynamic setting of treatment. The cross-sectional studies showed strong correlations of CSF QUIN with both CSF HIV RNA and blood QUIN levels, as well as with elevations in CSF white blood cells, CSF total protein and CSF:blood albumin ratio. In this group of subjects with a low incidence of active, untreated ADC, CSF QUIN did not correlate with ADC stage or measures of quantitative neurological performance. Antiviral treatment reduced the CSF QUIN levels in all the longitudinally followed, treated subjects. Kinetic modelling of CSF QUIN decay indicated that CSF QUIN levels were driven primarily by CSF HIV infection with a lesser contribution from blood QUIN levels. In three subjects with new-onset, untreated ADC, CSF QUIN decay paralleled both CSF HIV decrement and improvement in neurological performance. These studies show that CSF QUIN concentrations relate primarily to active CSF HIV infection and to a lesser extent to plasma QUIN. CSF QUIN serves as a marker of local infection with a wide dynamic range. The time course of therapy-induced changes links CSF QUIN to local infection and supports the action of antiviral therapy in ameliorating immunopathological brain injury and ADC.

Involvement of quinolinic acid in aids dementia complex

“…Furthermore, administration of zidovudine alone as well as HAART can lead to a reduction in CSF QUIN levels and improvement in neurological status (Heyes et al, 1991;Martin et al, 1992;Rausch et al, 1995;Sei et al, 1996;Look et al, 2000;Valle et al, 2004) in some demented patients. The same is true in monkeys infected with SIV (Heyes et al, 1991;Rausch et al, 1995).…”

Human Immunodeficiency Virus (HIV)-Induced Neurotoxicity: Roles for the NMDA Receptor Subtypes

“…HIV infection of macrophages within the brain is thought to be a critical factor in triggering events leading to neuronal damage and death, and multiple studies in vitro and in vivo indicate that excitotoxicity mediated by activation of macrophages plays a major role (Brenneman et al, 1988;Heyes et al, 1989;Dreyer et al, 1990;Giulian et al, 1990;Tardieu et al, 1992;Dawson et al, 1993;Lipton, 1993;Brew et al, 1995;Nottet et al, 1996;Power et al, 1998;Jiang et al, 2001;Kaul et al, 2001;Valle et al, 2004). Some of these models use HIV-infected monocytes/macrophages as a source of neurotoxins (Heyes et al, 1989;Giulian et al, 1990;Tardieu et al, 1992;Power et al, 1998), whereas others use application of recombinant proteins to neuronal cultures (Dreyer et al, 1990;Dawson et al, 1993;Lipton, 1993;Kaul et al, 2001) to model HIV/MDM neurotoxicity.…”

Quinolinic acid induces NMDA receptor-mediated lipid peroxidation in rat brain microvessels

“…21 However, the average levels of QUIN in brain tissue under the state of immune activation have been reported at 32 nmole/g. 22 Furthermore, morphological evidence suggests that the discrete subpopulations of QUIN-producing cells may secrete QUIN directly onto specific targets, including capillaries, 23 thus potentially generating very high local concentrations of QUIN.…”