Pathogenesis Of AIDS Dementia Complex Research Articles

AIDS Dementia Complex: Neurotoxicity in AIDS Patients.

AIDS dementia complex (ADC) is a nervous system disorder that harms the neurons in different parts of the brain. Various features are involved in altering the normal activities of neurons. Neurotoxicity is induced due to HIV viral proteins such as gp120, SDF, Tat, etc. These proteins target macrophages, glial cells, astrocytes, and release neurotoxins. These neurotoxins proved harmful for the neurons, caused apoptotic cell death by raising calcium, glutamate level and by producing various free radicals such as nitric oxide (NO·). Lipid peroxidation and lipids rafts also play a vital role in producing toxicity and apoptotic cell death. Membrane associated oxidative stress, cognitive impairment, and high level of HNE (4-hydroxynonenal); all are involved in ADC pathogenesis.

HIV-1-Associated Neurocognitive Disorders: Is HLA-C Binding Stability to β2-Microglobulin a Missing Piece of the Pathogenetic Puzzle?

AIDS dementia complex (ADC) and HIV-associated neurocognitive disorders (HAND) are complications of HIV-1 infection. Viral infections are risk factors for the development of neurodegenerative disorders. Aging is associated with low-grade inflammation in the brain, i.e., the inflammaging. The molecular mechanisms linking immunosenescence, inflammaging and the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, are largely unknown. ADC and HAND share some pathological features with AD and may offer some hints on the relationship between viral infections, neuroinflammation, and neurodegeneration. β2-microglobulin (β2m) is an important pro-aging factor that interferes with neurogenesis and worsens cognitive functions. Several studies published in the 80–90s reported high levels of β2m in the cerebrospinal fluid of patients with ADC. High levels of β2m have also been detected in AD. Inflammatory diseases in elderly people are associated with polymorphisms of the MHC-I locus encoding HLA molecules that, by associating with β2m, contribute to cellular immunity. We recently reported that HLA-C, no longer associated with β2m, is incorporated into HIV-1 virions, determining an increase in viral infectivity. We also documented the presence of HLA-C variants more or less stably linked to β2m. These observations led us to hypothesize that some variants of HLA-C, in the presence of viral infections, could determine a greater release and accumulation of β2m, which in turn, may be involved in triggering and/or sustaining neuroinflammation. ADC is the most severe form of HAND. To explore the role of HLA-C in ADC pathogenesis, we analyzed the frequency of HLA-C variants with unstable binding to β2m in a group of patients with ADC. We found a higher frequency of unstable HLA-C alleles in ADC patients, and none of them was harboring stable HLA-C alleles in homozygosis. Our data suggest that the role of HLA-C variants in ADC/HAND pathogenesis deserves further studies. If confirmed in a larger number of samples, this finding may have practical implication for a personalized medicine approach and for developing new therapies to prevent HAND. The exploration of HLA-C variants as risk factors for AD and other neurodegenerative disorders may be a promising field of study.

Increased menin expression associated with neural apoptosis in the frontal cortex of SIV infected macaques

Various types of neuronal damage have been reported in AIDS dementia complex (ADC). Human immunodeficiency virus (HIV) infected microglial/macrophage, not neuron directly in the brain. However, the damage of the /INS;neuron existed after the infection, in which the regulatory protein Tat of HIV-1 could be the critical factor. It has been recently reported that HIV-1 Tat transactivation requires menin, which/INS; hints that menin may be involved in the pathogenesis of ADC. However, the mechanism has not been elucidated completely.

Analysis of genetic diversity and amino acid sequence of HIV-1 tat from a patient with AIDS dementia complex

Objective To study the variation and characteristics of HIV-1 tat exon 1 gene from a patient with AIDS dementia complex（ ADC）, so as to research the pathogenesis of ADC. Methods The tat gene was amplified with nested PCR from genomic DNA which was extracted from lymph node, spleen and different brain tissues（ meninges, grey matter from frontal cortex, white matter from frontal cortex, temporal cortex and basal ganglia） of a patient who died of ADC. PCR products were cloned into the pGEM-T vector,after transformation and selection by ampicillin and blue/white spotting. Five of positive clones were sequenced. HIV-1 tat sequences were processed with BioEdit and MEGA4. With the softwares, Neighbor-Joining tree, p-Distances, values of ds/dn, and analysis of amino acid motifs were all done. Results The samples were all identified as HIV-1 B and genetic variation exists in HIV-1 tat isolated from different tissue;Compared with HXB2, sixteen sites of the amino acid seque nce coded by the HIV-1 tat gene which was isolated from the patient changed. In addition, part of the changes were different between periphery and brain,especially, the five Q54R changes from basal ganglia and one Q54R change from temporal cortex are deserve to follow with interest. Conclusion Variations exist in the HIV-1 tat genes extracted from the ADC patient and the variations from peripheral and central nerve tissues were different, whether the variations concerned with the pathogenesis of ADC need more research. Key words: Human immunodeficiency virus 1 （ HIV-1 ） HIV-1 tat AIDS dementia complex （ADC） Genetic diversity Amino acid sequence

In vivo expression of proinflammatory cytokines in HIV encephalitis: an analysis of 11 autopsy cases

As the pathogenesis of AIDS dementia complex (ADC), cytokines such as TNF-alpha and IL-1beta have been thought to have toxic effects on CNS cells and induce neuronal cell death. However, many of the discussions have been based on the studies done by in vitro experiments. There are only a few reports which demonstrate proinflammatory cytokines directly in vivo in HIV encephalitis (HIVE) brains, and roles of these cytokines with relation to HIV-1 infection are not yet clarified. In the present study, we examined 11 autopsy cases of HIVE using immunohistochemistry, and explored which cell types expressed these cytokines and whether expression of cytokines was related to viral infection. IL-1beta was detected in the frontal white matter of all 11 cases where microglial nodules were observed to varying degrees, whereas TNF-alpha was detected in seven cases. IL-1beta- or TNF-alpha-positive cells were almost restricted to CD68-positive macrophages/microglia and mild expression of these cytokines by astrocytes was observed in two cases with severe HIVE. IL-1beta was detected in some HIVp24-positive multinucleated giant cells. However, we could not detect TNF-alpha expression in the HIVp24-positive cells, which indicates that IL-1beta is induced by HIV-1 infection. In conclusion, a macrophage/microglia lineage is the main cell type to release cytokines in HIVE, and IL-1beta expression by HIV-1-infected cells may be one of the important factors for induction of HIVE. In addition, many non-infected macrophages/microglia as well as some astrocytes express IL-1beta and TNF-alpha, which might contribute to pathogenesis of ADC.

Expression of proinflammatory cytokines and its relationship with virus infection in the brain of macaques inoculated with macrophage‐tropic simian immunodeficiency virus

The pathogenesis of acquired immunodeficiency syndrome dementia complex (ADC) is still poorly understood. Many studies suggest that proinflammatory cytokines such as IL-1beta and TNF-alpha released by microglia/macrophages or astrocytes play a role in CNS injury. A microscopic finding of a microglial nodule with multinucleated giant cells (MNGCs) is a histopathologic hallmark of ADC and named HIV encephalitis. However, in vivo expression of these cytokines in this microenvironment of HIV encephalitis is not yet clarified. One of the main reasons is complexities of brain pathology in patients who have died from terminal AIDS. In this study, we infected two macaques with macrophage-tropic Simian immunodeficiency virus SIV239env/MERT and examined expression of TNF-alpha and IL-1beta in inflammatory lesions with MNGCs and its relation to virus-infected cells using immunohistochemistry. One macaque showed typical inflammatory lesions with MNGCs in the frontal white matter. Small microglial nodules were also detected in the basal ganglia and the spinal cord. SIVenv positive cells were detected mainly in inflammatory lesions, and seemed to be microglia/macrophages and MNGCs based on their morphology. Expression of IL-1beta and TNF-alpha were detected in the inflammatory lesions with MNGCs, and these positive cells were found to be negative for SIVenv by double-labeling immunohistochemistry or immunohistochemistry of serial sections. There were a few TNF-alpha positive cells and almost no IL-1beta positive cells in the area other than inflammatory lesions. Another macaque showed scattered CD3+ cells and CD68+ cells in the perivascular regions of the white matter. SIVenv and TNF-alpha was demonstrated in a few perivascular macrophages. These findings indicate that virus-infected microglia/macrophages do not always express IL-1beta and TNF-alpha, which suggests an indirect role of HIV-1-infected cells in cytokine-mediated pathogenesis of ADC. Our macaque model for human ADC may be useful for better understanding of its pathogenesis.

Human immunodeficiency virus infection and acquired immunodeficiency syndrome dementia complex: Role of cells of monocyte-macrophage lineage

The entry of human immunodeficiency virus (HIV) into the central nervous system (CNS) causes both the establishment of a lifelong viral reservoir in the brain and symptoms of neurological dysfunction that have an AIDS dementia complex (ADC) clinical appearance. Neurological dysfunction in ADC patients still remains an unresolved problem. However, ADC pathogenesis may be a multistep process that starts with HIV invasion of CNS by crossing the blood-brain barrier (BBB). It progresses by developing a chronic inflammatory status that can cause dysfunction in neurons and astrocytes that result in apoptotic death. Monocytes-macrophages (M/M) may play an important role by concealing the HIV transfer across the BBB. Furthermore, HIV-infected M/M could produce and release neurotoxic factors. In this review the main mediators and cells involved in pathogenesis and development of ADC are highlighted. A better understanding of the mechanisms involved in this process may help in a successful therapeutic approach to the neuropathogenesis of HIV infection.

HIV leucoencephalopathy and TNFα expression in neurones

Background: Human immunodeficiency virus (HIV) leucoencephalopathy (HIVL) is an uncommon and rapidly progressive form of AIDS dementia complex (ADC) that has remained poorly understood. Tumour necrosis factor α (TNFα), which...

Involvement of quinolinic acid in AIDS dementia complex.

Human immunodeficiency virus (HIV) infection is often complicated by the development of acquired immunodeficiency syndrome (AIDS) dementia complex (ADC). Quinolinic acid (QUIN) is an end product of tryptophan, metabolized through the kynurenine pathway (KP) that can act as an endogenous brain excitotoxin when produced and released by activated macrophages/microglia, the very cells that are prominent in the pathogenesis of ADC. This review examines QUIN's involvement in the features of ADC and its role in pathogenesis. We then synthesize these findings into a hypothetical model for the role played by QUIN in ADC, and discuss the implications of this model for ADC and other inflammatory brain diseases.

Expression of the urokinase plasminogen activator and its receptor in HIV-1-associated central nervous system disease

The urokinase plasminogen activator (uPA) and its receptor (uPAR) play important physiological functions in extracellular proteolysis, as well as cell adhesion and migration. Through dysregulation of these functions, the uPA/uPAR system might be involved in the pathogenesis of AIDS dementia complex (ADC), and, in fact, uPAR has been found to be overexpressed in the cerebrospinal fluid (CSF) and brain tissues of patients with ADC. On the other hand, its ligand uPA has been shown to down-regulate HIV replication in vitro. In this study, we examined uPAR and uPA expression in the brain of HIV-related lesions, as well as CSF levels of soluble uPAR (suPAR), uPA, and complexes between these two molecules (suPAR/uPA) in patients with HIV infection with or without ADC. uPAR was highly expressed by macrophages in both HIV encephalitis (HIV-E) or leukoencephalopathy (HIV-LE), with a distribution exceeding that of HIV p24 antigen. In contrast, uPA was detected only on rare cells in most of the cases. Both uPA and suPAR/uPA complex concentrations were significantly correlated with CSF suPAR levels, and CSF concentrations of both markers were higher in ADC patients than controls. However, uPA levels were substantially lower than corresponding suPAR levels. Although these findings remain correlative, they add support to the hypothesis that uPAR might be an important participant in the events leading to ADC. Additionally, these findings are consistent with a model in which overexpression of uPAR and overproduction of its soluble form may promote HIV replication via binding and removal of uPA from cell surface.

Decreased Homovanilic Acid in Cerebrospinal Fluid Correlates with Impaired Neuropsychologic Function in HIV-1-Infected Patients

To determine whether dopamine metabolism is abnormal in HIV infected patients and whether dopamine metabolism abnormalities are related to specific neuropsychologic characteristics in HIV-infected patients, we measured cerebrospinal fluid (CSF) levels of homovanilic acid (HVA), the primary dopamine metabolite, in 10 HIV-infected patients and compared it to HVA levels in CSF in a group of 13 healthy control subjects. HIV-infected patients were also assessed with a battery of neuropsychologic tests and HVA levels were then correlated with performance on specific neuropsychologic tests. The mean (+/-SD) HVA level in CSF was 100.9 +/- 29.3 nmol/L in the HIV-infected study group and 230.5 +/- 50.0 nmol/L in the non-HIV-infected control group (p < 0.0001). The decrease in concentrations of HVA in CSF correlated with impairment on performance on neuropsychologic testing (Spearman r = 0.67; p = 0.03). When the relationship between HVA levels and specific cognitive domains was evaluated, we observed trends for positive correlation between HVA levels and tests that measure motor speed (r = 0.59; p = 0.074) and those testing attention, concentration, and executive control (r = 0.54; p = 0.108). There was no relationship between performance on memory tests and CSF HVA levels (r = -0.0061; p = 0.987). These results further support the hypothesis that dopaminergic dysfunction plays an important role in the pathogenesis of AIDS dementia complex (ADC) and suggest that specific motor and cognitive abnormalities may be related to depressed dopaminergic activity. This may have important implications for the development of treatments or preventive strategies for ADC.

Human Immunodeficiency Virus Type 1 Envelope Glycoprotein gp120 Induces Tumor Necrosis Factora in Astrocytes

gp120 induction of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was studied in cultures of purified astrocytes. Incubation of pure mouse cortical astrocytes with gp120 IIIB induced the expression of TNF-alpha mRNA, assessed by in situ hybridization. Anti- TNF-alpha immunocytochemical staining of gp120 IIIB stimulated astrocytes indicated the presence of TNF-alpha. gp120 IIIB treatment also stimulated secretion of bioactive TNF-alpha from astrocytes, which was prevented by inhibitors of transcription and translation. Hippocampal and cerebellar astrocytes displayed similar behaviors. Further, gp120 displayed cytotoxicity for astrocytes that depended on macromolecular synthesis. The data are the first to show gp120 IIIB induction of de novo TNF-alpha production by pure astrocytes. Because TNF-alpha exerts a wide array of effects in the brain of infected individuals and has HIV-1 inducing activity as well, induction of this cytokine by gp120 IIIB in astrocytes may contribute importantly to the pathogenesis of AIDS dementia complex. Since TNF-alpha can stimulate astrocyte reactivity and proliferation by an autocrine mechanism, the extent of the gp120 effect could conceivably increase with HIV-1 disease progression in a self-amplifying loop, involving other cell types, thus favoring both virus persistence and a chronic disease state.

Measuring HIV-1 RNA and interferon-alpha in the cerebrospinal fluid of AIDS patients: insights into the pathogenesis of AIDS Dementia Complex.

The aim of this work was to study the role of HIV replication and the role of endogenous secretion of interferon-alpha in the pathogenesis of AIDS Dementia Complex (ADC). To accurately establish the diagnosis of ADC, 39 consecutive HIV-positive patients who presented with immune and intellectual deficiency underwent an extensive neurological evaluation. This included magnetic resonance imaging, neuropsychological testing and a lumbar puncture. The levels of HIV-1 RNA were measured in the cerebrospinal fluid (CSF) and blood by HIV Monitor (Roche Diagnostics) and those of interferon-alpha by an in-house biological assay. The diagnosis of ADC was established in 22 cases, which included nine out of the ten patients who had a high CSF viral load (above 4 log HIV-1 RNA copy per ml). Patients receiving highly active antiretroviral therapy had low viral loads in blood and CSF. In all 22 ADC patients, viral load in the CSF correlated with the staging of ADC (r=0.46, P=0.03), the CSF level of interferon-alpha (r=0.42, P=0.05) and with the bicaudate ratio (r=0.43, P=0.06), a measure of cerebral atrophy in the region of the caudate nucleus. No correlation was observed between CSF and plasma HIV-1 RNA. These results show that HIV may play a role in the neurological impairment of ADC patients possibly in part through the deleterious effect of interferon-alpha on the central nervous system and that highly active combination therapy should reduce or prevent these complications.

Impairment of excitatory amino acid transport in astroglial cells infected with the human immunodeficiency virus type 1.

Perturbation of astrocyte functions by HIV-1 infection may contribute to the pathogenesis of AIDS dementia complex (ADC). The present study investigated the possibility that astroglial transport of glutamate and aspartate, the major excitatory amino acids (EAAs) in the mammalian central nervous system (CNS), is altered by HIV-1 infection. Human U251 glioma cells were infected with the brain isolate SF162 of HIV-1. HIV-1 persisted in glial cells over several months. This nonproductive infection of glial cells was characterized by persistent expression of Nef over the time of the infection, and the transient presence of structural viral proteins, including the viral transmembrane glycoprotein gp41, which was detected during the initial 2 weeks following HIV-1 infection. The presence of gp41 in acutely HIV-1-infected glial cells coincided with a 36% decrease in D-[3H]aspartate uptake, owing to a reduction in the maximal transport capacity (vmax) for D-aspartate. The expression of typical astrocytic glutamate transporters EAAT1 and EAAT2 in U251 glioma cells was not altered by HIV-1 infection. To determine whether viral protein gp120, gp41, or Nef was involved in the impairment of EAA transport in acutely HIV-1-infected glial cells, effects of lentiviral lytic peptide type 1 (LLP-1) (corresponding to the carboxy terminus of gp41), recombinant SF2 gp120, and recombinant LAI Nef on D-[3H]aspartate uptake and the release of glutamate in glial cells were investigated. Only LLP-1 reduced D-[3H]aspartate uptake and facilitated the release of glutamate from glial cells in a concentration-dependent manner. These results suggest that the carboxy terminus of gp41 impairs EAA transport in glial cells, which may contribute to excitotoxic damage to neurons in HIV-1 infection of the CNS.

SIV infection of macaques--modeling the progression to AIDS dementia.

AIDS dementia complex affects 15-20% of HIV-infected adults and a greater percentage of HIV-infected children. Whether or not an HIV-infected individual develops neurological disease and how early in infection the clinical signs appear is most likely the net result of both viral virulence factors and host factors. Important viral factors include cell tropism and sequences that determine neurovirulence. The host factors include the cellular expression of viral co-receptors and maintenance of competent immune responses. The pathogenesis of AIDS dementia complex is difficult to study in the human host because of the difficulty in identifying acutely infected individuals and the inaccessibility of human brain tissue for examination during infection. The SIV/macaque model is excellent for the study of viral virulence factors and host responses to infection. This review outlines how the SIV/macaque model has been used to identify viral factors that are important for the development of neurological disease, to determine when HIV enters the brain, and to characterize the host immune responses affecting virus entry to the CNS and the development of neurological disease.

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

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 (SQpos) or in which QUIN biosynthesis had been inhibited (SQneg) 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 SQneg-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.

Quinolinic acid production by macrophages stimulated with IFN-gamma, TNF-alpha, and IFN-alpha.

Quinolinic acid (QUIN) has been associated with several inflammatory neurologic disorders, including AIDS dementia complex (ADC). Recent studies suggest that activation of macrophages with either HIV-1 or interferon-gamma (IFN-gamma) can lead to QUIN production. However, the importance of other cytokines, especially those related to the macrophage and that are especially important in ADC pathogenesis, remains unclear. We, therefore, sought to determine the role of tumor necrosis factor-alpha (TNF-alpha) and IFN-alpha in the production of QUIN. Primary human macrophages were stimulated with two different concentrations of these cytokines alone, in combination with each other, and with IFN-gamma. QUIN concentrations in the supernatants were then measured by mass spectrometry at 24, 48, and 72 hs. Results at 72 h showed significant increases in QUIN production in the cells stimulated with IFN-gamma (10297 +/- 170 nmol/L) and also in those stimulated with IFN-alpha (3600 +/- 113 nmol/L), whereas TNF-alpha-stimulated macrophages produced low levels of QUIN (1108 +/- 23 nmol/L). Macrophages stimulated with the cytokine combinations TNF-alpha and IFN-gamma, IFN-alpha, and IFN-gamma, and TNF-alpha and IFN-alpha also resulted in increases in QUIN production (11471 +/- 77.6 nmol/L, 16656 +/- 184 nmol/L, and 3369 +/- 120.5 nmol/L, respectively). The increases in QUIN production in all of the cytokine treatments approached or exceeded in vivo concentrations of QUIN that have been shown to be neurotoxic. These data further support a role for QUIN in cytokine-mediated neuronal death in inflammatory disorders of the brain, especially ADC.

HIV infection of macrophages and pathogenesis of AIDS dementia complex: interaction of the host cell and viral genotype.

AIDS dementia complex (ADC) develops in only a third of HIV-infected patients who progress to AIDS. Macrophages and microglial cells are the major cellular sites of productive HIV replication in brain. Using 11 blood isolates of HIV from asymptomatic patients there was marked variation in tropism and the level of productive infection in recently adherent monocytes and monocyte-derived macrophages cultured in vitro. However, less variation was seen with 19 blood isolates from advanced HIV infection and 11 postmortem tissue isolates from brain, cerebrospinal fluid, spleen, and lung. Newly adherent monocytes expressed CCR5 in all seven patients tested, consistent with their susceptibility to infection but not explaining the above variability. There is, also marked regional variability in neuropathology in the brain of patients with ADC. We have demonstrated that there was marked variation in the V3 sequences of HIV clones from different regions of the cortex of a patient with ADC, suggesting independent evolution of HIV replication in brain. Furthermore, production of the neurotoxin quinolinic acid from HIV-infected macrophages varied, depending on the host and source of HIV isolate. Hence variations in viral genotype, production by infected macrophages, and subsequent toxin production may contribute to the variability in neuropathology between individuals and between different regions of the brain in the same individual.

Elevated Glutamate in the Cerebrospinal Fluid of Patients With HIV Dementia

To the Editor. —The pathogenesis of acquired immunodeficiency syndrome (AIDS) dementia complex is controversial. Since no neuronal localization of human immunodeficiency virus (HIV) has been shown, it has been hypothesized that soluble factors, produced from infected macrophages, glial cells, or directly by the virus, might target the neurons and induce apoptotic cell death, resulting in brain atrophy and dementia. In vitro and in vivo experiments indicate that the viral proteins gp 120 and Tat may cause neuronal apoptosis, which can be blocked by antagonists of N -methyl-D-aspartate (NMDA) and non-NMDA receptors. 1-3 This evidence suggests that the glutamatergic system and excitotoxicity are involved in the pathogenesis of AIDS dementia complex. However, viral proteins do not bind to glutamate receptors: therefore, overstimulation of glutamate receptors seems to be mediated by interactions with endogenous glutamate or other excitatory amino acid receptor agonists. In fact, the toxic effect of gp 120 was prevented

Regulation of glutathione and cell toxicity following exposure to neurotropic substances and human immunodeficiency virus-1 in vitro.

The aim of the present study was to assess the toxic potential of drugs of abuse and other neuropharmacological agents in the pathogenesis of AIDS dementia complex (ADC), the neurological complication of AIDS. Neuroblastoma and glioblastoma cell lines expressing the dopamine transporter, as well as primary macrophages exposed to human immunodeficiency virus-1 (HIV-1), were used to investigate the possibility of any synergistic effect between the mode of toxicity of such substances and virus exposure. The drugs of abuse used in our experiments were cocaine and morphine, which exert their action, among others, on the dopaminergic system. Effects were compared to treatment with dopamine itself and a typical dopaminergic drug used pharmaceutically, selegiline. In macrophage cultures, glutathione (GSH) was upregulated strongly after treatment with dopamine, morphine or selegiline, and this effect was enhanced when cells were pre-exposed to virus. This upregulation is discussed as a compensatory reaction to an oxidative signal. When hydrogen peroxide plus iron sulfate was used as a strong oxidant in macrophages, GSH concentrations decreased as a result of cell injury. Cell numbers remained constant in all treatment groups. In contrast, in both neuroblastoma and glioblastoma cell lines, the modulation of GSH concentrations by neurotropic substances was accompanied by significant cell loss, which was exacerbated by HIV-1 pretreatment. Selegiline did not change cell numbers when incubated alone. However, when incubated following treatment with HIV-1 cell death was highly significant. Ascorbic acid (AA), included as antioxidant, totally restored cell loss in cultures treated with dopamine. However, no effect was observed in combined treatment of AA and morphine or selegiline. The results demonstrate a synergistic role in cellular toxicity due to neurotropic substances and HIV-1, and suggest that neuropharmacological agents may contribute to the pathogenesis of ADC.