Bruce J. Brew

Neurological complications of HIV infection

Cognitive disorders, vacuolar myelopathy, and sensory neuropathies associated with HIV are the most common disorders in patients with HIV AIDS, and are the focus of this review. These disorders are treatable and of those associated with HIV AIDS the pathogenic mechanisms are the most understood. Although triggered by productive HIV macrophage infections, aberrant immune activation plays a major role in inducing the CNS disorders. Novel therapies aimed at these inflammatory mechanisms can be effective. The sensory neuropathies associated with HIV infection are a major cause of morbidity; incidence may be increased by the toxic effects of specific antiretroviral drugs within the peripheral nervous system.

Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification

The phenotypic differentiation of systemic macrophages that have infiltrated the central nervous system, pericytes, perivascular macrophages, and the “real” resident microglial cells is a major immunocytochemical and immunohistochemical concern for all users of cultures of brain cells and brain sections. It is not only important in assessing the purity of cell cultures; it is also of fundamental importance in the assessment of the pathogenetic significance of perivascular inflammatory phenomena within the brain. The lack of a single membranous and/or biochemical marker allowing conclusive identification of these cells is still a major problem in neurobiology. This review briefly discusses the functions of these cells and catalogs a large number of membranous and biochemical markers, which can assist in the identification of these cells.

Changes to AIDS dementia complex in the era of highly active antiretroviral therapy

OBJECTIVES To determine the protective efficacy of highly active antiretroviral therapy (HAART) against AIDS dementia complex (ADC) relative to other initial AIDS-defining illnesses (ADIs), Australian AIDS notification data over recent years were examined. METHODS All initial ADIs in Australia over the period 1992-1997 were included. Three initial ADI groups were established: ADC; other predominantly central nervous system (CNS) ADIs (toxoplasmosis and cryptococcosis); and non-CNS ADIs. For each ADI grouping, the proportion of total ADls, and median CD4 cell count in the pre-HAART era (1992-1995) were compared with the HAART era (1996 and 1997). RESULTS Initial ADls peaked in Australia in 1994 (n = 1049), with a gradual decline to 1996 (n = 722), and a marked decline in 1997 (n = 367). ADC constituted 4.4% of initial ADIs over the period 1992-1995, but increased after the introduction of HAART to 6.0% in 1996 and 6.5% in 1997 (P = 0.02). In contrast, the proportion of other CNS ADIs (1992-1995, 8.1%; 1996, 6.0%; 1997, 8.2%; P = 0.41) was stable over the period 1992-1997. The median CD4 cell count at ADC diagnosis increased from 70/mm3 in 1992-1995 to 120/mm3 in 1996 and 170/mm3 in 1997 (P = 0.04). Although the median CD4 cell count also increased significantly over this period for both other CNS ADIs (40-60/mm3; P = 0.02), and non-CNS ADIs (60-70/mm3; P = 0.02), the increase was small. CONCLUSION A proportional increase in ADC compared with other ADIs and a marked increase in the median CD4 cell count at ADC diagnosis have occurred since the introduction of HAART in Australia. These changes suggest that HAART has a lesser impact on ADC than on other ADIs, with the poor CNS penetration of many antiretroviral agents a possible explanation.

Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection.

There is good evidence that the kynurenine pathway (KP) and one of its products, quinolinic acid (QUIN), play a role in the pathogenesis of neurological diseases, in particular AIDS dementia complex. Although QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the role of astrocytes in QUIN production is controversial. Using cytokine‐stimulated cultures of human astrocytes, we assayed key enzymes and products of the KP. We found that human astrocytes lack kynurenine hydroxylase so that large amounts of kynurenine and the QUIN antagonist kynurenic acid were produced. However, the amounts of QUIN that were synthesized were subsequently completely degraded. We then showed that kynurenine in concentrations comparable with those produced by astrocytes led to significant production of QUIN by macrophages. These results suggest that astrocytes alone are neuroprotective by minimizing QUIN production and maximizing synthesis of kynurenic acid. However, it is likely that, in the presence of macrophages and/or microglia, astrocytes become indirectly neurotoxic by the production of large concentrations of kynurenine that can be secondarily metabolized by neighbouring or infiltrating monocytic cells to form the neurotoxin QUIN.

Expression of indoleamine 2,3‐dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons

There is good evidence that the kynurenine pathway (KP) and one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neurological diseases. While QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the capacity of astrocytes and neurons to produce QUIN is controversial. Using interferon gamma (IFN‐γ)‐stimulated primary cultures of human mixed brain cells, we assayed expression of the KP regulatory enzyme indoleamine 2,3‐dioxygenase (IDO) and QUIN production by immunocytochemistry. Using IFN‐γ‐stimulated purified cultures of neurons, astrocytes, microglia and macrophages, we studied IDO expression by RT‐PCR and production of QUIN using mass spectrometry. We found that astrocytes, neurons, and microglia expressed IDO but only microglia were able to produce detectable amounts of QUIN. However, astrocytes and neurons had the ability to catabolize QUIN. This study also provides the first evidence of IDO expression and lack of production of QUIN in culture of primary human neurons.

Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre- and post-highly active antiretroviral therapy eras: A combined study of two cohorts

The objective of this study was to assess the prevalence and pattern of neuropsychological impairment in cohorts of human immunodeficiency virus (HIV)-infected individuals across pre- and post-HAART (highly active antiretroviral therapy) eras. Two cohorts of HIV-infected individuals attending tertiary referral hospital outpatient clinics were studied. The cohorts represented two eras of antiretroviral medication: monotherapy (n = 51) and HAART (n = 90). Each was compared in nine neuropsychological domains in regard to the prevalence as well as pattern of neuropsychological impairment. Because the authors intended to characterize the prevalence and pattern of neuropsychological deficits in nondemented advanced HIV-infected individuals, patients with a current diagnosis of acquired immunodeficiency syndrome (AIDS) dementia complex were not included. The prevalence of impairment was not significantly different across pre-HAART and HAART eras using a standard criterion to define impairment: −2 SD in two neuropsychological measures (41.1%/38.8%). Prevalence of deficits was not significantly reduced in patients with undetectable plasma viral load. The pattern of neuropsychological impairment was different across pre-HAART and HAART eras, with an improvement in attention, verbal fluency, visuoconstruction deficits, but a deterioration in learning efficiency and complex attention. This change remained even in patients with an undetectable plasma viral load, although the severity was partially diminished. Neuropsychological deficits remain common in the HAART era, essentially uninfluenced by HAART. The finding that some neuropsychological functions are improving while other are deteriorating indicates that these deficits do not reflect “burnt out” damage but rather that there is an active intracerebral process occurring, the nature of which is still to be determined.

Validity of the CogState Brief Battery: Relationship to Standardized Tests and Sensitivity to Cognitive Impairment in Mild Traumatic Brain Injury, Schizophrenia, and AIDS Dementia Complex

This study examined the validity of the four standard psychological paradigms that have been operationally defined within the CogState brief computerized cognitive assessment battery. Construct validity was determined in a large group of healthy adults. CogState measures of processing speed, attention, working memory, and learning showed strong correlations with conventional neuropsychological measures of these same constructs (rs = .49 to .83). Criterion validity was determined by examining patterns of performance on the CogState tasks in groups of individuals with mild head injury, schizophrenia, and AIDS dementia complex. Each of these groups was impaired on the CogState performance measures (Cohens ds = -.60 to -1.80) and the magnitude and nature of this impairment was qualitatively and quantitatively similar in each group. Taken together, the results suggest that the cognitive paradigms operationally defined in the CogState brief battery have acceptable construct and criterion validity in a neuropsychological context.

Levels of Human Immunodeficiency Virus Type 1 RNA in Cerebrospinal Fluid Correlate with AIDS Dementia Stage

The relationship between the presence and severity of AIDS dementia complex (ADC) and the levels of human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid (CSF) were assessed. Nineteen patients with ADC (stages 1-3), 6 without ADC (group 1), and 10 (group 2) without ADC but with cryptococcal meningitis or progressive multifocal leukoencephalopathy were studied. There was a significant relationship between increasing CSF virus burden and ADC severity (P = .0006) but not with plasma burden and ADC severity. In group 2, CSF HIV-1 RNA levels in patients with cryptococcal meningitis were elevated. These results show that CSF HIV-1 RNA concentrations correlate well with ADC severity but may also be increased by central nervous system infections, such as cryptococcal meningitis.

Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia.

Astrocyte infection with human immunodeficiency virus (HIV) is considered rare, so astrocytes are thought to play a secondary role in HIV neuropathogenesis. By combining double immunohistochemistry, laser capture microdissection, and highly sensitive multiplexed polymerase chain reaction to detect HIV DNA in single astrocytes in vivo, we showed that astrocyte infection is extensive in subjects with HIV‐associated dementia, occurring in up to 19% of GFAP+ cells. In addition, astrocyte infection frequency correlated with the severity of neuropathological changes and proximity to perivascular macrophages. Our data indicate that astrocytes can be extensively infected with HIV, and suggest an important role for HIV‐infected astrocytes in HIV neuropathogenesis. Ann Neurol 2009;66:253–258

Characterization of the Kynurenine Pathway in Human Neurons

The kynurenine pathway is a major route of l-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.