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PubMed1995

The development of animal model systems for HIV-1 encephalitis and its associated dementia.

The human immunodeficiency virus (HIV) is neuroinvasive and can be neurovirulent. Indeed, 20-30% of individuals with the acquired immune deficiency syndrome (AIDS) develop cognitive and motor dysfunction (termed the AIDS dementia complex or HIV dementia) coincident with advanced immunosuppression. Despite massive research efforts to discern viral neuropathogenic mechanisms, much remains incompletely understood. Recently, we and others developed animal model systems to elucidate how HIV infection within the brain can lead to impairment of central nervous system function. In this report, we evaluate each of the published animal models for their ability to mirror HIV dementia. Ease of handling and expense were also under consideration. Ultimately, studies in animal systems should permit a better understanding of the nature of HIV-1-induced neurological injury and aid in the development of effective treatments for this dreaded complication of HIV infection.

AIDS Dementia Complex↗
PubMed1997

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.

AIDS Dementia Complex↗
PubMed1999

Meningitis in a community with a high prevalence of tuberculosis and HIV infection.

OBJECTIVES: To evaluate the spectrum of aetiologies, and distinguishing clinical and laboratory features, of meningeal infection in a community with a high prevalence of tuberculosis (TB) and HIV infection. SETTING: A hospital serving mineworkers, originating from rural areas of Southern Africa. DESIGN: Prospective cohort of 60 consecutive lumbar punctures (LPs), performed for suspected meningitis. MEASUREMENTS: Clinical history and examination; concurrent cerebrospinal fluid (CSF) and blood samples; mortality status six months after entry to study. RESULTS: 38 of 57 patients (66.7%) were HIV-1 positive, 59.5% of whom had a CD4 count <200 cells/mm3. Nine patients had tuberculous meningitis (TBM) and two had tuberculomas; four developed disease while on TB therapy. There was one case of multidrug, and two of isoniazid-resistant TBM. There were nine episodes of cryptococcal meningitis (seven patients), nine of aseptic meningitis, two of neurosyphilis and 20 normal LPs, including four with AIDS dementia complex (ADC). Ten patients with meningococcal infection, part of a larger outbreak, were significantly younger (p=0.004). All patients with tuberculous, cryptococcal (most immune-suppressed p<0.001) and aseptic meningitis were HIV-1 positive. Within six months, 19 patients had died. Death was associated with HIV positivity (p=0.004), low CD4 count (p<0.001) and a diagnosis of cryptococcal meningitis, CNS TB or ADC. CONCLUSION: HIV has a major impact on the burden of disease and mortality, with a predominance of opportunistic chronic meningitides, despite a meningococcal outbreak, in this community. Of concern is the development of TBM despite therapy, and the emergence of drug-resistant strains.

AIDS Dementia Complex↗
PubMed1999

SPECT with 99mTc-HMPAO in subjects with HIV infection: cognitive dysfunction correlates with high uptake.

We prospectively studied a cohort of 25 HIV-1 infected individuals with no clinical signs of encephalopathy with 99mTc-HMPAO-SPECT. The findings were correlated with magnetic resonance imaging (MRI), neuropsychological testing and clinical staging aiming at the early diagnosis of HIV encephalopathy by single photon emission computed tomography (SPECT). A total of 25 matched seronegative controls were subject to neuropsychological testing only. A total of 24 patients and controls were monitored for 6-46 months (mean and median 26 months). No patients developed AIDS dementia complex during the study; 3 patients developed minimal symptoms (MSK classification stage 0.5). There was a significant decline in 99mTc-HMPAO uptake over time and neuropsychological abnormalities progressed. Unexpectedly, there was a correlation of high cortical and subcortical 99mTc-HMPAO uptake and low performance in cognitive dysfunction tests, indicating a possible inflammatory reaction in the brain with increased blood flow due to HIV infection. We conclude that, in non-demented HIV-infected individuals, both the 99mTc-HMPAO uptake and functional level slowly decrease over time, but the regional cerebral blood flow decrease could be masked by a direct HIV-induced inflammatory reaction in the brain, which gives a 99mTc-HMPAO hyperfixation.

AIDS Dementia Complex↗
PubMed2002

HIV-1-induced production of endothelin-1 in an in vitro model of the human blood-brain barrier.

Evidence suggests that the HIV-1 envelope glycoproteins play a role in the central nervous system (CNS) complications of AIDS. Endothelin-1 (ET-1) has also been implicated in brain injury and the progression of the AIDS dementia complex (ADC). Here, we used a real-time reverse transcription polymerase chain reaction assay and an immunometric assay to show that in vitro model of the blood-brain barrier (BBB) consisting of a monolayer co-culture of astrocytes and human brain microvascular endothelial cells (A-HBMEC) increased its expression of ET-1 mRNA and secretion of ET-1 peptide when infected with HIV-1. The enhanced expression of ET-1 occurred independently of viral replication as it was also induced by the viral glycoprotein coat HIV-1g120SF. These results show that one mechanism by which HIV-1 might affect the CNS is by inducing release of ET-1 by the BBB.

AIDS Dementia Complex↗
PubMed1995

Combination therapy from a clinician's perspective.

A number of important scientific questions have been answered in recent years concerning how HIV causes disease and whether combinations of antiretroviral agents might be more effective than monotherapies. However, a considerable number of questions remain unanswered regarding when to start treatment and what regimen to start with. It is also obvious that significant disparity exists between what is possible in therapeutic terms, in the clinic, and what has been demonstrated in in vitro studies and clinical trials. In translating what we have learned about combination therapy in clinical trials to application in a clinical setting, it is necessary to consider a number of important factors. First, the availability of antiretroviral agents as licensed products varies considerably between countries, as do the indications for these agents. Physicians in many countries are presently faced with prescribing therapeutic regimens that are already known to be suboptimal. With the speed of release of new data, there is growing disparity between our therapeutic knowledge and what is possible in the clinic. Patient compliance is also a very important consideration in the development of combination therapy, as patients may be expected to take large numbers of tablets for very long periods of time. Trials of combination therapies to date have already provided some insight into patients' willingness to comply with dosing regimens. A further consideration for physicians treating early-stage patients for prolonged periods is the prevention of development of HIV-associated CNS disease. Zidovudine is effective in preventing the onset of AIDS-dementia complex but little is known about the efficacy of other antiretroviral agents. To prevent the re-emergence of this disease to levels seen before the introduction of zidovudine (AZT) in 1987, it might be important to include AZT in all combination therapy regimens. For combination therapy to be approved and used on a widespread basis, effective tools or markers for monitoring the efficacy of therapeutic regimens are required. Tools such as viral load measurements require regulatory approval on a worldwide scale and should be economically and logistically accessible for regular use in the clinic. The increase in cost of HIV management associated with combination therapy is a significant factor in determining its widespread acceptance. It is heartening to see that collaborative efforts are already under way to address this important issue.

AIDS Dementia Complex↗
PubMed1997

Stable neurological function in subjects treated with 2'3'-dideoxyinosine.

AIDS Dementia Complex (ADC) is a frequent and devastating complication of HIV infection. There is evidence that zidovudine (ZDV) has an effect in alleviating the symptoms of ADC, and may have a role in its prevention. It is therefore important that new antiretroviral therapies be evaluated not only for the risk of neurologic side effects, but also for their relative efficacy to ZDV in the prevention of ADC. The present study reports the effects of 2'3'-dideoxyinosine (DDI, didanosine, Videx) therapy on neuropsychological performance in the context of several large clinical trials targeting advanced systemic HIV-1 infection. Subjects treated with DDI had stable neurologic performance in quantitative tests over a 1 year period and were similar to zidovudine treated subjects.

AIDS Dementia Complex↗
PubMed1989

[EEG topography in HIV-positive hemophiliacs].

HIV-central nervous system manifestations, here the AIDS-Dementia complex, are at the moment of special interest owing to its unexpected development. With EEG-topography one can expect to gain more information about possible changes in frequency according to topographical location. We recorded 69 HIV-positive hemophiliacs (23 WR 2, 26 WR 3-5 and 6 patients) plus 50 HIV-seronegative controls with a 12 channel EEG-topography evaluation. During the critical examination we looked for the results of two parameters: a) alpha 1-3/alpha 4 and b) alpha 4-4/9. In comparison to the control group we found a statistical significance (p less than 0.05) for WR 2-6 in alpha 1-3/alpha 4 index. Concerning the alpha 1-4/9 index one can only recognize a statistical significance (p less than 0.05) for WR 3-6 patients in comparison to the controls.

AIDS Dementia Complex↗
PubMed1990

The involvement of the cerebral cortex in human immunodeficiency virus encephalopathy: a morphological and immunohistochemical study.

The encephalopathy resulting from direct infection of the brain by human immunodeficiency virus (HIV), which correlates clinically with the AIDS dementia complex, has been reported as being localized to the white matter where it induces myelin loss, gliosis and perivascular infiltration by mononuclear macrophages and multinucleated giant cells. Damage to the cortical grey matter in HIV encephalopathy was investigated in nine randomly selected HIV-positive cases with or without clinical or morphological evidence of encephalopathy and in five age-matched controls, using routine histology and immunohistochemical methods [glial fibrillary acidic protein (GFAP), microglia and HIV antibodies]. Increased numbers of GFAP-expressing astrocytes and Ricinus communis agglutinin 1-120-expressing microglial cells were found in all the HIV-positive cases (including asymptomatic) and their severity could be correlated with the severity of the encephalopathy in the white matter; the increase in number of cells expressing GFAP was diffuse and the intensity of the staining higher than that of microglial cells. The subpial region was the most severely involved. It is suggested that involvement of the cortical grey matter is more common in HIV infection than previously suspected and that clinical evidence of a dementing process in AIDS is not necessarily due only to white matter lesions.

AIDS Dementia Complex↗
PubMed1997

Biochemical changes in the frontal lobe of HIV-infected individuals detected by magnetic resonance spectroscopy.

We have developed a proton magnetic resonance spectroscopy method that selectively can sample cortical gray matter and adjacent white matter in the frontal lobe. We have used this approach to study a group of patients (n = 7) infected with HIV and clinical manifestations of the AIDS dementia complex (ADC), a group of patients (n = 8) infected with HIV without any indications of ADC, and seven controls. The patients without ADC had a statistically significant increase in the ratio of myo-inositol to creatine in white matter compared with normal controls. In contrast, the group of patients with ADC had almost normal levels of myo-inositol to creatine in both gray matter and white matter and showed a statistically significant decrease in the N-acetylaspartate to creatine ratio in gray matter compared with either the normal controls or the patients without ADC. Patterns of spectral abnormalities correlated with neuropsychological measures of frontal lobe dysfunction, suggesting that the evaluation of frontal lobe metabolism by magnetic resonance spectroscopy can play a role in the early detection of ADC, in determining its progression, and in assessing responses to therapeutic interventions.

AIDS Dementia Complex↗
PubMed2001

Quinolinic acid is produced by macrophages stimulated by platelet activating factor, Nef and Tat.

Activated macrophages produce quinolinic acid (QUIN), a neurotoxin, in several inflammatory brain diseases including AIDS dementia complex. We hypothesized that IL1-beta, IL6, transforming growth factor (TGF-beta2 and platelet activating factor could increase macrophage QUIN production. And that the HIV-1 proteins Nef, Tat and gp41 may also increase synthesis of QUIN by macrophages. At 72 h there were significant increases in QUIN production in the cells stimulated with PAF (914 +/- 50 nM) and Nef (2781 +/- 162 nM), with somewhat less production by Tat stimulation (645 +/- 240 nM). The increases in QUIN production approximated in vitro concentrations of QUIN shown to be neurotoxic and correlated closely with indoleamine 2,3-dioxygenase induction. IL1-beta, IL6, TGF-beta2 and gp41 stimulation produced no significant increase in QUIN production. These results suggest that some of the neurotoxicity of PAF, nef and tat may be mediated by QUIN.

AIDS Dementia Complex↗
PubMed1997

Meta-analysis of five randomized controlled trials comparing continuation of zidovudine versus switching to didanosine in HIV-infected individuals.

A meta-analysis of the original data from 2411 patients in the ACTG 116A, ACTG116B/117, ACTG175, BMS010 and CTN002 trials was conducted to improve the estimate of the effect of switching from zidovudine to didanosine on rates of clinical progression, to better quantify the rates of neurological events (including AIDS dementia and peripheral neuropathy) and to examine the effects of switching from zidovudine to didanosine among women and racial subgroups. In total, 1012 patients received zidovudine therapy, 557 received high-dose didanosine and 842 received didanosine. The median duration of follow-up was 15 months. Ninety-one percent of patients were male, 78% were white, mean age was 36.5 years. The median CD4 count was 195 cells/mm3 (range: 0-762) and the median duration of prior zidovudine therapy was 14 months (range: 0.1-94). There were 336 deaths and 686 new AIDS-defining illnesses (ADIs) or deaths. After stratification by study and adjusting for baseline CD4 count and presence of an AIDS diagnosis prior to baseline, the relative risks of death associated with switching from zidovudine to high-dose didanosine or to didanosine were 0.94 (P = 0.64) and 0.77 (P = 0.07), respectively. The relative risks of a new ADI or death associated with switching from zidovudine to high-dose didanosine and didanosine were 0.78 (P = 0.01) and 0.66 (P = 0.0001), respectively. There were 21 documented cases of AIDS dementia complex (ADC) during the entire follow-up period. The rates per 100 person years of follow-up were 0.70, 0.65 and 0.41 for the zidovudine, high-dose didanosine and didanosine arms, respectively. There were no significant differences in risks of ADC between treatment arms (zidovudine versus high-dose didanosine: P = 0.30, zidovudine versus didanosine: P = 0.97, didanosine versus high-dose didanosine: P = 0.41). Our data confirm a clinical benefit and CD4 increase associated with a switch from zidovudine to didanosine therapy. No statistical differences were detected between doses of didanosine with respect to survival or progression to a new ADI or death. Furthermore, there was no statistical difference in the frequency of ADC between treatment arms.

AIDS Dementia Complex↗
PubMed1995

Distinct expressions of three cytokines by IL-1-stimulated astrocytes in vitro and in AIDS brain.

Interleukin-1 (IL-1) is elevated in brain tissue of individuals who died with acquired immunodeficiency syndrome (AIDS) and other diseases where this cytokine likely stimulates reactive astrocytosis. IL-1 stimulates, among others, production of interleukin-6 (IL-6), granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha) in cultured astrocytes and astrocytoma cell lines. These and other cytokines may contribute to the neuropathogenesis after infection by human immunodeficiency virus type-1 (HIV-1). For example, concentration of TNF-alpha is increased in brain tissue of individuals who died with AIDS and correlates with the severity of AIDS Dementia Complex (ADC). TNF-alpha and IL-6 have been immunocytochemically detected in brain tissue but they have not been localized to astrocytes. We, therefore, examined the expression of IL-6, GM-CSF, and TNF-alpha in human primary astrocytes and astrocytoma cell lines U251 and 253 exposed to IL-1 in serum-free medium. In addition, we immunocytochemically assayed GM-CSF expression by astrocytes in brain tissue (n = 8). The three cytokines were differentially induced in cultured astrocytes by IL-1. The astrocytoma cell lines recapitulated cytokine-specific patterns of expression in astrocytes. The patterns were characterized by amounts produced, compartmentalization (intra- and/or extracellular), time courses, and optimal doses of IL-1 for induction. GM-SCF-like immunoreactivity was detected in some but not all, GFAP+ cells. GM-CSF+/GFAP+ cells were detected in only three of seven cases containing GM-CSF immunoreactivity. Thus, a discrepancy may exist between human astrocytic cytokine expression in vitro and in tissue. Novel methods therefore may need to be developed to recapitulate in vitro the heterogeneity of astrocytic cytokine expression in AIDS and other brain tissue.

AIDS Dementia Complex↗
PubMed1999

Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex.

OBJECTIVE: To investigate the relation between biochemical alterations and disease severity in HIV-cognitive motor complex (HIV-CMC). BACKGROUND: HIV-CMC encompasses both the milder form (HIV-minor cognitive motor disorder [HIV-MCMD]) and the more severe form (HIV-dementia). There is no validated marker to monitor disease severity noninvasively. METHODS: A total of 54 patients with HIV-CMC (20 with HIV-MCMD, 34 with HIV-dementia) and 29 seronegative healthy volunteers were evaluated for cerebral metabolite abnormalities using proton (1H) MRS in the frontal cortex, frontal white matter, and basal ganglia. RESULTS: The three subject groups showed different concentrations of myoinositol (MI; p = 0.0005) and choline-containing compounds (CHO; p = 0.004) in the frontal white matter. HIV-dementia patients had metabolite changes in all three brain regions whereas HIV-MCMD patients had abnormalities in the frontal white matter only. HIV-CMC patients had elevated MI (p < 0.0001) and CHO (p = 0.004) levels with increasing AIDS dementia complex stage, and N-acetyl compounds (NA) were decreased only in moderate to severe stages of dementia. Furthermore, CD4 count and CSF viral load, but not plasma viral load, showed significant effects on cerebral metabolite concentrations, which in turn showed significant effects on the HIV-dementia scale. CONCLUSIONS: In early stages of HIV-CMC, frontal white matter showed evidence of glial proliferation (with elevated MI and CHO levels) and cell membrane injury (with increased CHO levels), but no significant neuronal injury (with normal NA concentrations). HIV-MCMD and HIV-dementia patients have different neurochemical abnormalities. Because these biochemical alterations are related to clinical disease severity, they may be useful surrogate markers for noninvasive quantitative assessment of brain injury in patients with HIV-CMC.

AIDS Dementia Complex↗
PubMed1995

Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA.

Tumor necrosis factor alpha (TNF-alpha) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid, TNF-alpha caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kappa B, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-alpha, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-alpha induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions.

AIDS Dementia Complex↗
PubMed1994

Localized brain proton MRS metabolic patterns in HIV-related encephalopathies.

We have examined 9 healthy volunteers and 63 HIV-patients (16 asymptomatic patients and 47 patients with clinical AIDS-dementia complex, ADC) by magnetic resonance spectroscopy (MRS) and imaging (MRI) on a Siemens Magnetom SP63 (1.5 T). Proton MRS of the brain was performed at 63 MHz using the PRESS sequence (echo time = 135 ms, TR = 1.6 s). Four main results have been found: (1) HIV-related encephalopathy induces significant modifications of brain metabolism analyzed by MRS and the most sensitive metabolic parameter is the N-acetyl-aspartate/Choline ratio, (2) the correlation between MRS and MRI is good in 75% of patients, (3) in 4 of the 16 neuro-asymptomatic patients (i.e. 25%) a metabolic encephalopathy was found while MRI was still normal, and (4) MR spectra describe 3 different pathological metabolic patterns in the brain of HIV patients. Two patterns might correspond to the two entities of HIV-induced lesions i.e. HIV encephalitis and HIV-related progressive leukoencephalopathy.

AIDS Dementia Complex↗
PubMed2005

Aciclovir protects against quinolinic-acid-induced oxidative neurotoxicity.

AIDS-related encephalopathy, including AIDS dementia complex (ADC) and the opportunistic disease, herpes simplex encephalitis (HSE), are postulated to arise due to the release of neurotoxic products, such as quinolinic acid (QUIN), by activated microglial cells in the brain. QUIN causes a cascade of events to occur, which leads to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. The antiherpes antiviral aciclovir has been reported to protect against neuron loss in HSE, but the mechanism for this neuroprotection is unknown. Therefore, this study was conducted to investigate whether aciclovir has the ability to inhibit QUIN-induced lipid peroxidation in rat brain homogenates, after in-vitro and in-vivo exposure to QUIN and aciclovir. The thiobarbituric acid (TBA) assay was the method used to analyse lipid peroxidation. Rat brains were also examined histologically after in-vivo exposure to visually assess whether neuron loss was suppressed. The results show that aciclovir inhibits the QUIN-induced lipid peroxidation, in a dose-dependent manner. Furthermore, aciclovir reduced necrosis of hippocampal neurons and retained the characteristic morphology, integrity and arrangement of these cells. Thus, it appears that aciclovir has neuroprotective properties, which could possibly be useful in the treatment of AIDS-related encephalopathy.

AIDS Dementia Complex↗
PubMed1995

Quinolinic acid production is related to macrophage tropic isolates of HIV-1.

We sought to determine whether the neurotoxin quinolinic acid (QUIN) was produced by macrophages or lymphocytes infected with isolates of HIV-1 with varying degrees of macrophage tropism derived from patients with varying stages of AIDS dementia complex (ADC). Highly macrophage tropic isolates and minimally macrophage tropic isolates were used to inoculate macrophages and QUIN production was measured. Similarly, QUIN production from macrophages was monitored using a purified cell free highly macrophage tropic isolate and laboratory isolates SF33 and SF2. Each of these experiments was also performed with lymphocytes. We found that macrophages infected with macrophage tropic isolates of HIV-1 led to QUIN production while lymphocytes did not produce QUIN. The ability of the HIV-1 infected macrophages to produce QUIN was related to the viral inoculum and the degree of macrophage tropism of the isolate. The severity of ADC in the patient from whom a particular isolate was derived was not per se a determining factor for QUIN production. Purified cell free ADC isolates also led to QUIN production by macrophages thereby suggesting that HIV-1 infection alone is capable of inducing QUIN production.

AIDS Dementia Complex↗