Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal loss is, frequently found in brains of patients with human immunodeficiency virus (HIV)-encephalopathy. Extensive apoptosis of neurons is probably involved in the development of HIV-encephalopathy. The present study was designed to investigate the mechanism of neuronal apoptosis. For this purpose, we examined autopsy brains of two patients with HIV-encephalopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and active forms of caspase-3- and -8-positive cells, including neurons, were found in the perivascular regions of the brains. In these regions, TNF-related apoptosis-inducing ligand (TRAIL)+ macrophages were also observed. We also examined brains of HIV-1-infected mouse model inoculated with human cells. In these brains, TUNEL+ neurons were also found in the perivascular region, the site where infiltrated HIV-1-infected and TRAIL-expressing macrophages were observed. Using an in vitro-culture system, we also demonstrated that the HIV-1-infected monocyte-derived macrophages preferentially expressed TRAIL and that the addition of HIV-1-infected macrophages or human TRAIL-overexpressing mouse cells to cultured mouse primary neurons/glia resulted in neuronal apoptosis. Our results suggest the involvement of TRAIL expressed on HIV-1-infected macrophages in the induction of neuronal apoptosis in infected brain.
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PMID:TNF-related apoptosis-inducing ligand (TRAIL) induces neuronal apoptosis in HIV-encephalopathy. 1271 15

Acquired immunodeficiency syndrome (AIDS)-associated dementia is often characterized by chronic inflammation, with infected macrophage infiltration of the CNS resulting in the production of human immunodeficiency virus type 1 (HIV-1) products, including tat, and neurotoxins that contribute to neuronal loss. In addition to their established role in leukocyte recruitment and activation, we identified an additional role for chemokines in the CNS. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to protect mixed cultures of human neurons and astrocytes from tat or NMDA-induced apoptosis. Neuronal and astrocytic apoptosis in these cultures was significantly inhibited by co-treatment with MCP-1 or RANTES but not IP-10. The protective effect of RANTES was blocked by antibodies to MCP-1, indicating that RANTES protection is mediated by the induction of MCP-1. The NMDA blocker, MK801, also abolished the toxic effects of both tat and NMDA. Tat or NMDA treatment of mixed cultures for 24 h resulted in increased extracellular glutamate ([Glu]e) and NMDA receptor 1 (NMDAR1) expression, potential contributors to apoptosis. Co-treatment with MCP-1 inhibited tat and NMDA-induced increases in [Glu]e and NMDAR1, and also reduced the levels and number of neurons containing intracellular tat. These data indicate that MCP-1 may play a novel role as a protective agent against the toxic effects of glutamate and tat.
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PMID:MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. 1275 88

Growth hormone (GH) is neuroprotective, presumably through its actions on GH receptor-mediated pathways. Here, we examined the effects of GH using in vitro and in vivo assays of human immunodeficiency virus (HIV)-induced neuronal injury. Neuronal cultures were in assays of neurotoxicity induced by supernatants from HIV-1 tat-transfected monocytoid cells (Tat supernatant). GH treatment reduced neuronal death compared with untreated cultures (p < 0.001), which was blocked by a GH receptor antagonist, B2036. Tat supernatant-induced p53 expression in neurons was also reduced by GH treatment. Expression of both p53 and GH receptor were increased in brain tissue from HIV-infected persons compared with controls (p < 0.05). Mice receiving intrastriatal implants of Tat supernatant and treated with GH showed less neurobehavioral abnormalities together with reduced neuroinflammation and neuronal injury compared with untreated animals (p < 0.01). Three acquired immunodeficiency syndrome-defined patients with neurocognitive impairment were serially evaluated during daily GH treatment showing a sustained improvement in neuropsychological performance (p < 0.01). GH prevents neuronal death through its actions on neurons involving a p53-mediated pathway and also improved in vivo neurological function, indicating that GH may have a role in the treatment of HIV-induced neurodegeneration.
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PMID:Growth hormone prevents human immunodeficiency virus-induced neuronal p53 expression. 1459 50

Neuronal loss has been observed in post mortem brains of patients with human immunodeficiency virus type 1 (HIV-1). Experimental evidence has implicated HIV-1-derived envelope glycoprotein 120 (gp120) in the neuronal cell death observed in these patients. However, the intrinsic mechanisms by which gp120 causes neurotoxicity are still unknown. We have recently shown that the neurotoxic effect of gp120 in vitro is reduced by brain-derived neurotrophic factor (BDNF). We therefore tested the hypothesis that low levels of BDNF render neurons more sensitive to gp120. Gp120 was injected acutely into the striatum of BDNF heterozygous mice and wild-type littermates. BDNF heterozygous mice exhibited more apoptotic neurons in the striatum than wild-type mice, suggesting that BDNF is neuroprotective also in vivo. Because several neurodegenerative disorders are characterized by lack of trophic support, we tested the hypothesis that gp120 may cause apoptosis by reducing BDNF expression. Gp120 was injected acutely in the rat striatum and BDNF levels determined by a two-site immunoassay at various times after the injection. Gp120 elicited a dramatic decrease in BDNF protein levels by 24 h. Reduced BDNF levels were still present at 4 days. Cellular localization of BDNF immunoreactivity revealed that gp120 decreases BDNF immunoreactivity mainly in neuronal processes. This effect of gp120 precedes the peak of caspase-3 activation and neuronal cell death. We propose that one of the mechanisms whereby gp120 causes neurotoxicity is a reduction of the neurotrophic factor environment crucial for cell survival.
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PMID:Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death. 1557 39

Cognitive, behavioral, and motor impairments, during progressive human immunodeficiency virus type 1 (HIV-1) infection, are linked to activation of brain mononuclear phagocytes (MP; perivascular macrophages and microglia). Activated MPs effect a giant cell encephalitis and neuroinflammatory responses that are mirrored in severe combined immunodeficient (SCID) mice injected with human monocyte-derived macrophages (MDM). Whether activated human MDMs positioned in the basal ganglia affect hippocampal neuronal plasticity, the brain subregion involved in learning and memory, is unknown. Thus, immunohistochemical techniques were used for detection of newborn neurons (polysialylated neuronal cell adhesion molecule [PSA-NCAM]) and cell proliferation (Ki-67) to assay MDM effects on neuronal development in mouse models of HIV-1 encephalitis. Immunodeficient (C.B.-17/SCID and nonobese diabetic/SCID, NOD/SCID) and immune competent (C.B.-17) mice were injected with uninfected or HIV-1-infected MDM. Sham-operated or unmanipulated mice served as controls. Neuronal plasticity was evaluated in the hippocampal dentate gyrus (DG) at days 7 and 28. By day 7, increased numbers of Ki-67+ cells, PSA-NCAM+ cells and dendrites in DG were observed in sham-operated animals. In contrast, significant reductions in neuronal precursors and altered neuronal morphology paralleled increased microglial activation in both HIV-1-infected and uninfected MDM-injected animals. DG cellular composition was restored at day 28. We posit that activated MDM induce inflammation and diminish DG neuronal plasticity. These data provide novel explanations for the cognitive impairments manifested during advanced HIV-1 infection.
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PMID:Macrophage-induced inflammation affects hippocampal plasticity and neuronal development in a murine model of HIV-1 encephalitis. 1607 35

Infection by the lentivirus, human immunodeficiency virus type 1 (HIV-1), results in a variety of syndromes involving both the central (CNS) and the peripheral (PNS) nervous systems. Productive HIV-1 infection of the CNS is chiefly detectable in perivascular macrophages and microglia. HIV-1 encoded transcripts and proteins have also been detected in the PNS; however, productive viral replication appears to be sparse and restricted to the macrophage cell population. Despite the absence of productive infection of neurons, HIV-1 infection has been associated with neuronal loss in distinct regions of the brain. Neuronal cell loss may occur through both necrosis and apoptosis, although neuronal apoptosis appears to be a feature of AIDS, as only rare apoptotic neurons have been demonstrated in a few pre-AIDS cases. Although there is no clear consensus as to the underlying mechanism of HIV-induced neuropathogenesis, two complementary concepts predominate. Firstly, HIV-1 encoded proteins injure neurons directly without requiring the intermediary functions of nonneuronal cells. Alternatively, neuronal apoptosis may result indirectly from the secretion of neurotoxic host molecules by resident brain macrophages or microglia in response to HIV-1 infection, stimulation by viral proteins or immune activation. Herein, we review the neurological disorders and their underlying mechanisms associated with HIV infection, focusing on HIV-associated dementia (HAD) and HIV sensory neuropathy (HIV-SN). The evidence that neuronal loss in HIV-1-infected individuals may be due to neuronal apoptosis is then discussed. This review also summarizes the current data supporting both the direct and indirect mechanisms by which neuronal death may occur during infection with HIV-1 or the closely related lentiviruses SIV and FIV. Lastly, strategies are examined for treating or preventing HAD by targeting specific neurotoxic mechanisms.
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PMID:Regulation of neural cell survival by HIV-1 infection. 1629 36

Neuronal damage in human immunodeficiency virus type 1 (HIV-1) infection in the brain is thought to occur at least in part through NMDA receptor (NMDAR) excitation initiated by soluble neurotoxins from HIV-infected brain macrophages. Furthermore, brain regions enriched in NMDAR-2A (NR2A) and NMDAR-2B (NR2B) subunits, such as the hippocampus, are particularly vulnerable. Using cultured rat hippocampal cells and HIV-1-infected human monocyte-derived macrophages (HIV/MDM), we examined the role of NR2A and NR2B in HIV/MDM-induced hippocampal neuronal death. We used the primary HIV-1 strain Jago derived from the CSF of an individual with HIV-associated dementia and that robustly replicates in MDM. We found the following: (1) hippocampal neuronal susceptibility to HIV/MDM excitotoxins varies according to the developmental expression patterns of NR2A and NR2B; (2) NMDAR activation by HIV/MDM results in neuronal calpain activation, which results in neuronal death; and (3) selective antagonists of homomeric NR2B/NR2B- and heteromeric NR2A/NR2B-containing NMDARs, as well as an inhibitor of calpain activity, afford neuroprotection against HIV/MDM. These studies establish a clear link between macrophage HIV infection, neuronal NR2A and NR2B activation, and calpain-mediated hippocampal neuronal death. They further suggest a dominant role for NR2A and NR2B in determining neuronal susceptibility in HIV-infected brain. Antagonists of NR2A and NR2B subunits as well as inhibitors of calpain activation offer attractive neuroprotective approaches against HIV in both developing and mature brain.
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PMID:Human immunodeficiency virus (HIV)-induced neurotoxicity: roles for the NMDA receptor subtypes. 1642 18

Neuronal damage in dorsal root ganglia (DRGs) with accompanying axonal injury is a key feature of human immunodeficiency virus (HIV)-related distal sensory polyneuropathy (DSP). In a model of HIV-related DSP, we observed numerous CD3+ T lymphocytes (p < 0.05) in DRGs from feline immunodeficiency virus (FIV)-infected animals, which also exhibited low CD4+ and high CD8+ lymphocyte levels in blood accompanied by a selective loss of small-diameter sural nerve axons (p < 0.05). FIV-infected lymphocytes cocultured with syngeneic DRGs caused neuronal damage, indicated by neurite retraction, neuronal soma atrophy, and loss (p < 0.05). In contrast, supernatants from FIV-infected or uninfected lymphocytes were minimally neurotoxic, despite high FIV virion levels. Among lymphocyte subsets cocultured with DRG cultures, CD8+ T cells from both FIV-infected and uninfected lymphocytes selectively caused DRG neuronal injury (p < 0.05). FIV-infected CD8+ T cells showed markedly increased CD154 expression (p < 0.05), whereas neurons were the predominant cells expressing CD40 in DRGs. Blocking CD154 on activated CD8+ T cells protected DRG neurons (p < 0.05). These findings indicated that CD8+ T cells were principal effectors of DRG neuronal injury after FIV infection through a CD40-CD154 interaction in a cell contact-dependent manner.
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PMID:CD8+ lymphocyte-mediated injury of dorsal root ganglion neurons during lentivirus infection: CD154-dependent cell contact neurotoxicity. 1657 46

Existing data concerning the role of the delta-chemokine fractalkine (CX3CL1) and its receptor (CX3CR1) in lentivirus-induced encephalitis are limited and controversial. We explored, by quantitative in situ hybridization and immunohistochemistry, the cell-specific changes of CX3CL1 and CX3CR1 in rhesus macaque brain during simian immunodeficiency virus (SIV) infection and antiretroviral treatment. Neuronal expression of CX3CL1 was significantly reduced in cortex and striatum of AIDS-diseased monkeys as compared with uninfected and asymptomatic SIV-infected monkeys. CX3CL1 mRNA was increased in some endothelial cells and newly induced in astrocytes and macrophages focally in areas of SIV burden and inflammatory infiltrates. In most CX3CL1-positive astrocytes and macrophages, the transcription factor NF-kappaB was translocated to the nucleus. CX3CR1 was upregulated in scattered, nodule, and giant cell-forming microglia/macrophages and mononuclear infiltrates close to CX3CL1-induced cells in the brain. Treatment of AIDS monkeys with the central nervous system-permeant 6-chloro-2',3'-dideoxyguanosine fully reversed SIV burden, productive inflammation, nuclear NF-kappaB translocation as well as focal induction of CX3CL1 in astrocytes and macrophages and downregulation in neurons. In contrast, diffuse CX3CR1-positive microgliosis and GFAP-positive astrogliosis were partially reversed by 6-chloro-2',3'-dideoxyguanosine. Thus, focally induced CX3CL1 may be a target for therapeutic intervention to limit ongoing inflammatory infiltration into brain in lentivirus infection.
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PMID:Fractalkine expression in the rhesus monkey brain during lentivirus infection and its control by 6-chloro-2',3'-dideoxyguanosine. 1714 91

The chemokine receptor CXCR4 regulates neuronal survival and differentiation and is involved in a number of pathologies, including cancer and human immunodeficiency virus (HIV). Recent data suggest that chemokines act in concert with neurotransmitters and neuropeptides, such as opioids. This study aimed to determine whether mu-opioid agonists alter the effect of CXCL12 (the specific CXCR4 ligand) on central neurons. Neuronal expression of CXCR4 and micro-opioid receptors (MORs) was analyzed by Western blot, immunostaining, and flow cytometry. Single-cell studies showed that all CXCR4-positive neurons coexpress MORs. Treatment of neuronal cultures with the selective MOR agonist DAMGO or the endogenous peptide endomorphin-1 inhibited intracellular signaling pathways (ERK1/2 and Akt) activated by CXCL12. Furthermore, DAMGO abolished the neuroprotective effect of CXCL12 in N-methyl-d-aspartate (NMDA) neurotoxicity studies. The effects of DAMGO and endomorphin-1 were inhibited by a general or a micro-specific opioid receptor antagonist, and not caused by changes in neuronal CXCR4 levels. DAMGO did not affect CXCL12-induced internalization of CXCR4. The authors propose that interactions between MOR and CXCR4 signaling can modulate the action of CXCL12 on neuronal survival-which may have important implications to neuroAIDS as well as other neuroinflammatory disorders.
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PMID:Modulation of neuronal CXCR4 by the micro-opioid agonist DAMGO. 1716 64


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