Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0085584 (encephalopathy)
18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine receptors CCR5 and CXCR4 are co-receptors together with CD4 for human immunodeficiency virus (HIV)-1 entry into target cells. Macrophage-tropic HIV-1 viruses use CCR5 as a co-receptor, whereas T-cell-line tropic viruses use CXCR4. HIV-1 infects the brain and causes a progressive encephalopathy in 20 to 30% of infected children and adults. Most of the HIV-1-infected cells in the brain are macrophages and microglia. We examined expression of CCR5 and CXCR4 in brain tissue from 20 pediatric acquired immune deficiency syndrome (AIDS) patients in relation to neuropathological consequences of HIV-1 infection. The overall frequency of CCR5-positive perivascular mononuclear cells and macrophages was increased in the brains of children with severe HIV-1 encephalitis (HIVE) compared with children with mild HIVE or non-AIDS controls, whereas the frequency of CXCR4-positive perivascular cells did not correlate with disease severity. CCR5- and CXCR4-positive macrophages and microglia were detected in inflammatory lesions in the brain of children with severe HIVE. In addition, CXCR4 was detected in a subpopulation of neurons in autopsy brain tissue and primary human brain cultures. Similar findings were demonstrated in the brain of adult AIDS patients and controls. These findings suggest that CCR5-positive mononuclear cells, macrophages, and microglia contribute to disease progression in the central nervous system of children and adults with AIDS by serving as targets for virus replication.
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PMID:Localization of HIV-1 co-receptors CCR5 and CXCR4 in the brain of children with AIDS. 942 34

The role of nonproductive infection of astrocytes by human immunodeficiency virus type 1 (HIV-1), characterized by the overexpression of nef, in brain disease progression is largely unknown. We investigated the consequences of stable expression of nef from the HIV-1 strain LAI in the human astrocytic cell line U373. DNA synthesis induced by endothelin-1 (ET-1) was largely decreased by nef. Stable expression of nef did not affect the ET-1-induced tyrosine phosphorylation of focal adhesion kinase, an adhesion-dependent pathway known to participate in DNA synthesis in astrocytes. Conversely, the activation of extracellular signal-regulated kinase (ERK) by ET-1 was largely inhibited in cells stably or transiently expressing nef. A similar inhibitory action of nef on ERK activation was observed after direct stimulation of G proteins. Furthermore, the inhibitory action of nef did not require protein kinase C (PKC) and affected mainly the PKC-independent pathway of ERK activation. Following chemokine receptor CXCR4-mediated infection of U373 cells stably expressing CXCR4 with the T-tropic HIV-1 strain m7-NDK, ET-1-induced activation of ERK was also inhibited. Altogether, these results indicate that intracellular signaling pathways associated with the growth factor activity of ET-1 are impaired in nef-expressing and HIV-1-infected astrocytes, suggesting that infection of astrocytes may play a significant role in the neuropathogenesis of HIV-1 encephalopathy.
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PMID:The HIV-1 nef protein inhibits extracellular signal-regulated kinase-dependent DNA synthesis in a human astrocytic cell line. 945 74

Human immunodeficiency virus (HIV-1) infects the brain and causes a progressive encephalopathy in 20 to 30% of infected children and adults called AIDS dementia complex. Evidence from in vitro and in vivo studies suggests a role for the viral envelope glycoprotein gp120, as a mediator of neurotoxicity. However, the site of interaction of gp120 with neurons and astrocytes to mediate neuronal death is still unknown. Recently the chemokine receptors, CCR5 and CXCR4, have been identified as co-receptors together with CD4 for HIV-1 entry into the target cells, suggesting a possible role for these receptors in the pathogenesis of the HIV-1 infection in the brain. Here we report the expression of CCR5 and CXCR4 in many different rat brain areas. We also found both receptors in cultured type I astrocytes demonstrating that glial cells may represent an important target for chemokines in vivo. Indeed, the functional capacity of CXCR4 receptor in astrocytes was demonstrated showing that SDF 1 alpha induced an increase of intracellular calcium concentration.
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PMID:Expression of chemokine receptors in the rat brain. 1041 11

The resistance or susceptibility of inbred strains of mice to various pathogens and autoimmune diseases such as EAE has been linked to differences in the balance between cytokines associated with Th1- and Th2-type immune responses. Previous work from this laboratory on the mouse strain specific resistance to mouse adenovirus type I (MAV-1)-induced encephalopathy revealed subtle differences in the transcription rates of several immunologically important molecules that was evident prior to infection. In this study, we show striking differences in cytokine, chemokine and chemokine receptor mRNA expression in the spleens of normal, immunologically naive C57BL/6J, BALB/cJ and SJL/J mice. Messenger RNAs for interferon (IFN)-gamma and the chemokine IFN gamma inducible protein (IP)-10 were preferentially expressed in C57BL/6J spleens, whereas in BALB/cJ spleens mRNAs for lymphotoxin-beta, interferon-beta, transforming growth factor-beta, and the chemokine receptors CCR3 and CXCR4 predominated. A unique profile of chemokine receptors was found in spleens from normal SJL/J mice that correlated with the presence of polymorphisms within the CCR-3 gene. The patterns of gene expression fit well into the Th1/Th2 paradigm for C57BL/6J and BALB/cJ strains and suggest an important role for chemokines, as well as cytokines, in contributing to the genetic basis of the immune response.
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PMID:Cytokine, chemokine and chemokine receptor mRNA expression in different strains of normal mice: implications for establishment of a Th1/Th2 bias. 1069 17

The alpha chemokine receptor CXCR4 is used as the major coreceptor for the cell entry of T-cell-tropic human immunodeficiency virus-1 (HIV-1) isolates. Activation of this coreceptor by its natural ligand SDF1alpha is associated with an intracellular Ca(2+) increase. Because the HIV-1 glycoprotein 120 (gp120) is shedded from the surface of HIV-1-infected cells and is regarded as an injurious molecule in the pathogenesis of HIV-1-associated encephalopathy (HIVE), we investigated the effects of gp120 on the intracellular Ca(2+) regulation of astrocytes and neurons. After 5 days in vitro (DIV), SDF1alpha (50 nM) elicited a pertussis toxin-sensitive intracellular Ca(2+) increase due to Ca(2+) release from internal stores that was reduced by a blocking monoclonal antibody against the CXCR4 receptor in astrocytes and neurons. Parallel with the development of the SDF1alpha response, cells became sensitive to direct application of gp120 (1.25 microg/ml), which, similarly to SDF1alpha, elicited a transient intracellular Ca(2+) increase. However, short-term incubation with gp120 for 60 to 120 min induced a reduction of glutamate- or ATP-evoked intracellular Ca(2+) responses only in astrocytes and not in neurons, although functional CXCR4 receptors were expressed in both cell types. Therefore, our data strongly suggest that the CXCR4 receptor-mediated intracellular signaling pathway of gp120 differs in astrocytes and neurons.
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PMID:Functional CXCR4 receptor development parallels sensitivity to HIV-1 gp120 in cultured rat astroglial cells but not in cultured rat cortical neurons. 1240 67

Human immunodeficiency virus type 1 (HIV-1)-associated central nervous system disorders, including encephalopathy, often occur in the late stage of HIV-1 infection. Some inflammatory cytokines and HIV-1 antigens released from infected microglia or brain macrophages are considered to play an important role in neuropathogenesis. In this study, an in vitro assay system has been established for the evaluation of neural cell death, which would be predictive of the pathogenesis of neural cell death in vivo. The human neuroblastoma cell line SK-N-SH was differentiated to a neural phenotype with retinoic acid, while the promyelocytic cell line HL-60 and its HIV-1-infected clone OM-10.1 were differentiated to macrophages with phorbol myristate acetate. When neural (differentiated SK-N-SH) cells were cocultured with either uninfected or HIV-1-infected macrophages (differentiated HL-60 or OM-10.1 cells, respectively) for 3-5 days, significant neural cell death was observed in the cells cocultured with infected macrophages. Direct contact with macrophages was not necessary for the induction of neural cell death, since indirect coculture or coculture supernatants could also induce neural cell death. Large amounts of cytokines and chemokines were released in the coculture supernatants. The CXCR4 antagonist AMD3100 and the HIV-1 transcription inhibitor K-37 partially inhibited neural cell death. These results indicate that this system seems to be a useful tool for the evaluation of compounds against HIV-1-induced neural cell death.
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PMID:Establishment of an in vitro assay system mimicking human immunodeficiency virus type 1-induced neural cell death and evaluation of inhibitors thereof. 1260 87

APJ, a G protein-coupled seven-transmembrane receptor, has been shown to serve as a co-receptor for the entry of human immunodeficiency virus type 1 (HIV-1), and it is dramatically expressed in central nervous system (CNS)-based cells. ALX40-4C was identified as a small-molecule antagonist of the chemokine receptor CXCR4, which can specifically inhibit HIV-1 entry via this co-receptor. In this study, we demonstrated that ALX40-4C inhibited both APJ- and CXCR4/APJ-mediated cell membrane fusion in a dose-dependent manner. In competitive binding assays, (125)I-Apelin13 was replaced by ALX40-4C with an IC(50) of 2.9 microM, as compared with an IC(50) of 0.2 nM for Apelin13. Furthermore, ALX40-4C could block ligand-induced APJ internalization and signaling. ALX40-4C, as an antagonist to APJ, directly binds to and prevents use of APJ as a HIV-1 co-receptor. Thus, ALX-4C has potential utility for further elucidation of HIV-1 neuropathogenesis and therapy of HIV-1-induced encephalopathy.
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PMID:Binding of ALX40-4C to APJ, a CNS-based receptor, inhibits its utilization as a co-receptor by HIV-1. 1289 Jun 32

Human immunodeficiency virus type 1 (HIV-1) infection in its human host often results in progressive dementia and encephalopathy in adults and children, respectively. The mechanisms underlying virus-induced neurocognitive dysfunction are not fully understood. However, several studies strongly suggest that secretory viral and immune products from infected brain macrophages and microglia affect the onset and tempo of disease. One critical neurotoxin among these secretory products is the HIV-1 envelope glycoprotein gp120. To better understand how HIV-1 gp120 may affect cognitive function, we studied its effects on long-term potentiation (LTP) in the CA1 region of rat hippocampus, the brain region best linked to learning and memory. Although no effects were observed on basal synaptic transmission, HIV-1 gp120 inhibited LTP in a concentration-dependent manner in the presence of gamma-aminobutyric acid type A (GABAA) receptor antagonist. Heat-inactivated gp120 failed to block LTP. The HIV-1 gp120-mediated LTP inhibition was blocked by T140, a chemokine receptor CXCR4 antagonist, demonstrating gp120 inhibition of LTP via CXCR4. HIV-1 gp120 V3 loop peptides mimicked the inhibitory effects of HIV-1 gp120 protein on LTP. Monoclonal antibodies against the V3 loop epitope KRIHI eliminated the HIV-1 gp120 effects on LTP. These results further underscore the importance of HIV-1 gp120 in the pathogenesis of HIV-1-associated cognitive impairments seen during progressive viral infection.
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PMID:Human immunodeficiency virus type 1 gp120 inhibits long-term potentiation via chemokine receptor CXCR4 in rat hippocampal slices. 1640 Jun 60

HIV encephalopathy is one of the complexified viral diseases. In the infected brains, HIV-infection is restricted in macrophages and microglia although its damage extends to neurons and oligodendrocytes. Accumulating evidences have suggested that many viral and host factors are involved in this disease. However, its precise mechanism is still unsolved. To examine the mechanism of the disease, we developed an HIV-1-infected human cell-transplanted mouse model and TNF-related apoptosis-inducing ligand was identified as a neurotoxic host factors in HIV-infected brain. Next, we examined the neurotoxic host factors using co-culture system with macrophage-tropic HIV-1-infected macrophages as followings: Target brain cells are murine neuron/glia mixed culture, murine neurospehre-forming culture and rat brain hippocampus slice culture. In these systems, neurons and neural stem cells were preferentially damaged. On the other hand, we also identified two anti-HIV genes, CD 14 and CD63 (dN), which inhibit HIV-1-induced cytotoxicity using a lentiviral screening system. Because they express on monocyte or activated macrophage and microglia, these results suggest that CXCR4-using HIV-1 cannnot expand inside of brain. We also extended the screening system to identify the host factors which protect against HIV-1-induced encephalopathy. Our study will contibute to development of new therapeutic strategy for HIV encephalopathy as well as other CNS diseases.
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PMID:[HIV encephalopathy]. 1644 54

Despite HAART, a significant number of HIV-1-infected patients develop neurological complications. However, the presence of specific neurotropic HIV-1 strains, the extent of viral replication in the brain, and the type of cells infected remain controversial issues. To address this controversy we have analyzed different V3 loop sequences of viral isolates from four vertically HIV-1-infected children who developed HIV-1-related encephalopathy. Moreover, we have determined that some biological and molecular properties of HIV-1 might contribute to AIDS neurological dysfunctions. We detected very different HIV-1 isolates (X4 and R5) in the brain despite no great differences in clinical, pathological, or immunological parameters. In vitro, no differences in replicative competence in glial or neuroblastoma cells were observed between virus isolated from the blood of children with or without clinical neurological symptoms. The expression of both CXCR4 and CCR5 RNAs was observed in the brain independently of HIV-1 infection and viral strain predominant in this location. Our results failed to show a particular phenotypic property of the HIV-1 virus that might explain its neurovirulence and/or neurotropism.
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PMID:Lack of association of HIV-1 biological or molecular properties with neurotropism for brain cells. 1695 3


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