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)

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.
 ...
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

The chemokine receptor CXCR4 plays a crucial role in the survival and trafficking of leukaemia cells and requires further attention as human immunodeficiency virus type I (HIV-I) utilises CXCR4 as the major coreceptor for cellular entry. We demonstrated that inhibitors of histone deacetylases, currently being tested in clinical trials for the treatment of various tumours, extensively downregulated CXCR4 protein and mRNA levels in leukaemia cell lines and lymphoblasts from patients with childhood acute leukaemia. As a result, the ability of stromal cell-derived factor-1 to induce cellular migration was impaired. Repression of CXCR4 transcription by inhibitors of histone deacetylases might therefore represent a promising novel approach in the treatment of acute leukaemias.
 ...
PMID:Histone deacetylase inhibitors potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia. 1247 74

The chemokine receptor CXCR4 and its cognate ligand, stromal cell-derived factor-1alpha (CXCL12), regulate lymphocyte trafficking and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated chemotaxis of T-lymphocytes are not completely elucidated. In the present study, we examined the role of the membrane tyrosine phosphatase CD45, which regulates antigen receptor signaling in CXCR4-mediated chemotaxis and mitogen-activated protein kinase (MAPK) activation in T-cells. We observed a significant reduction in CXCL12-induced chemotaxis in the CD45-negative Jurkat cell line (J45.01) as compared with the CD45-positive control (JE6.1) cells. Expression of a chimeric protein containing the intracellular phosphatase domain of CD45 was able to partially restore CXCL12-induced chemotaxis in the J45.01 cells. However, reconstitution of CD45 into the J45.01 cells restored the CXCL12-induced chemotaxis to about 90%. CD45 had no significant effect on CXCL12 or human immunodeficiency virus gp120-induced internalization of the CXCR4 receptor. Furthermore, J45.01 cells showed a slight enhancement in CXCL12-induced MAP kinase activity as compared with the JE6.1 cells. We also observed that CXCL12 treatment enhanced the tyrosine phosphorylation of CD45 and induced its association with the CXCR4 receptor. Pretreatment of T-cells with the lipid raft inhibitor, methyl-beta-cyclodextrin, blocked the association between CXCR4 and CD45 and markedly abolished CXCL12-induced chemotaxis. Comparisons of signaling pathways induced by CXCL12 in JE6.1 and J45.01 cells revealed that CD45 might moderately regulate the tyrosine phosphorylation of the focal adhesion components the related adhesion focal tyrosine kinase/Pyk2, focal adhesion kinase, p130Cas, and paxillin. CD45 has also been shown to regulate CXCR4-mediated activation and phosphorylation of T-cell receptor downstream effectors Lck, ZAP-70, and SLP-76. Our results show that CD45 differentially regulates CXCR4-mediated chemotactic activity and MAPK activation by modulating the activities of focal adhesion components and the downstream effectors of the T-cell receptor.
 ...
PMID:Differential regulation of CXCR4-mediated T-cell chemotaxis and mitogen-activated protein kinase activation by the membrane tyrosine phosphatase, CD45. 1251 55

CD4 is the principal binding site for human and simian immunodeficiency virus (HIV/SIV) receptor interactions and the a chemokine receptor CXCR4 has been implicated as a primordial lentivirus receptor. This study sought to determine the relevance of CD4 and CXCR4 in virus-receptor interactions for the prototype lentivirus, maedi-visna virus (MVV) of sheep. Neither CD4 nor alpha/beta chemokine receptors represent principal receptors for MVV since human osteosarcoma cells devoid of these molecules were susceptible to productive infection. Interestingly, the presence of either CD4 and/or CXCR4 on indicator cells dramatically enhanced MVV-induced cell fusion (syncytium formation) for three independent virus strains. Syncytium formation results from virus-receptor interactions and can be inhibited by receptor ligands. However, neither SDF-la that binds CXCR4 nor recombinant gp120 (rgp120) that binds CD4 could specifically inhibit the observed enhancement of MVV-induced cell fusion under conditions that significantly reduced HIV-1-induced cell fusion. Our observations suggest that CD4 and CXCR4 may represent optional auxiliary components of an MVV receptor (or receptor complex) that facilitate MVV-mediated membrane fusion events, a feature important for virus entry. This potential accessory role for CXCR4 in MW receptor interactions may reflect the distant relationship between the ovine (MVV) and the human/feline lentiviruses (HIV/FIV).
 ...
PMID:The influence of CD4 and CXCR4 on maedi-visna virus-induced syncytium formation. 1258 36

Determining the critical structural features a ligand must possess in order to bind to its receptor is of key importance to the understanding of vital biological processes and to the rational design of small molecule therapeutics to modulate receptor function. We have developed a general strategy for determining such ligand binding motifs using low temperature NMR structures of peptides with the desired receptor binding properties. This approach has been successfully applied to determine a binding motif for the chemokine receptor CXCR4. The motif identified provides a detailed guide for the design of small molecule antagonists against CXCR4, which are much sought after to aid in the treatment of a number of conditions including human immunodeficiency virus type 1 infection and a variety of cancers.
 ...
PMID:Unmasking ligand binding motifs: identification of a chemokine receptor motif by NMR studies of antagonist peptides. 1262 40

Chemokines are the chemoattractant cytokines which function briefly in inflammatory processes and also act as regulatory bridge molecules between innate and acquired immunity. Chemokines mediate their effects by binding to cell surface receptors that belong to the seven transmembrane domain superfamily of proteins, which are found mainly on the surface of leucocytes, macrophages and lymphocytes. Besides the functions in the immune system, certain chemokine receptors also function as co-receptors, in addition to CD4 molecule, for human immunodeficiency virus (HIV) entry into the target cells. Of these a beta-chemokine receptor CCR5 and an alpha chemokine receptor CXCR4 are the major co-receptors required for macrophage-tropic and T cell-tropic viruses, respectively. Genetic analysis has revealed the importance of chemokine receptor genes in the disease progression, and the identification of genetic polymorphisms such as alterations in the CCR5 gene that prevent surface expression, leads explaining why some people with CCR5 mutation are protected from HIV infection. Today it is accepted that chemokine gene deletion mutations and high production of chemokines are the host factors which take place in the resistance mechanisms of HIV-infected non- or slow-progressors. Depending on these data, recent studies have focused on chemokine receptor inhibitors and/or chemokine antagonists as the new therapeutic strategies that prevent HIV from interacting with receptors and block HIV infection. In this review, latest developments in chemokine receptor researches with a particular focus on their roles in HIV pathogenesis and resistance to HIV infection, have been discussed.
 ...
PMID:[Chemokine receptors: their role in human immunodeficiency virus (HIV) pathogenicity and resistance to HIV infections]. 1283 82

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.
 ...
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 (HIV)-associated sensory neuropathy (HIV-SN) is the most common neurological complication of HIV infection. Currently, the pathogenesis of HIV-SN is unknown. Because there is no convincing evidence of neuronal infection, HIV neurotoxicity is likely to be effected either by secreted viral proteins such as the envelope glycoprotein gp120 or by neurotoxic cytokines released from infected/activated glial cells. We describe a model of gp120 toxicity to primary sensory neurons, in which gp120 induces neuritic degeneration and neuronal apoptosis. We show that Schwann cells, the cells that ensheath peripheral nerve axons, and which traditionally have been viewed as having a passive, supporting role, mediate this neurotoxicity. Ligation of the chemokine receptor CXCR4 on Schwann cells by gp120 resulted in the release of RANTES, which induced dorsal root ganglion neurons to produce tumor necrosis factor-alpha and subsequent TNFR1-mediated neurotoxicity in an autocrine fashion. This newly described Schwann cell-neuron interaction may be pathogenically relevant not only in HIV-SN but also in other peripheral neuropathies.
 ...
PMID:Schwann cell chemokine receptors mediate HIV-1 gp120 toxicity to sensory neurons. 1295 61

The human immunodeficiency virus type 1 (HIV-1) glycoprotein gp120 causes neuronal cell death; however, the molecular mechanisms of the neurotoxic effect remain largely unresolved. It has been suggested that gp120 evokes cell death by inducing the release of neurotoxins, including glutamate. The objective of this work was to examine the role of glutamate in gp120-mediated neurotoxicity. We used as an experimental tool cerebellar granule cells prepared from 8-day-old rat cerebella, in which both glutamate and gp120 cause cell death. Cerebellar granule neurons were exposed to gp120 or glutamate alone or in combination with the glutamate receptor antagonist MK801 as well as other antiglutamatergic compounds. Cell viability was measured at various times by using several markers of cell death and apoptosis. MK801, at a concentration that blocked glutamate-induced neuronal cell death, failed to prevent gp120-mediated apoptotic cell death. Moreover, interleukin-10, which has previously been shown to block glutamate toxicity in these neurons, was not neuroprotective against gp120. Because gp120 toxicity is mediated by activation of the chemokine receptor CXCR4, neurons were incubated with the CXCR4 inhibitor AMD3100. This compound prevented gp120- but not glutamate-mediated cell death. These findings suggest that gp120 is toxic to neurons even in the absence of the virus and that the toxic mechanism involves primarily activation of CXCR4 receptor. Therefore, antagonists to the CXCR4 receptor may be more suitable compounds for inhibiting HIV-1 neurotoxicity.
 ...
PMID:The chemokine receptor CXCR4 and not the N-methyl-D-aspartate receptor mediates gp120 neurotoxicity in cerebellar granule cells. 1468 50

The envelope glycoprotein complex (Env), encoded by the human immunodeficiency virus (HIV-1), kills uninfected cells expressing CD4 and/or the chemokine receptor CXCR4 or CCR5, via at least three independent mechanisms. First, the soluble Env product gp120 can induce the apoptotic cell death of lymphocytes, neurons, and myocardiocytes, via interaction with surface receptors. Second, Env present on the surface of HIV-1 infected cells can transiently interact with cells expressing CD4 and CXCR4/CCR5, thereby provoking a hemifusion event that results in the death of the uninfected cell. Third, the interaction between Env on infected cells and its receptors on uninfected cells can result in syncytium formation. Such syncytia undergo apoptosis after a phase of latency. In several models of Env-induced apoptosis, early signs of mitochondrial membrane permeabilization (MMP) become manifest. Such signs include a loss of the mitochondrial transmembrane potential and the release of cytochrome c and AIF. The mechanisms of Env-triggered apoptotic MMP may involve an elevation of cytosolic Ca(2+), reactive oxygen species and/or the transcriptional activation of p53, with the consequent expression of pro-apoptotic proteins such as Bax, which permeabilizes mitochondrial membranes. The implications of these findings for the pathophysiology of HIV-1 infection is discussed.
 ...
PMID:Mitochondrial apoptosis induced by the HIV-1 envelope. 1503 90


<< Previous 1 2 3 4 5 6 7 8 9 Next >>