Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding of HIV type 1 (HIV-1) envelope glycoproteins to the surface of a CD4(+) T cell transduces intracellular signals through the primary envelope receptor, CD4, and a coreceptor, either CCR5 or CXCR4. Furthermore, envelope-CD4(+) cell interactions increase rates of apoptosis in peripheral blood mononuclear cells (PBMCs). We demonstrate that in primary T lymphocytes, recombinant HIV-1 envelope proteins induce the activation of caspase-3 and caspase-6, which belong to a family of cysteine proteases that, upon activation, promote programmed cell death. Envelope-mediated activation of caspase-3 and caspase-6 depended on envelope-CD4 receptor interactions; CCR5-utilizing as well as CXCR4-utilizing envelopes elicited this response. Focal adhesion kinase (FAK) is a substrate of both caspase-3 and caspase-6, and inactivation of FAK by these caspases promotes apoptosis. En-velope treatment of lymphocytes led to the cleavage of FAK in a manner consistent with caspase-mediated cleavage.
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PMID:HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells. 1065 4

Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins interact with CD4 and chemokine receptors on T cells to deliver signals that trigger either activation, anergy, or apoptosis. However, the molecular mechanisms driving these responses remain poorly understood. In this study we demonstrate that apoptosis is induced upon HIV-1 envelope binding to the chemokine receptor CXCR4. Cells expressing a mutant form of CXCR4 with a C-terminal deletion were also sensitive to HIV-1 envelope-mediated apoptosis, indicating that the cytoplasmic tail of CXCR4 is not required to induce the apoptotic pathway. The specificity of this process was analyzed using several inhibitors of gp120-CD4-CXCR4 interaction. Monoclonal antibodies directed against the gp120-binding site on CD4 (ST4) and against CXCR4 (MAB173) prevented the apoptotic signal in a dose-dependent manner. The cell death program was also inhibited by SDF-1alpha, the natural ligand of CXCR4, and by suramin, a G protein inhibitor that binds with a high affinity to the V3 loop of HIV-1 gp120 envelope protein. These results highlight the role played by gp120-binding on CXCR4 to trigger programmed cell death. Next, we investigated the intracellular signal involved in gp120-induced apoptosis. This cell death program was insensitive to pertussis toxin and did not involve activation of the stress- and apoptosis-related MAP kinases p38(MAPK) and SAPK/JNK but was inhibited by a broad spectrum caspase inhibitor (z-VAD.fmk) and a relatively selective inhibitor of caspase 3 (z-DEVD.fmk). Altogether, our results demonstrate that HIV induces a caspase-dependent apoptotic signaling pathway through CXCR4.
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PMID:Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120). 1070 41

Regeneration and tolerance factor (RTF) is a novel membrane protein that has a diverse expression pattern and immunoregulatory properties. RTF is expressed in vivo on the surface of individuals with B cell chronic lymphocytic leukemia and on activated T lymphocytes of HIV infected individuals as determined by their coexpression with CD38 and HLA-DR. The unique expression patterns of this protein in vivo lead us to investigate its expression in vitro. The activation of human PBMCs through the TCR, using anti-CD3 antibody and PMA, upregulated cell surface expression of RTF from 2. 3% to 91.2% (mean channel fluorescence [MCF] increased threefold). The activation of Jurkat T cells through the TCR upregulated surface expression of RTF from 8.3% (MCF-1.3) to 58.7% (MCF-13.1). The Jurkat T-cell line was used as a model system to explore RTF's role in cellular activation. Using the Jurkat T-cell model, we found anti-RTF antibody induces apoptosis. The addition of anti-RTF antibody increased annexin V binding by threefold compared with the IgG1 kappa isotype control antibody (p < 0.00002) and activated caspase 3. These data indicate that RTF is expressed during T-cell activation and may be associated with apoptosis.
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PMID:Regeneration and tolerance factor's potential role in T-cell activation and apoptosis. 1108 9

HIV-1 induces apoptosis and leads to CD4+ T-lymphocyte depletion in humans. It is still unclear whether HIV-1 kills infected cells directly or indirectly. To elucidate the mechanisms of HIV-1-induced apoptosis, we infected human CD4+ T cells with HIV-1. Enzymatic analysis with fluorometric substrates showed that caspase 2, 3, and 9 were activated in CD4+ T cells with peak levels 48 h after infection. Immunoblotting analysis confirmed the cleavage of pro-caspase 3 and 9, and of specific caspase substrates. Release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria was observed in HIV-infected cells. The cytochrome c and AIF release preceded the reduction of the mitochondrial transmembrane potential and nuclear chromatin condensation. H IV infection led to phosphorylation of p53 at the Ser15 residue, detectable as early as 24 h after infection. The p53 phosphorylation was followed by increased mRNA and protein expression of p21, Bax, HDM2, and p53. Up-regulation of surface FasL expression, accompanied by a down-regulation of Fas-associated proteins (FADD, DAXX, and RIP), was observed 72 h after infection. Our results suggest that HIV activates the p53 pathway, leading to cytochrome c and AIF release with ensuing caspase activation.
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PMID:HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial-mediated mechanism. 1109 84

Persistent activation of the immune system is one of the hallmarks of HIV-1 infection. In this study we analysed the induction of factors involved in cytokine signal transduction, such as STAT 1 proteins and IRF-1 mRNA, in normal peripheral blood mononuclear cells (PBMC) exposed to HIV-infected cells, and the induction of apoptosis. Western blot analyses and reverse transcriptase-polymerase chain reaction results indicate that both cells infected with a X4 strain and cells infected with a R5 strain are able to increase intracellular levels of STAT 1alpha and beta proteins as well as IRF-1 mRNA. This effect was prevented by neutralizing antibodies against interferon-alpha (IFN-alpha). HIV-1-infected cells dose-dependently induced apoptotic commitment in normal PBMC, as revealed by DNA fragmentation analysis, but this was not accompanied by an increase of caspase-3 activity, even if a slight up-regulation of IL-1beta-converting enzyme mRNA was detected. Apoptosis induction could be abrogated mainly by antibodies against tumour necrosis factor-alpha (TNF-alpha) and, to a lesser extent, by antibodies against IFN-gamma. All these findings suggest that uninfected PBMC can undergo activation of signal transduction and apoptosis after exposure to bystander HIV-infected cells, subsequent to the induction of cytokines such as IFNs and TNF-alpha.
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PMID:Activation of signal transduction and apoptosis in healthy lymphomonocytes exposed to bystander HIV-1-infected cells. 1112 43

The HIV-1 nef gene, essential for AIDS pathogenesis, encodes a 27-kDa protein (Nef) whose biochemical and biological functions are unclear. It has been suggested that Nef expression contributes to the T cell depletion observed during the disease by promoting their apoptosis. We report that in CD4(+) human lymphoblastoid cell lines transfected with the nef cDNA obtained from three different HIV-1 strains, expression of the Nef protein enhances and accelerates the response to four unrelated apoptotic agents (staurosporine, anisomycin, camptothecin, and etoposide) but not to an anti-Fas agonist Ab. Nef reduces the expression of the anti-apoptotic proteins Bcl-2 and Bcl-X(L) and induces a striking enhancement of apoptotic hallmarks, including mitochondrial depolarization, exposure of phosphatidylserine on the cell surface, activation of caspase-3, and cleavage of the caspase target poly(ADP-ribose) polymerase. Interestingly, the peptide Z-Val-Ala-DL-Asp-fluoromethylketone (a broad-spectrum caspase inhibitor) reduces, but does not abolish, phosphatidylserine exposure, suggesting that Nef also activates a caspase-independent apoptotic pathway. Surprisingly, Nef expression increases DNA degradation but without causing oligonucleosomal fragmentation. An increased apoptotic response and down-modulation of Bcl-2/Bcl-X(L) following Nef expression are observed also in NIH-3T3 fibroblasts. These data show that Nef enhances programmed cell death in different cell types by affecting multiple critical components of the apoptotic machinery independently from the Fas pathway.
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PMID:Apoptosis enhancement by the HIV-1 Nef protein. 1112 79

We previously showed that HIV-1 gp120-induced apoptosis in primary human umbilical vein endothelial cell cultures (HUVEC), through CCR5 and CXCR4. Here, we have found that agonists of protein kinase C (PKC), basic fibroblast growth factor (bFGF), and short exposure to low concentrations of phorbol esters were found to block gp120-induced apoptosis in HUVEC cultures. PKC antagonists, sphingosine, H7, and extended exposure of cultures to high concentrations of phorbol esters were also found to block gp120-induced apoptosis in HUVEC cultures. A significant increase in the total amount of cellular PKC enzymatic activity was observed on exposure of HUVEC to gp120. No increase in total PKC activity was observed on exposure of HUVECs to the natural ligands SDF-1alpha, or regulated-on-activation normal T-expressed and secreted (RANTES) cells, and gp120-induced PKC induction was found to be totally blocked by CXCR4 antibodies and partially blocked by the caspase 3 inhibitor, DEVD-CHO. Alternatively, CXCR4 antibodies and DEVD-CHO totally blocked apoptosis. Finally, gp120-induced effects were found to be insensitive to pertussis toxin. Accumulated evidence suggests PKC involvement at multiple points in the gp120-induced apoptotic pathway; also suggests involvement of the CXCR4 receptor internalization pathway, and potentially suggests different downstream effects of gp120-receptor interactions and natural ligand-receptor interactions.
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PMID:Involvement of protein kinase C in HIV-1 gp120-induced apoptosis in primary endothelium. 1114 Dec 37

To investigate the effect of Nef on Fas-mediated apoptosis, we compared T cells, both population and subclones stably expressing Nef from HIV-1(NL432), with Nef(-) control cells. Fas-mediated apoptosis was significantly delayed in Nef(+) cells as determined by annexin V staining and the percentage of apoptotic cells was lower in all Nef-expressing cells than in the control cells by a maximum of 10-fold. Next we measured cell surface levels of Fas to test whether the delayed apoptosis in Nef(+) cells was due to reduced cell surface expression of Fas. We found that there was no significant difference in the surface level of Fas between the Nef(+) and Nef(-) cells. To further define the steps affected by Nef in the Fas signaling pathway, the activation of caspase-3 and caspase-8 was investigated. A reasonable correlation was found between the magnitude of apoptosis measured by annexin V staining and the enzymatic activity of caspase-3. The overall level of caspase-8 activity in Nef(+) cells was also lower than in Nef(-) cells, although the extent of inhibition was not as significant as seen for caspase-3. Overall, our results indicate that long-term stable expression of Nef, which mimicks persistent or latent infection in vivo, confers resistance against anti-Fas Ab-induced apoptosis through inhibition of caspase-3 and caspase-8 activation.
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PMID:Stable expression of human immunodeficiency virus type 1 Nef confers resistance against Fas-mediated apoptosis. 1117 89

The type-I ribosome-inactivating protein trichosanthin (TCS) has a broad spectrum of biological and pharmacological activities, including abortifacient, anti-tumour and anti-HIV activities. We have found for the first time that TCS stimulated the production of reactive oxygen species (ROS) in JAR cells (a human choriocarcinoma cell line) in a time- and concentration-dependent manner by using the fluorescent probe 2',7'-dichlorofluorescein diacetate with confocal laser scanning microscopy. ESR spectral studies and the inhibition of ROS formation by the superoxide radical anion (O(2)(-.)) scavenger superoxide dismutase, the H(2)O(2) scavenger catalase and the hydroxyl radical (OH(.)) scavenger mannitol suggested the involvement of O(2)(-.), H(2)O(2) and OH(.). TCS-induced ROS formation was shown to be dependent on the presence of both extracellular and intracellular Ca(2+); moreover, ROS production paralleled the intracellular Ca(2+) elevation induced by TCS, suggesting that ROS production might be a consequence of Ca(2+) signalling. TCS-induced activation of caspase-3 was initiated within 2 h; however, TCS-induced production of ROS was initiated within 5 min, suggesting that the production of ROS preceded the activation of caspase-3. Simultaneous observation of the nuclear morphological changes via two-photon laser scanning microscopy and ROS production via confocal laser scanning microscopy revealed that ROS is involved in the apoptosis of JAR cells. The involvement of ROS was also confirmed by the inhibition of TCS-induced cell death by the antioxidant Trolox and the ROS scavengers catalase and mannitol. Diethylenetriaminepenta-acetic acid, an inhibitor of metal-facilitated OH(.) formation, markedly inhibited TCS-induced cell death, suggesting that TCS induced OH(.) formation via the Fenton reaction. The finding that ROS is involved in the TCS-induced apoptosis of JAR cells might provide new insight into the anti-tumour and anti-HIV mechanism of TCS.
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PMID:Reactive oxygen species involved in trichosanthin-induced apoptosis of human choriocarcinoma cells. 1131 Nov 27

Deregulation of the Fas/FasL pathway in activated T cells is suspected to contribute to the abnormal apoptosis that drives their progressive depletion during HIV-1 infection. However, the role of serum soluble Fas (sFas) is unclear. Here we investigated both sFas and anti-Fas IgG levels in a cohort of 227 HIV-1-infected patients with respect to their T cell apoptosis. By using optimized ELISAs, we found that serum titers of sFas and anti-Fas were linearly correlated in 17 severely lymphopenic subjects as compared with other patients grouped in relation to their single expression of anti-Fas and sFas, or with double-negative control patients. Cytofluorimetric measurement of the subdiploid DNA-containing cell population by both PI and TUNEL revealed an increased occurrence of cell death in vitro, in particular in patients with elevations of sFas. We also found that fresh CD4(+) cells from these patients showed high levels of both caspase 3 (CPP32) and its molecular targets, namely PARP and CK18. In addition, their in vitro proliferative rate was inhibited by sFas, in particular in patients with undetectable levels of the soluble receptor in vivo as well as in normal donors. In these subjects the Fas-related caspase 8 (FLICE) was significantly increased in cells treated with the recombinant Fas. These results support the contention that functionally exhausted T cells may undergo apoptosis in response to the persistent in vivo stimulation by sFas. This may elucidate the described occurrence of enhanced cell death in advanced HIV-1 infection in association with serum elevations of the soluble receptor.
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PMID:Anti-Fas (CD95/Apo-I) autoantibodies and soluble Fas levels concur in T cell depletion in HIV type 1 infection. 1137 56


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