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:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus (HIV) gp120 induces multiple cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3-kinase) pathway. The role of the PI3-kinase pathway in HIV-1 replication is not understood. Here we examined whether HIV-1 gp120 upregulates the PI3-kinase pathway and whether PI3-kinase activity plays a role in virus replication in primary human CD4(+) T cells and macrophages. Soluble and virion-associated HIV-1 gp120 induced calcium mobilization and phosphorylation of the PI3-kinase downstream effectors PKB/Akt and p70 S6 kinase. gp120-induced PI3-kinase activity and calcium mobilization were inhibited by pertussis toxin and blocking antibodies directed against CCR5 and CXCR4, suggesting that the signaling is mediated through the chemokine receptor. The PI3-kinase inhibitor LY294002 inhibited infection of CD4(+) T cells and macrophages with X4 and R5 HIV-1-pseudotyped viruses at concentrations that did not induce cell toxicity or downregulate HIV-1 coreceptor expression. When gp120-induced signaling was bypassed with the vesicular stomatitis virus G envelope protein, infection was still sensitive to PI3-kinase inhibition, suggesting that basal PI3-kinase activity is required for infection. LY294002 inhibited HIV-1 infection when added after viral entry and did not affect formation of the HIV-1 reverse transcriptase products R/U5 and long terminal repeat/Gag in the presence of the inhibitor. However, when the inhibitor was added after viral integration had occurred, no inhibition of HIV infection was observed. Our studies show that inhibition of the PI3-kinase signaling pathway suppresses virus infection post-viral entry and post-reverse transcription but prior to HIV gene expression. This type of host-virus interaction has implications for anti-HIV therapeutics that target cellular signaling machinery.
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PMID:Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. 1255 92

Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi's sarcoma (KS), encodes a chemokine receptor homologue, the viral G protein-coupled receptor (vGPCR), that has been implicated in KS pathogenesis. Expression of vGPCR constitutively activates several signaling pathways, including NF-kappa B, and induces the expression of proinflammatory and angiogenic factors, consistent with the inflammatory hyperproliferative nature of KS lesions. Here we show that vGPCR also constitutively activates the nuclear factor of activated T cells (NF-AT), another transcription factor important in regulation of the expression of inflammatory cytokines and related factors. NF-AT activation by vGPCR depended upon signaling through the phosphatidylinositol 3-kinase-Akt-glycogen synthetase kinase 3 (PI3-K/Akt/GSK-3) pathway and resulted in increased expression of NF-AT-dependent cell surface molecules (CD25, CD29, Fas ligand), proinflammatory cytokines (interleukin-2 [IL-2], IL-4), and proangiogenic factors (granulocyte-macrophage colony-stimulating factor GMCSF and TNF alpha). vGPCR expression also increased endothelial cell-T-cell adhesion. Although infection with HHV-8 is necessary to cause KS, coinfection with human immunodeficiency virus type 1 (HIV-1), in the absence of antiretroviral suppressive therapy, increases the risk of KS by many orders of magnitude. NF-AT and NF-kappa B activation by vGPCR was greatly increased by the HIV-1 Tat protein, although Tat alone had little effect on NF-AT. The enhancement of NF-AT by Tat appears to be mediated through collaborative stimulation of the PI3-K/Akt/GSK-3 pathway by vGPCR and Tat. Our data further support the idea that vGPCR contributes to the pathogenesis of KS by a paracrine mechanism and, in addition, provide the first evidence of collaboration between an HIV-1 protein and an HHV-8 protein.
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PMID:Human herpesvirus 8-encoded vGPCR activates nuclear factor of activated T cells and collaborates with human immunodeficiency virus type 1 Tat. 1271 69

Nef alters the cell surface expression of several immunoreceptors, which may contribute to viral escape. We show that Nef modifies major histocompatibility complex class II (MHC II) intracellular trafficking and thereby its function. In the presence of Nef, mature, peptide-loaded MHC II were down-modulated at the cell surface and accumulated intracellularly, whereas immature (invariant [Ii] chain-associated) MHC II expression at the plasma membrane was increased. Antibody internalization experiments and subcellular fractionation analyses showed that immature MHC II were internalized from the plasma membrane but had limited access to lysosomes, explaining the reduced Ii chain degradation. Immunoelectron microscopy revealed that Nef expression induced a marked accumulation of multivesicular bodies (MVBs) containing Nef, MHC II, and high amounts of Ii chain. The Nef-induced up-regulation of surface Ii chain was inhibited by LY294002 exposure, indicating the involvement of a phosphatidylinositol 3-kinase, whose products play a key role in MVB biogenesis. Together, our results indicate that Nef induces an increase of the number of MVBs where MHC II complexes accumulate. Given that human immunodeficiency virus recruits the MVB machinery for its assembly process, our data raise the possibility that Nef is involved in viral assembly through its effect on MVBs.
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PMID:Human immunodeficiency virus-1 Nef expression induces intracellular accumulation of multivesicular bodies and major histocompatibility complex class II complexes: potential role of phosphatidylinositol 3-kinase. 1367 18

Human immunodeficiency virus (HIV)-1 infection is often complicated with neurologic disorders, but the pathogenesis of HIV-1 encephalopathy is incompletely understood. Tat (HIV-1 transactivator protein) is released from HIV-1-infected cells and has been detected in the sera and cerebrospinal fluid of HIV-1-infected patients. Tat, along with increased inflammatory cytokines such as interferon-gamma (IFN-gamma), have been implicated in the pathogenesis of HIV-1-associated blood-brain barrier dysfunction. The present study examined the effects of Tat and IFN-gamma on human brain microvascular endothelial cells (HBMECs), which constitute the blood-brain barrier. Tat produced cytotoxicity of HBMECs, but required IFN-gamma. IFN-gamma treatment of HBMECs up-regulates vascular endothelial growth factor receptor-2 (VEGFR2/KDR), which is known to be the receptor for Tat. Tat activated KDR in the presence of IFN-gamma, and Tat-mediated cytopathic changes involve its interaction with KDR and phosphatidylinositol 3-kinase (PI3K). Further understanding and characterization of Tat-HBMEC interactions should help us understand HIV-1 neuropathogenesis and develop strategies to prevent HIV-1 encephalopathy.
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PMID:Human immunodeficiency virus type 1 tat-mediated cytotoxicity of human brain microvascular endothelial cells. 1460 71

Integrin-mediated adhesion and B cell antigen receptor (BCR) signaling play a critical role in B cell development and function, including antigen-specific B cell differentiation. Here we show that the BCR controls integrin alpha4beta1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 and fibronectin. Molecular dissection of the underlying signaling mechanism by a combined biochemical, pharmacological, and genetic approach demonstrates that this BCR-controlled integrin-mediated adhesion requires the (consecutive) activation of Lyn, Syk, phosphatidylinositol 3-kinase, Bruton's tyrosine kinase (Btk), phospholipase C (PLC)gamma2, IP3R-mediated Ca2+ release, and PKC. In contrast, activation of mitogen-activated protein kinase kinase (MEK) or extracellular signal-regulated kinase (ERK) is not required, and simultaneous activation of MEK, ERK, and PKB is not sufficient either. Furthermore, Btk is also involved in the control of integrin-mediated adhesion of preB cells. The control of integrin alpha4beta1-mediated B cell adhesion by the BCR involves cytoskeletal reorganization and integrin clustering. These results reveal a novel function for the BCR and Btk, i.e., regulation of integrin alpha4beta1 activity, thereby providing new insights into the control of B cell development and differentiation, as well as into the pathogenesis of the immunodeficiency disease X-linked agammaglobulineamia (XLA).
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PMID:The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. 1461 42

We have studied the molecular genetics of 27 Brazilian families with ataxia telangiectasia (AT). Five founder effect haplotypes accounted for 55.5% of the families. AT is an autosomal recessive disorder of childhood onset characterized by progressive cerebellar ataxia, ocular apraxia, telangiectasia, immunodeficiency, radiation sensitivity, chromosomal instability, and predisposition to cancer. The ATM gene spans more than 150 kb on chromosome region 11q23.1 and encodes a product of 3056 amino acids. The ATM protein is a member of the phosphatidylinositol 3-kinase (PI-3K) family of proteins and is involved in cell cycle control and DNA repair pathways. DNA was isolated from lymphoblastoid cell lines and haplotyped using four STR markers (D11S1818, NS22, D11S2179, D11S1819) within and flanking the ATM gene; all allele sizes were standardized in advance. In addition to the STR haplotypes, SNP haplotypes were determined using 10 critical polymorphisms. The entire gene was screened sequentially by protein truncation testing (PTT), single strand conformation polymorphism (SSCP), and then denaturing high performance liquid chromatography (dHPLC) to identify the disease-causing mutations. Of the expected 54 mutations, 50 were identified. All mutations but one, led to a truncated or null form of the ATM protein (nonsense, splice site, or frameshift). Five families (18.5%) carried a deletion of 3450nt (from IVS28 to Ex31), making this one of the two most common Brazilian mutations. Mutations were located throughout the entire gene, with no clustering or hotspots. Standardized STR haplotype analysis greatly enhanced the efficiency of mutation screening.
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PMID:Five haplotypes account for fifty-five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: seven new mutations. 1503 71

Chemokines are important mediators of inflammation. It has been demonstrated that there is an increase in chemokine expression in both the sera and brain of individuals infected with human immunodeficiency virus type 1 (HIV-1). The HIV-1 viral protein, Tat, a transcriptional regulator, has been detected in the central nervous system (CNS) of infected individuals, and has been demonstrated to induce chemokines from various cells within the brain. The authors now show that the interaction of human microglia, the resident phagocytes of the brain, with Tat leads to dramatic increases in the secretion of the chemokines CCL2, CXCL8, CXCL10, CCL3, CCL4, and CCL5. Treatment of microglia with Tat plus specific inhibitors of signal transduction pathways demonstrated that the induction of each chemokine is regulated differently. Tat-induced expression of CCL2 and CCL4 was mediated by the activation of the extracellular regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K) pathway, whereas the induction of CXCL8 and CCL3 was mediated only by the p38 MAPK pathway. Tat-induced CXCL10 expression was mediated, to some extent, by activation of the ERK1/2 MAPK pathway, phosphatidylinositol 3-kinase pathway, and the p38 MAPK pathway, whereas CCL5 expression was not mediated by any pathway tested. Western blot analysis demonstrated phosphorylation of ERK 1/2 and Akt upon stimulation of microglia with Tat. These data suggest that a soluble HIV-1 viral protein can alter the chemokine balance in the brain, which can then lead to an influx of inflammatory cells and contribute to the neuropathogenesis of HIV-1 infection.
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PMID:Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. 1520 27

Patients with the human immunodeficiency virus type 1 (HIV-1) develop in the late phase of infection a complex of neurological signs termed Acquired Immune Deficiency Syndrome-Related Dementia (ADC). These patients exhibit cortical and subcortical atrophy. Considerable experimental data indicate that the HIV-1 envelope glycoprotein gp120 may be one of the agents causing neuronal cell death. Gp120 causes neuronal cell death both in vitro and in vivo by activating a caspase-dependent apoptotic pathway, and in particular caspase-3. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to prevent gp120-mediated apoptosis of cerebellar granule cells by inhibiting caspase-3 activation. However, the signal transduction pathway that contributes to the neuroprotective effects of BDNF has not been determined. BDNF binds with high affinity to the tyrosine kinase receptor TrkB and activates different intracellular signaling cascade including the extracellular signal-related kinases (ERK) and the phosphatidylinositol 3-kinase (PI3-K). Pharmacological inhibition of TrkB or ERK1/2, but not PI3-K, greatly reduced the ability of BDNF to block gp120-mediated apoptosis of cerebellar granule cells. These findings suggest that TrkB-mediated activation of ERK1/2 is the main signaling pathway that contributes to neuroprotection against gp120.
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PMID:Brain-derived neurotrophic factor activation of TrkB protects neurons from HIV-1/gp120-induced cell death. 1558 99

Ataxia-telangiectasia (AT) is an autosomal recessive inherited disease caused by mutational inactivation of the ATM gene. It is a multisystemic disease, characterized by progressive neurological dysfunction, especially in the cerebellum, oculo-cutaneous telangiectasia, immunodeficiency, recurrent sino-pulmonary infections and high incidence of neoplasms. The responsible gene, ATM, encodes a large protein that belongs to a family of protein kinases with a phosphatidylinositol 3-kinase (Pi3K) domain. ATM is a key regulator of cell cycle checkpoints that causes DNA repair or apoptosis. Several studies report ATM function in target cells (such as neurons, fibroblast, endothelium, germ cells, lymphocytes). The pleiotropic phenotypes of AT reflect the multifaceted activities of ATM protein. In nucleus (lymphocytes, fibroblasts, germ cells) ATM is involved in regulation of cell-cycle checkpoints; in cytoplasm ATM regulates redox state (neurons).
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PMID:[Ataxia-telangiectasia: a review]. 1642 18

The marine organisms produce many metabolic substances with numerous pharmacological activities. It has been suggested that ilimaquinone, a metabolite of sea sponge, can induce vesiculation of the Golgi apparatus and display several biological activities, such as anti-human immunodeficiency virus, anti-inflammation as well as anti-microbial activities. In this study, the sulforhodamine B assays showed that ilimaquinone induced a concentration-dependent anti-proliferative effect in several types of cancer cell lines, including prostate cancer PC-3 and LNCaP, non-small cell lung cancer A549 and hepatocellular carcinoma Hep3B cells. The anticancer mechanism of ilimaquinone in the representative PC-3 cells was identified. Ilimaquinone induced a time-dependent increase of G(1) phase arrest and a subsequent increase of hypodiploid sub-G(1) phase (apoptosis) of the cell cycle. The arrest of the cell cycle was associated with a sustained high level of nuclear cyclin E but the absence of DNA synthesis by flow cytometric analysis, indicating an incomplete S phase. Although ilimaquinone-induced Golgi vesiculation, the data showed that the inhibition of cancer cell growth was not through the Golgi fragmentation. Several biological kinases and transcription factors were examined in this study. The data demonstrated that ilimaquinone did not activate extracellular signal-regulated kinase and phosphatidylinositol 3-kinase but induce the up-regulation and nuclear translocation of growth arrest and DNA damage inducible gene 153 (CHOP/GADD153). Furthermore, ilimaquinone-mediated anti-proliferative effect is significantly reduced in the antisense CHOP/GADD153-overexpressing cells. Ilimaquinone also inhibited DNA binding of NF-kappaB; however, this inhibitory effect could not explain ilimaquinone-induced anticancer effect. In summary, it is suggested that ilimaquinone induces the anti-proliferative effect through the G(1) arrest of the cell cycle and the up-regulation and nuclear translocation of CHOP/GADD153.
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PMID:Ilimaquinone, a marine sponge metabolite, displays anticancer activity via GADD153-mediated pathway. 1714 May 62


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