UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously found that the angiogenic factors TNFalpha and HIV-1 Tat activate an NAD(P)H oxidase in endothelial cells, which operates upstream of c-Jun N-terminal kinase (JNK), a MAPK involved in the determination of cell fate. To further understand oxidant-related signaling pathways, we screened lung and endothelial cell libraries for interaction partners of p47(phox) and recovered the orphan adapter TNF receptor-associated factor 4 (TRAF4). Domain analysis suggested a tail-to-tail interaction between the C terminus of p47(phox) and the conserved TRAF domain of TRAF4. In addition, TRAF4, like p47(phox), was recovered largely in the cytoskeleton/membrane fraction. Coexpression of p47(phox) and TRAF4 increased oxidant production and JNK activation, whereas each alone had minimal effect. In addition, a fusion between p47(phox) and the TRAF4 C terminus constitutively activated JNK, and this activation was decreased by the antioxidant N-acetyl cysteine. In contrast, overexpression of the p47(phox) binding domain of TRAF4 blocked endothelial cell JNK activation by TNFalpha and HIV-1 Tat, suggesting an uncoupling of p47(phox) from upstream signaling events. A secondary screen of endothelial cell proteins for TRAF4-interacting partners yielded a number of proteins known to control cell fate. We conclude that endothelial cell agonists such as TNFalpha and HIV-1 Tat initiate signals that enter basic signaling cassettes at the level of TRAF4 and an NAD(P)H oxidase. We speculate that endothelial cells may target endogenous oxidant production to specific sites critical to cytokine signaling as a mechanism for increasing signal specificity and decreasing toxicity of these reactive species.
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PMID:Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase. 1202 63

Brain microvascular endothelial cells (BMVECs) present an incomplete barrier to human immunodeficiency virus type 1 (HIV-1) neuroinvasion. In order to clarify the mechanisms of HIV-1 invasion, we have examined HIV-1 uptake and transcellular penetration in an in vitro BMVEC model. No evidence of productive infection was observed by luciferase, PCR, and reverse transcriptase assays. Approximately 1% of viral RNA and 1% of infectious virus penetrated the BMVEC barrier without disruption of tight junctions. The virus upregulated ICAM-1 on plasma membranes and in cytoplasmic vesiculotubular structures. HIV-1 virions were entangled by microvilli and were taken into cytoplasmic vesicles through surface invaginations without fusion of the virus envelope with the plasma membrane. Subsequently, the cytoplasmic vesicles fused with lysosomes, the virions were lysed, and the vesicles diminished in size. Upon cell entry, HIV-1 colocalized with cholera toxin B, which targets lipid raft-associated GM1 ganglioside. Cholesterol-extracting agents, cyclodextrin and nystatin, and polyanion heparin significantly inhibited virus entry. Anti-CD4 had no effect and the chemokine AOP-RANTES had only a slight inhibitory effect on virus entry. HIV-1 activated the mitogen-activated protein kinase (MAPK) pathway, and inhibition of MAPK/Erk kinase inhibited virus entry. Entry was also blocked by dimethylamiloride, indicating that HIV-1 enters endothelial cells by macropinocytosis. Therefore, HIV-1 penetrates BMVECs in ICAM-1-lined macropinosomes by a mechanism involving lipid rafts, MAPK signaling, and glycosylaminoglycans, while CD4 and chemokine receptors play limited roles in this process.
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PMID:Human immunodeficiency virus type 1 enters brain microvascular endothelia by macropinocytosis dependent on lipid rafts and the mitogen-activated protein kinase signaling pathway. 1205 Mar 82

Leptin, the Ob gene product, is an adipocyte hormone that centrally regulates weight control. In addition, other effects of leptin in peripheral tissues have been described. Thus, leptin has been found to regulate reproduction, haematopoiesis and immune function. We have found recently that leptin has a stimulatory effect on human peripheral blood mononuclear cells (PBMC). Monocytes are activated by leptin alone whereas T lymphocytes need a suboptimal stimulus of PHA or ConA before further activation by leptin. These effects are mediated by the long isoform of the leptin receptor, which has been shown to trigger signalling in PBMC. In fact, we have found that human leptin stimulates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in PBMC. In order to assess possible regulation of the long isoform of the leptin receptor (Ob-R) in mononuclear cells upon activation, we have studied the expression of Ob-R by RT-PCR and Western blotting in PBMC activated in vitro by PHA or ConA and in vivo in HIV-infected patients. We have found that in vitro activation and in vivo HIV infection correlates with an increase in leptin receptor expression in PBMC. Moreover, the leptin receptor is tyrosine phosphorylated in PBMC from HIV-infected patients, suggesting that the leptin receptor is activated. These results are consistent with the suggested role of leptin in modulating the immune response.
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PMID:Leptin receptor (Ob-R) expression is induced in peripheral blood mononuclear cells by in vitro activation and in vivo in HIV-infected patients. 1210 31

Japanese encephalitis virus (JEV) infection generates a rapid inflammatory response including peripheral neutrophil leucocytosis and infiltration of neutrophils into extraneural tissue. The level of inflammation correlates well with the clinical outcome in Japanese encephalitis patients. Non-steroidal anti-inflammatory drugs (NSAIDs), used medicinally for their analgesic and anti-inflammatory properties, are being considered for prevention of cardiovascular disease and cancer, as well as for treatment of human immunodeficiency virus infection. Apart from their ability to inhibit prostaglandin synthesis, the mechanisms underlying the beneficial therapeutic effects are largely unknown. We used aspirin, indomethacin and sodium salicylate to study the role of NSAIDs in JEV propagation in vitro. We found that NSAIDs suppressed JEV propagation in neuronal and non-neuronal cells. Blockade of cyclooxygenase activity by NSAIDs caused decreased production of free radicals and prostaglandins. However, these pharmacological alterations did not seem to correlate well with the antiviral effects. When cells were treated with the mitogen-activated protein kinase (MAPK) inhibitors PD 98059 and SB 203580, salicylate lost its antiviral effect. The activation of MAPK by anisomycin mimicked the action of salicylate in suppressing JEV-induced cytotoxicity. The decreased phosphorylation of extracellular signal-regulated kinase (ERK) was induced by JEV infection and the decrease in ERK was reversed by salicylate. Our data suggest that the signalling pathways of MAPK play a role in the antiviral action of salicylate.
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PMID:Suppression of Japanese encephalitis virus infection by non-steroidal anti-inflammatory drugs. 1212 53

Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present study was undertaken to investigate the effect of the HIV-1 tat gene on the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astroglia. Expression of the tat gene as RSV-tat but not that of the CAT gene as RSV-CAT in U373MG astroglial cells led to the induction of NO production and the expression of iNOS protein and mRNA. Induction of NO production by recombinant HIV-1 Tat protein and inhibition of RSV-tat-induced NO production by anti-Tat antibodies suggest that RSV-tat-induced production of NO is dependent on Tat and that Tat is secreted from RSV-tat-transfected astroglia. Similar to U373MG astroglial cells, RSV-tat also induced the production of NO in human primary astroglia. The induction of human iNOS promoter-derived luciferase activity by the expression of RSV-tat suggests that RSV-tat induces the transcription of iNOS. To understand the mechanism of induction of iNOS, we investigated the role of NF-kappaB and C/EBPbeta, transcription factors responsible for the induction of iNOS. Activation of NF-kappaB as well as C/EBPbeta by RSV-tat, stimulation of RSV-tat-induced production of NO by the wild type of p65 and C/EBPbeta, and inhibition of RSV-tat-induced production of NO by deltap65, a dominant-negative mutant of p65, and deltaC/EBPbeta, a dominant-negative mutant of C/EBPbeta, suggest that RSV-tat induces iNOS through the activation of NF-kappaB and C/EBPbeta. In addition, we show that extracellular signal-regulated kinase (ERK) but not that p38 mitogen-activated protein kinase (MAPK) is involved in RSV-tat induced production of NO. Interestingly, PD98059, an inhibitor of the ERK pathway, and deltaERK2, a dominant-negative mutant of ERK2, inhibited RSV-tat-induced production of NO through the inhibition of C/EBPbeta but not that of NF-kappaB. This study illustrates a novel role for HIV-1 tat in inducing the expression of iNOS in human astrocytes that may participate in the pathogenesis of HIV-associated dementia.
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PMID:Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia. 1216 19

The transcription factor NF-kappaB is regulated by the IkappaB family of proteins. The nonphosphorylatable, nondegradable superrepressor IkappaBalpha (srIkappaBalpha) mutant is a potent inhibitor of NF-kappaB activity when expressed in cells. We generated a form of srIkappaBalpha in which its N terminus is fused to the protein transduction domain of HIV TAT (TAT-srIkappaBalpha). Purified TAT-srIkappaBalpha protein rapidly and efficiently entered HeLa or Jurkat T cells. TAT-srIkappaBalpha, when exogenously added to HeLa cells, inhibited in a dose-dependent manner TNF-alpha- or IL-1beta-induced NF-kappaB activation and binding of NF-kappaB to its consensus DNA sequence. TAT-srIkappaBalpha was coimmunoprecipitated with the p65 subunit of NF-kappaB, and this interaction was resistant to stimulation with IL-1beta. Therefore, TAT-srIkappaBalpha-mediated inhibition could result from its nonreversible binding and sequestration of endogenous NF-kappaB. In contrast, exogenously added TAT-srIkappaBalpha did not inhibit IL-1beta-induced activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinases or the phosphorylation and degradation of endogenous IkappaBalpha. These results identify a novel way for direct regulation of NF-kappaB activity in diverse cell types that may be useful for therapeutic purposes.
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PMID:Inhibition of NF-kappa B activity by a membrane-transducing mutant of I kappa B alpha. 1219 29

We transduced dominant negative (dn) HIV TAT-Ras protein into mature human eosinophils to determine the signaling pathways and mechanism involved in integrin-mediated adhesion caused by cytokine, chemokine, and chemoattractant stimulation. Transduction of TAT-dnRas into nondividing eosinophils inhibited endogenous Ras activation and extracellular signal-regulated kinase (ERK) phosphorylation caused by IL-5, eotaxin-1, and fMLP. IL-5, eotaxin-1, or fMLP caused 1) change of Mac-1 to its active conformation and 2) focal clustering of Mac-1 on the eosinophil surface. TAT-dnRas or PD98059, a pharmacological mitogen-activated protein/ERK kinase inhibitor, blocked both focal surface clustering of Mac-1 and the change to active conformational structure of this integrin assessed by the mAb CBRM1/5, which binds the activation epitope. Eosinophil adhesion to the endothelial ligand ICAM-1 was correspondingly blocked by TAT-dnRas and PD98059. As a further control, we used PMA, which activates ERK phosphorylation by postmembrane receptor induction of protein kinase C, a mechanism which bypasses Ras. Neither TAT-dnRas nor PD98059 blocked eosinophil adhesion to ICAM-1, up-regulation of CBRM1/5, or focal surface clustering of Mac-1 caused by PMA. In contrast to beta(2)-integrin adhesion, neither TAT-dnRas nor PD98059 blocked the eosinophil adhesion to VCAM-1. Thus, a substantially different signaling mechanism was identified for beta(1)-integrin adhesion. We conclude that H-Ras-mediated activation of ERK is critical for beta(2)-integrin adhesion and that Ras-protein functions as the common regulator for cytokine-, chemokine-, and G-protein-coupled receptors in human eosinophils.
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PMID:Blockade of focal clustering and active conformation in beta 2-integrin-mediated adhesion of eosinophils to intercellular adhesion molecule-1 caused by transduction of HIV TAT-dominant negative Ras. 1219 40

Superantigens are microbial proteins that induce massive activation, proliferation, and cytokine production by CD4+ T cells via specific Vbeta elements on the TCR. In this study we examine superantigen enhancement of Ag-specific CD4+ T cell activity for humoral B cell responses to T-dependent Ags BSA and HIV gp120 envelope, type I T-independent Ag LPS, and type II T-independent Ag pneumococcal polysaccharides. Injection of BSA followed by a combination of superantigens staphylococcal enterotoxin A and staphylococcal enterotoxin B (SEB) 7 days later enhanced the anti-BSA Ab response in mice approximately 4-fold as compared with mice given BSA alone. The anti-gp120 response was enhanced approximately 3-fold by superantigens. The type II T-independent Ag pneumococcal polysaccharide response was enhanced approximately 2.3-fold by superantigens, whereas no effect was observed on the response to the type I T-independent Ag LPS. The superantigen effect was completely blocked by the CD4+ T cell inhibitory cytokine IL-10. SEB-stimulated human CD4+ T cells were examined to determine the role of the mitogen-activated protein (MAP) kinase signal transduction pathway in superantigen activation of T cells. Inhibitors of the mitogen pathway of MAP kinase blocked SEB-induced proliferation and IFN-gamma production, while an inhibitor of the p38 stress pathway had no effect. Consistent with this, SEB activated extracellular signal-regulated kinase/MAP kinase as well as MAP kinase-interacting kinase, a kinase that phosphorylates eIF4E, which is an important component of the eukaryotic protein synthesis initiation complex. Both kinases were inhibited by IL-10. Thus, superantigens enhance humoral immunity via Ag-specific CD4+ T cells involving the stress-independent pathway of MAP kinase.
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PMID:Superantigen enhancement of specific immunity: antibody production and signaling pathways. 1221 4

The capacity of the HIV-1 envelope glycoprotein gp120 to induce intracellular signals is thought to contribute to HIV-1 pathogenesis. Here, we report that gp120 binding resulted in activation of the mitogen-activated protein kinase (MAPK) in CD4(+) lymphocytes prestimulated through their T-cell receptor (TCR). However, gp120 did not activate this pathway in either freshly isolated quiescent T cells or nonproliferating CD4(+) lymphocytes prestimulated with the interleukin-7 (IL-7) cytokine. This response was not solely dependent on proliferation per se because proliferating IL-7-prestimulated umbilical cord (UC)-derived T lymphocytes did not exhibit significant MAPK activation upon gp120 binding. Nevertheless, like peripheral blood lymphocytes, MAPK recruitment was induced by gp120 in UC T cells following TCR prestimulation. The lack of a gp120-mediated signaling response was not due to decreased gp120 receptor levels; CD4 expression was modified neither by IL-7 nor by TCR engagement, and high levels of functional CXCR4 were present on IL-7-treated lymphocytes. In addition to CD4 and CXCR4, recent evidence suggests that glycosphingolipids in raft microdomains serve as cofactors for HIV-1 fusion. The ganglioside GM1, a marker of rafts, was augmented in TCR-stimulated but not IL-7-stimulated T lymphocytes, and disruption of rafts inhibited gp120-induced signaling. Thus, stimulation of a mitogenic pathway by gp120 appears to require receptor binding in the context of membrane microdomains. These studies reveal a mechanism via which gp120 may differentially modulate the fate of activated and quiescent T cells in vivo.
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PMID:gp120-mediated induction of the MAPK cascade is dependent on the activation state of CD4(+) lymphocytes. 1223 68

Neuronal damage and death are consistent pathologic findings in the brains of patients with ADC, and multiple cell model systems have demonstrated neurotoxicity through the effects of HIV-1 infection in macrophages and microglia. Brain MRI studies (1H-MRS) indicate that reversible neuronal cell dysfunction occurs early during the course of HIV-1 infection, long before overt symptoms of ADC appear. Epidemiologic studies suggest that a high viral load in the CNS is a major risk factor for ADC and that HAART may significantly reduce, but not eliminate, the risk of developing ADC. Targeted adjunctive therapies administered early are likely necessary to maximize CNS protection against HIV, and rational approaches to such therapy are rapidly evolving through in vitro analysis of the mechanisms of HIV-associated neurotoxicity. Soluble factors released by infected cells may directly or indirectly damage neurons and induce apoptosis at the level of NMDA subtype of glutamate receptors, and NMDA receptor antagonists represent a major therapeutic option currently under intense clinical investigation. Likewise, drugs with antioxidant or free radical scavenging effects offer another rational approach to adjunctive therapy and are also under intense clinical scrutiny. Finally, agents that inhibit neuronal death-signaling pathways (e.g., p38 MAPK inhibitors) and that stimulate cell survival pathways (e.g., Akt/PKB) may represent the next investigational step in designing anti-ADC therapies.
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PMID:Neuropathogenesis of central nervous system HIV-1 infection. 1224 93

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