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)

In HIV-infected patients, concurrent infections with bacteria and viruses are known to induce HIV replication as assessed by increases in plasma HIV RNA levels. In the present study, we determined the cell surface receptor and molecular mechanisms of enterobacterial LPS-induced HIV transcription. Human dermal microvessel endothelial cells (HMEC) were transfected with an HIV-long terminal repeat (LTR)-luciferase construct and subsequently stimulated with purified bacterial LPS. Our studies demonstrate that human Toll-like receptor 4 (TLR4) mediates LPS-induced NF-kappaB and HIV-LTR activation in HMEC through IL-1 signaling molecules, namely myeloid differentiation protein, IL-1R-associated kinase, TNFR-associated factor, and NF-kappaB-inducing kinase. Cotransfection of HMEC with HIV-LTR-luciferase and TLR4 cDNA from LPS-hyporesponsive C3H/HeJ mice abrogates LPS-induced HIV transcription as does the use of dominant-negative mutants of the IL-1 signaling molecules. Transfection of HMEC with an HIV-LTR-mutant that lacks the NF-kappaB binding site or pretreatment of cells with chemical inhibitors of the NF-kappaB pathway also blocked LPS-induced HIV-LTR transactivation. These data support the conclusion that TLR4 mediates enterobacterial LPS-induced HIV transcription via IL-1 signaling molecules and NF-kappaB activation plays an important role in HIV-LTR transactivation.
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PMID:Bacterial lipopolysaccharide activates HIV long terminal repeat through Toll-like receptor 4. 1116 Feb 91

The present study was designed to evaluate the effect of the HIV-1 envelope glycoprotein gp120 on the expression of beta-chemokines in cultured monocytes/macrophages. Treatment of either freshly isolated 1-day-cultured monocytes or 7-day-cultured monocyte-derived macrophages (MDM) with recombinant gp120-IIIB resulted in a specific and dose-dependent enhancement of secretion of monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, and RANTES as well as a clear-cut increase in transcript accumulation. The expression of these mRNA was increased, but not superinduced, in the presence of cycloheximide. beta-Chemokine secretion was also induced after exposure of monocyte cultures to gp120-JRFL and aldrithiol-2-inactivated R5 and X4 HIV-1 strains, retaining conformational and functional integrity of envelope proteins. In contrast, no beta-chemokine secretion was triggered by X4 and R5 gp120 or aldrithiol-2-inactivated virus treatment of monocytoid cell lines that were fully responsive to LPS. The gp120-mediated effect was independent of its interaction with CD4, as preincubation with soluble CD4 did not abrogate beta-chemokine induction. Moreover, triggering of CD4 receptor by a specific Ab did not result in any beta-chemokine secretion. Interestingly, engagement of CCR5 and CXCR4 receptors by specific Abs as well as treatment with CCR5 and CXCR4 ligands induced beta-chemokine secretion. On the whole, these results indicate that HIV-1 stimulates monocytes/macrophages to produce beta-chemokines by a specific interaction of gp120 with HIV-1 coreceptors on the cell membrane. The expression of these related polypeptides may represent an important cellular response for regulating both the extent of viral infection and the recruitment of immune cells.
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PMID:HIV-1 gp120 stimulates the production of beta-chemokines in human peripheral blood monocytes through a CD4-independent mechanism. 1131 74

Heat-killed Brucella abortus (HBa) has been proposed as a carrier for therapeutic vaccines for individuals with immunodeficiency, due to its abilities to induce interleukin-2 (IL-2) and gamma interferon (IFN-gamma) in both CD4(+) and CD8(+) T cells and to upregulate antigen-presenting cell functions (including IL-12 production). In the current study, we investigated the ability of HBa or lipopolysaccharide isolated from HBa (LPS-Ba) to elicit beta-chemokines, known to bind to the human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and to block viral cell entry. It was found that human peripheral blood mononuclear cells secreted beta-chemokines following stimulation with HBa, and this effect could not be blocked by anti-IFN-gamma neutralizing antibodies. Among purified T cells, macrophage inflammatory protein 1alpha and 1beta (MIP-1alpha and MIP-1beta, respectively) secretion was observed primarily in human CD8(+) T cells. The kinetics of beta-chemokine induction in T cells were slow (3 to 4 days). The majority of beta-chemokine-producing CD8(+) T cells also produced IFN-gamma following HBa stimulation, as determined by triple-color intracellular staining. A significant number of CD8(+) T cells contained stored MIP-1beta that was released after HBa stimulation. Both HBa and LPS-Ba stimulated high levels of MIP-1alpha and MIP-1beta production in elutriated monocytes and even higher levels in macrophages. In these cells, beta-chemokine mRNA was upregulated within 30 min and proteins were secreted within 4 h of stimulation. The monocyte- and macrophage-derived beta-chemokines were sufficient to block CCR5-dependent HIV-1 envelope-mediated cell fusion. These data suggest that, in addition to the ability of HBa to elicit antigen-specific humoral and cellular immune responses, HBa-conjugated HIV-1 proteins or peptides would also generate innate chemokines with antiviral activity that could limit local viral spread during vaccination in vivo.
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PMID:Human peripheral blood T cells, monocytes, and macrophages secrete macrophage inflammatory proteins 1alpha and 1beta following stimulation with heat-inactivated Brucella abortus. 1134 47

Chemokines are involved in the inhibition of HIV-1 infection and in the pathogenesis of tissue injury in a number of conditions, including endotoxemia and alcoholic liver disease. CC chemotactic peptides (MIP-1alpha, MCP-1 and RANTES) are produced by a wide variety of cell types in response to immunological stimuli, bacterial endotoxin and gp120 from HIV-1 and HIV-2. This work tests the hypothesis that prior exposure to endotoxin and/or ethanol in vivo inhibits the production of CC-chemokines following a secondary challenge with HIV-1 gp120 in vitro. Male Sprague-Dawley rats received in intravenous infusion of ethanol to maintain blood ethanol level at 170 mg/dl for 3 hr. Escherichia coli LPS (1 mg/Kg) was given intravenously 5 min after the ethanol bolus was injected. Control groups received similar volumes of saline. Three hr after LPS treatment, Kupffer cells were obtained and treated with HIV-1 gp120 (5 microg/10(6) cells/24 hr). At the end of the incubation period, cells were obtained for RT-PCR analysis of CC-chemokine mRNA expression. Chemokine release in culture supernatants was measured by ELISA. Results show that in vivo ethanol was associated with downregulation of MIP-1alpha and MCP-1 mRNA expression and protein release in primary cultures of Kupffer cells. However, ethanol alone primed isolated Kupffer cells for enhanced RANTES mRNA and protein release in the presence or absence of HIV-1 gp120. These results demonstrate that acute ethanol intoxication and endotoxemia may selectively act as a desensitizing agent in response to a secondary challenge with bacterial or viral products.
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PMID:Acute alcohol intoxication and endotoxemia desensitize HIV-1 gp120-induced CC-chemokine production by Kupffer cells. 1138 97

The smallest unit of bacterial peptidoglycans known to be endowed with biological activities is muramyl dipeptide (MDP). A clinically acceptable synthetic derivative of MDP, namely murabutide (MB), has been found to present interesting pharmacological properties and to suppress HIV-1 replication in monocyte-derived macrophages (MDM). We have addressed the signaling events activated in MDM following stimulation with either MB or the potent immunostimulant LPS. We also examined whether signaling by muramyl peptides involves the use of cell surface receptors, including CD14 and Toll-like receptor 2 (TLR2) or TLR4 that are known to be signal-transducing receptors for other bacterial cell wall components. We demonstrate that, unlike LPS, the safe immunomodulator MB selectively activates extracellular signal-regulated kinases (Erk) 1/2, in the absence of detectable Jun N-terminal kinase (JNK) or p38 mitogen-activated kinase activation. Furthermore, STAT1 activation but weak or no activation of STAT3 or STAT5 respectively, could be detected in MB-stimulated MDM. Using MonoMac6 cells, we observed high C/EBPbeta and AP-1 but weaker and transient NF-kappaB activation by MB.Moreover, the truncated form of C/EBPbeta, known to repress HIV-1 transcription, was detected in extracts from MB-treated THP-1 cells. Surprisingly, neither MB nor MDP were able to transduce signals via CD14 and TLR2 or 4. These findings present major differences in the early cell activation process between LPS and muramyl peptides, and strongly argue for the implication of co-receptors other than TLR2 and TLR4 in mediating the signaling events induced by defined subunits of bacterial peptidoglycans.
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PMID:Macrophage stimulation with Murabutide, an HIV-suppressive muramyl peptide derivative, selectively activates extracellular signal-regulated kinases 1 and 2, C/EBPbeta and STAT1: role of CD14 and Toll-like receptors 2 and 4. 1144 48

New generation vaccines, particularly those based on recombinant proteins and DNA, are likely to be less reactogenic than traditional vaccines, but are also less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. Adjuvants can be broadly separated into two classes, based on their principal mechanisms of action; vaccine delivery systems and 'immunostimulatory adjuvants'. Vaccine delivery systems are generally particulate e.g. emulsions, microparticles, iscoms and liposomes, and mainly function to target associated antigens into antigen presenting cells (APC). In contrast, immunostimulatory adjuvants are predominantly derived from pathogens and often represent pathogen associated molecular patterns (PAMP) e.g. LPS, MPL, CpG DNA, which activate cells of the innate immune system. Once activated, cells of innate immunity drive and focus the acquired immune response. In some studies, delivery systems and immunostimulatory agents have been combined to prepare adjuvant delivery systems, which are designed for more effective delivery of the immunostimulatory adjuvant into APC. Recent progress in innate immunity is beginning to yield insight into the initiation of immune responses and the ways in which immunostimulatory adjuvants may enhance this process. However, a rational approach to the development of new and more effective vaccine adjuvants will require much further work to better define the mechanisms of action of existing adjuvants. The discovery of more potent adjuvants may allow the development of vaccines against infectious agents such as HIV which do not naturally elicit protective immunity. New adjuvants may also allow vaccines to be delivered mucosally.
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PMID:Recent developments in adjuvants for vaccines against infectious diseases. 1156 99

HIV transgenic mice bearing multiple copies of a noninfectious (Deltagag/pol) proviral DNA were tested for the systemic production of nitric oxide (NO). Serum levels of NO metabolites were reduced about 50% in HIV transgenic mice compared with nontransgenic sibling mice. This difference persisted when NO production was induced with peritoneal injections of bacterial endotoxin (LPS). Peritoneal inflammatory macrophages, but not resident peritoneal macrophages, derived from HIV-1 transgenic mice and activated in vitro with LPS and IFN-gamma (or tumor necrosis factor alpha and IFN-gamma) also produced about 50% less NO than did macrophages harvested from nontransgenic littermates. Isogenic, transgenic mice bearing mutated nef or vpr genes had normal serum levels of NO metabolites and their macrophages produced normal levels of NO when stimulated. An explanation for the reduced NO response of HIV[Vpr+Nef+] macrophages was not apparent from measured levels of iNOS expression, viral gene expression, or arginase activity in activated macrophages. Inhibition of nitric oxide synthase (NOS) isoforms with L-NAME or aminoguanidine blocked time-dependent increases in HIV gene expression in activated macrophages cultured ex vivo. Inhibition with L-NAME occurred despite high levels of NO generated by iNOS, and exogenously supplied NO induced HIV gene expression only weakly, suggesting that cNOS had the greater influence on proviral gene induction. This system is presented as a model of HIV-1 proviral gene expression and dysfunction in macrophages.
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PMID:A defect in HIV-1 transgenic murine macrophages results in deficient nitric oxide production. 1159 Jan 96

The bacterial endotoxin LPS is a potent stimulator of monocyte and macrophage activation and has been shown to protect differentiated macrophages from de novo infection by HIV-1. However, the mechanisms of this inhibitory activity of LPS are not fully understood. We investigated the effect of LPS on the early post-binding steps of HIV-1 replication in primary macrophages. Paradoxically, when applied together with the virus, LPS stimulated entry of HIV-1 into macrophages, as judged by the amount of internalized HIV-1 RNA and p24. This stimulatory activity did not depend on receptors used for entry and did not require new protein synthesis. However, internalized viral RNA and p24 were rapidly degraded in LPS-stimulated macrophages. Surprisingly, while degradation of HIV-1 p24 in LPS-treated cells was inhibited by bafilomycin A1, HIV-1 RNA was not protected by this agent, suggesting that viral RNA is degraded by a pH-independent mechanism. These results indicate that LPS stimulates both virus uptake and virus degradation in macrophages.
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PMID:Lipopolysaccharide stimulates HIV-1 entry and degradation in human macrophages. 1171 80

Receptors for the bacterial chemotactic peptide fMLP are implicated in inflammation and host defense against microbial infection. We investigated the expression and function of fMLPR in microglial cells, which share characteristics of mononuclear phagocytes and play an important role in proinflammatory responses in the CNS. The expression of the genes encoding formyl peptide receptor (FPR)1 and FPR2, the high- and low-affinity fMLPR, was detected in a murine microglial cell line N9, but these cells did not respond to chemotactic agonists known for these receptors. N9 cells incubated with bacterial LPS increased the expression of fMLPR genes and developed a species of specific, but low-affinity, binding sites for fMLP, in association with marked calcium mobilization and chemotaxis responses to fMLP in a concentration range that typically activated the low-affinity receptor FPR2. In addition, LPS-treated N9 cells were chemoattracted by two FPR2-specific agonists, the HIV-1 envelope-derived V3 peptide, and the 42 aa form of the amyloid beta peptide which is a pathogenic agent in Alzheimer's disease. Primary murine microglial cells also expressed FPR1 and FPR2 genes, but similar to N9 cells, exhibited FPR2-mediated activation only after LPS treatment. In contrast to its effect on the function of FPR2, LPS reduced N9 cell binding and biological responses to the chemokine stromal cell-derived factor-1alpha. Thus, LPS selectively modulates the function of chemoattractant receptors in microglia and may promote host response in inflammatory diseases in the CNS.
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PMID:Bacterial lipopolysaccharide selectively up-regulates the function of the chemotactic peptide receptor formyl peptide receptor 2 in murine microglial cells. 1175 90

The macaque-simian immunodeficiency virus (SIV) system is one of the best animal models available to study the role of dendritic cells (DCs) in transmission and pathogenesis of HIV, as well as to test DC-based vaccine and therapeutic strategies. To better define and optimize this system, the responsiveness of macaque monocyte-derived DCs to a variety of maturation stimuli was examined. Characteristic immunophenotypic and functional DC maturation induced by standard monocyte conditioned medium (MCM) was compared to the activation induced by a panel of stimuli including soluble CD40L, LPS, Poly I:C, PGE(2)/TNFalpha, and a cocktail mixture of PGE(2)/TNFalpha/IL-1beta/IL-6. Immunophenotypic analysis confirmed that all stimuli induced stable up-regulation of CD25, CD40, CD80, CD83, CD86, HLA-DR, DC-LAMP (CD208), and DEC-205 (CD205). In general, macaque DCs exhibited weaker responses to LPS and Poly I:C than human DCs, and soluble CD40L stimulation induced variable expression of CD25. Interestingly, while the endocytic capacity of CD40L-matured cells was down-modulated comparably to DCs matured with MCM or the cocktail, the T cell stimulatory activity was not enhanced to the same extent. The particularly reproducible and potent T cell stimulatory capacity of cocktail-treated DCs correlated with a more homogenous mature DC phenotype, consistently high levels of IL-12 production, and better viability upon reculture compared to DCs activated by other stimuli. Furthermore, cocktail-matured DCs efficiently captured and presented inactivated SIV to SIV-primed T cells in vitro. Thus, the cocktail represents a particularly potent and useful stimulus for the generation of efficacious immunostimulatory macaque DCs.
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PMID:Enhanced in vitro stimulation of rhesus macaque dendritic cells for activation of SIV-specific T cell responses. 1179 91

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