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

Chemokines constitute a large and still growing family of structurally-related small (8-10 kDa) cytokines that have chemotactic activity for leukocytes. Recently, some receptors for chemokines were reported to be used as a co-receptor by HIV at infection. In addition to their well-established role in inflammatory response and recently-reported role as a co-receptor for HIV, recent data suggest that chemokines and their receptors physiologically and pathologically play crucial roles as the mediators for intercellular communication among the cells intrinsic to and recruited into the brain; i.e., neurons, astrocytes, microglia, endothelial cells and leukocytes. Some chemokines such as SDF-1 and fractalkine are constitutively produced in the brain, implicating that they have an important role in maintenance of CNS homeostasis or determination of the patterning of neurons and/or glial cells in developing brain and normal adult brain. Chemokines such as MCP-1, MIP-1 alpha and CINC were shown to be induced by various neuroinflammatory stimuli, suggesting that they are involved in various neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, stroke and AIDS dementia syndrome. Chemokines and their receptors are potential targets for therapeutic intervention in neurodegenerative diseases.
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PMID:[Chemokines as mediators for intercellular communication in the brain]. 1087 3

A new group of cytokins, having the properties of chemoattractants and named "chemokins", has been characterized. These structurally related low-molecular proteins (8-10 kD) with 20-90% homology in amino acids contain 4 conservative disulfide-linked cysteins whose location determines which of the groups (CXC, CC, C) they belong to. Chemokins regulate the migratory activity of all types of leukocytic cells. Target cells are affected by chemokins through specific receptors (at least 9 types) of the rhodopsin family, including 7 transmembrane domains. Chemokins play an important role in the pathogenesis of many diseases, especially those of inflammatory nature. Some chemokins (RANTES, MIP-1) and their receptors are linked with the development of HIV infection. Chemokins serve as the basis of medicinal preparations, blocking or enhancing the migratory activity of leukocytes. Our newly developed preparation, based on a complex of natural cytokins, induces, when used locally, the influx of neutrophils and macrophages to the zone of tissue destruction, acting as chemokins.
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PMID:[Chemokines--a new family of cytokines regulating leukocyte migration]. 1087 8

The platelet-activating factor (PAF) plays a major role in neuropathogenesis associated with human immunodeficiency virus (HIV) infection by enhancing the inflammatory syndrome and viral replication, particularly in cells of the macrophage lineage, and its neurotoxic properties. We therefore evaluated the ability of PAF-R antagonists to inhibit HIV-1 replication and down-modulate the synthesis of pro-inflammatory mediators in healthy or HIV-1-infected macrophages. PMS-601 demonstrated the highest anti-HIV activity. Considering its mode of action and anti-inflammatory properties, PMS-601 interferes with early and late steps of the HIV biological cycle and decreases the synthesis of PAF, TNF-alpha, MIP-1 alpha, MIP-1 beta and RANTES. Altogether, these results suggest that PAF-receptor antagonists, and particularly PMS-601, could be of potential value as treatment adjuvants in HIV infection.
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PMID:[Antiretroviral ant anti-inflammatory properties of a novel platelet activation factor antagonist, PMS-601]. 1094 51

CCR5 and CXC chemokine receptor 4 (CXCR4) are coreceptors for CD4 as defined by HIV-1 glycoprotein (gp) 120 binding. Pretreatment of T cells with gp120 results in modulation of both CCR5 and CXCR4 responsiveness, which is dependent upon p56(lck) enzymatic activity. The recent findings that pretreatment of T cells with a natural CD4 ligand, IL-16, could alter cellular responsiveness to macrophage-inflammatory protein-1ss (MIP-1ss) stimulation, prompted us to investigate whether IL-16 could also alter CXCR4 signaling. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes also results in loss of stromal derived factor-1alpha (SDF-1alpha)/CXCR4-induced chemotaxis; however, unlike MIP-1ss/CCR5, the effects were not reciprocal. There was no effect on eotaxin/CCR3-induced chemotaxis. Desensitization of CXCR4 by IL-16 required at least 10-15 min pretreatment; no modulation of CXCR4 expression was observed, nor was SDF-1alpha binding altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56(lck)-dependent inhibitory signal for CXCR4, which is independent of its tyrosine catalytic activity. By contrast, IL-16/CD4 desensitization of MIP-1ss/CCR5 responses requires p56(lck) enzymatic activity. IL-16/CD4 inhibition of SDF-1alpha/CXCR4 signals requires the presence of the Src homology 3 domain of p56(lck) and most likely involves activation of phosphatidylinositol-3 kinase. These studies indicate the mechanism of CXCR4 receptor desensitization induced by a natural ligand for CD4, IL-16, is distinct from the inhibitory effects induced by either gp120 or IL-16 on CCR5.
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PMID:Desensitization of CXC chemokine receptor 4, mediated by IL-16/CD4, is independent of p56lck enzymatic activity. 1108 73

The mechanism through which VIP prevents neurotoxicity associated with HIV envelope protein has been shown to involve the release of a beta-chemokine, MIP-1 alpha. Astrocytes stimulated with subnanomolar concentrations of VIP caused the release of MIP-1 alpha and RANTES, both of which have been shown to prevent neuronal cell death associated with gp120. It is further proposed that gp120 causes neuronal cell death, in part, by competing with endogenous chemokines at various chemokines receptors in the brain that are necessary for neuronal survival. Although the chemokines are known to be mediators of inflammation, our studies suggest that these compounds have additional roles as neuroprotective agents that depend on the concentration of chemokine, cellular microenvironment, and stage of development of target neurons. Our studies further imply that in a developing system, stimulation with a MIP-1 alpha like substance is necessary for neuronal survival and interference with this action results in neuronal cell death.
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PMID:Chemokines released from astroglia by vasoactive intestinal peptide. Mechanism of neuroprotection from HIV envelope protein toxicity. 1119 13

The duration from initial infection with HIV-1 to CD4 lymphocyte depletion and progression to AIDS varies among infected individuals. Despite treatment with highly active antiretroviral therapy (HAART), patients still show different stages of disease progression. We examined the role of beta-chemokines and its receptor, CCR5 in HIV-1 infected children in order to define determinants of HIV progression among treated individuals. Population was divided in two groups: Group 1--Long Term Non Progressors (LTNP) includes 10 patients with B1-B2 CDC disease classification and with a less aggressive therapy (only 2 in HAART); Group 2--Rapid Progressors (RP) includes 9 patients with C3 disease classification. All the patients had a CCR5 wild type (wt) genotype indicating that they do not have the 32 base-pair deletion associated with slower progression. There was an increased production of MIP 1-beta in 8/10 LTNP but only in 4/9 Progressors (Paired t-test/Wilcoxon Sign test, p-value < 0.05). The change in the levels of MIP-1 beta after PHA stimulation was statistically significant in both groups. The levels of RANTES increased in LTNP and RP and the change of the levels after mitogen stimulation was statistically significant for both groups included. The production of RANTES and MIP-1 beta in response to stimulation between both groups was not statistically significant. The production of MIP-1 alpha was variable in both groups and the difference in the levels after mitogen stimulation between the groups was not statistically significant. These results suggest that beta-chemokines do not play an important role in HIV-1 progression in children undergoing HAART.
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PMID:CCR5 and beta-chemokines in HIV-1 infected children. 1130 Jan 23

Chemokines direct immune cells toward sites of infection by establishing a gradient across the extracellular matrix of the tissue. This gradient is thought to be stabilized by ligation of chemokines to sulfated polysaccharides known as glycosaminoglycans (GAGs) that are found on the surface of endothelial and other cells as well as in the tissue matrix. GAGs interact with chemokines and in some cases cause them to aggregate. The interaction between cell surface GAGs and chemokines has also been postulated to play a role in the anti-HIV activity of some chemokines, including MIP-1beta. Since many proteins interact with GAGs by utilizing basic residues, we mutated R18, K45, R46, and K48 in MIP-1beta to investigate the role of these residues in GAG binding and CCR5 function. We find that no single amino acid substitution alone has a dramatic effect on heparin binding, although change at R46 has a moderate effect. However, binding to heparin is completely abrogated in a mutant (K45A/R46A/K48A) in which the entire "40's loop" has been neutralized. A functional study of these mutants reveals that the charged residues in this 40's loop, particularly K48 and R46, are critical mediators of MIP-1beta binding to its receptor CCR5. However, despite the partially overlapping function of the residues in the 40's loop in binding to both CCR5 and heparin, the presence of cell surface sugars does not appear to be necessary for the ability of MIP-1beta to function on its receptor CCR5, as enzymatic removal of GAGs from cells results in little effect on MIP-1beta activity. Because the means by which the chemokine gradient transmits information to the recruited cells is not well defined, we also mutated the basic residues in MIP(9), a truncated form of MIP-1beta that is impaired in its ability to dimerize, to probe whether the quaternary structure of this chemokine influences its ability to bind heparin. None of the truncated variants bound as well as the full-length proteins containing the same mutation, suggesting that the MIP-1beta dimer participates in heparin binding.
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PMID:Importance of basic residues and quaternary structure in the function of MIP-1 beta: CCR5 binding and cell surface sugar interactions. 1130 15

The National Institute of Allergy and Infectious Diseases (NIAID) director, Anthony S. Fauci, M.D., presented findings at the 3rd Conference on Retroviruses and Opportunistic Infections that may help shed light on how HIV escapes the body's immune response following initial infection. NIAID researchers have found that certain subsets of CD8+ T cells that are known to fight against HIV, called cytotoxic T lymphocytes (CTLs), multiply quickly after initial infection and then disappear completely after a short period of work. The research also shows that the CTLs tend to accumulate in the bloodstream rather than the lymph nodes, where the virus is replicating. Dr. Fauci also presented new findings on the HIV suppressor molecules. Building on previous work demonstrating that CD8+ T cells are able to block HIV expression, NIAID researchers have found that cytokine interleukin-2 is a strong inducer of the CD8 suppressor phenomenon, but interleukin-12 is not. Chemokines suppress in vitro virus replication in cells from HIV-infected people by making CD8+ T cells secrete three immune-signalling molecules, RANTES, MIP-1alpha and MIP-1B. NIAID researchers found that CD8-depleted cells also secrete the three molecules resulting in the conclusion that not all HIV suppression is due to CD8+ T cells. The researchers have also learned that although the molecules may suppress HIV in one model system, they may not do it in another model.
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PMID:Fauci presents new findings on HIV escape mechanisms and HIV suppressor molecules. 1136 93

Human RANTES (CCL5) and MIP-1alpha (CCL3) bind and activate several CC chemokine receptors. RANTES is a high-affinity ligand for CCR1 and CCR5, and it binds CCR3 with moderate affinity and CCR4 with low affinity. MIP-1alpha has similar binding characteristics to RANTES except that it does not bind to CCR3. Here we have generated a chimera of human MIP-1alpha and RANTES, called MIP/RANTES, consisting of the eight amino terminal residues of MIP-1alpha preceding the CC motif, and the remainder of the sequence is RANTES. The chimera is able to induce chemotaxis of human monocytes. MIP/RANTES has >100-fold reduction in binding to CCR1 and does not bind to CCR3 but retains full, functional binding to CCR5. It has equivalent affinity for CCR5 to MIP-1alpha and RANTES, binding with an IC(50) of 1.12 nM, and is able to mobilize calcium and induce endocytosis of CCR5 in PBMC in a manner equi-potent to RANTES. It also retains the ability to inhibit R5 using HIV-1 strains. Therefore, we conclude that the amino terminus of RANTES is not involved in CCR5 binding, but it is essential for CCR1 and CCR3.
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PMID:A chimeric MIP-1alpha/RANTES protein demonstrates the use of different regions of the RANTES protein to bind and activate its receptors. 1140 85

Chemokines are implicated in the pathogenesis of alcoholic liver disease and human immunodeficiency virus-1 (HIV-1) infection. Thus, this work examined the regulation of chemokines --i.e., cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2)--produced by hepatocytes after HIV-1 glycoprotein 120 (gp120) vaccination in Wistar rats fed with ethanol for 30 weeks. HIV-1 gp120 in complete Freund's adjuvant was given by intrainguinal route at a dose of 5 g/kg, followed by two booster shots in incomplete Freund's adjuvant at a weekly interval. Samples were taken 1 week after the last injection was given. Results show that anti-HIV-1 gp120 antibody titer was suppressed by 40% in the ethanol-fed rats, compared with findings in the parallel controls. However, serum CINC and MIP-2 levels were more elevated in the ethanol-fed rats than in the pair-fed group. The likely sources of these chemokines are the hepatocytes. After HIV-1 gp120 treatment, isolated hepatocytes obtained from the ethanol-fed group produced more CINC and MIP-2 than did those of pair-fed rats. Concomitantly, mRNA expression for these two chemokines and hepatic sequestration of neutrophils were upregulated. Ethanol feeding alone suppressed chemokine release, but it did not alter mRNA expression in isolated hepatocytes. Administration of Freund's adjuvant (without HIV-1 gp120) did not induce chemokine release in vivo and did not prime isolated hepatocytes for enhanced chemokine production in vitro. These results show that chronic ethanol intoxication affects the ability of the host to respond to HIV-1 gp120 vaccination.
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PMID:Chronic ethanol intoxication enhances the production of cytokine-induced neutrophil chemoattractant and macrophage inflammatory protein-2 by hepatocytes after human immunodeficiency virus-1 glycoprotein 120 vaccination. 1152 80


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