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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CCR5 gene encodes a cell-surface chemokine receptor molecule that serves as a co-receptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). A mutation in this gene may alter the expression or the function of the protein product, thereby altering chemokine binding and/or signalling or HIV-1 infection of cells that normally express CCR5 protein. Individuals homozygous for a 32-bp deletion allele of CCR5 (CCR5 delta32), heritable as a Mendelian trait, are relatively resistant to HIV-1 infection. The CCR5 delta32 mutation is present in the Caucasian population at different frequencies. The aim of this study was to investigate the frequency of truncated alleles of the CCR5 delta32 gene in a Sicilian population, as the interpopulation variation in CCR5 delta32 frequency may be a significant factor in the prediction of AIDS endemicity in future studies. We examined 901 healthy individuals from several Sicilian provinces. We found a mean (+/- standard deviation) delta32 allele frequency (fr) of 0.04 +/- 0.012. The highest value was observed in the province of Messina, with a mean delta32 allele frequency of 0.06 +/- 0.024, where we collected samples from a cohort of 114 HIV-1-infected individuals. The observed frequency amongst these patients was quite low (fr = 0.03 +/- 0.031) compared to the healthy population, although the difference was not statistically significant.
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PMID:Distribution of the mutated delta 32 allele of the CCR5 gene in a Sicilian population. 1593 25

Despite a number of recent therapeutic advancements, there remains an urgent need to develop a new class of therapy for human immunodeficiency virus (HIV). This review summarises attempts at blocking HIV binding and entry into host cells, an approach that would provide theoretical advantages over the currently available drugs targeting enzymes (reverse transcriptase and protease), brought into play in the later stages of the viral life cycle. The multi-step process of HIV entry into cells, binding of the surface glycoprotein (gp120) to the CD4 receptor and one of the chemokine receptors, followed by the membrane fusion step mediated by the transmembrane glycoprotein (gp41), has recently been understood with greater clarity. The importance of the chemokine co-receptors, such as CCR5 and CXCR4, for HIV entry may help to explain the limitations of earlier approaches using recombinant soluble CD4 or polyanionic compounds to interfere non-specifically with HIV glycoprotein function. Conversely, previous investigations demonstrating the in vitro inhibitory potential of beta chemokines themselves, or small-molecule chemokine receptor inhibitors, may now be understood in a new light. Promising laboratory investigations (particularly with the bicyclam compound, AMD3100) and extensive pharmaceutical experience with related chemical structures suggest great potential for targeting the chemokine nexus. Finally, the evolution of transmembrane peptide investigations from the laboratory to early clinical trials is described. Clinical trials of T-20, a peptide designed to inhibit gp-41 mediated fusion, have provided 'proof of concept' that therapeutics targeting a viral entry event can result in safe and potent inhibition of viral replication. The author speculates on the future prospect of using novel therapeutic strategies aimed at the initial interactions between HIV and target cells, in the battle against AIDS.
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PMID:Therapeutic potential of blocking HIV entry into cells: focus on membrane fusion inhibitors. 1599 42

The chemokine receptors CXCR4 and CCR5 are the main coreceptors used by the T-cell-tropic (CXCR4-using, X4) and macrophage-tropic (CCR5-using, R5) HIV-1 strains, respectively, for entering their CD4+ target cells. In this review, we focus on the function of these chemokine receptors in HIV infection and their role as novel targets for viral inhibition. Besides some modified chemokines with antiviral activity, several low-molecular weight CCR5 and CXCR4 antagonistic compounds have been described with potent antiviral activity. The best CXCR4 antagonists described are the bicyclam derivatives, which consistently block X4 but also R5/X4 viral replication in PBMCs. We believe that chemokine receptor antagonists will become important new antiviral drugs to combat AIDS. Both CXCR4 and CCR5 chemokine receptor inhibitors will be needed in combination and even in combinations of antiviral drugs that also target other aspects of the HIV replication cycle to obtain optimum antiviral therapeutic effects.
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PMID:HIV chemokine receptor inhibitors as novel anti-HIV drugs. 1600 54

Human immunodeficiency virus type 1 (HIV-1) infection is initiated by binding of the viral envelope glycoprotein gp120 to CD4 followed by a chemokine receptor, but these interactions may also take place independently from infection. gp120 stimulation of primary human macrophages is known to trigger production of cytokines implicated in pathogenesis, particularly tumor necrosis factor alpha (TNF-alpha), but the mechanisms have not been determined. We sought to define the pathways responsible for TNF-alpha secretion by monocyte-derived macrophages (MDM) following HIV-1 gp120 stimulation. MDM exposure to recombinant macrophage-tropic (R5) gp120 led to dose- and donor-dependent release of TNF-alpha, which was cyclohexamide-sensitive and associated with up-regulated message. Pretreatment with specific inhibitors of the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1/2 (ERK-1/2; PD98059, U0126) and p38 (SB202190, PD169316) inhibited the secretion of TNF-alpha. gp120-elicited TNF-alpha production was also blocked by phosphatidylinositol-3 kinase (PI-3K) inhibitors (wortmannin, LY294002). Moreover, PI-3K inhibition ablated gp120-induced phosphorylation of p38 and ERK-1/2. The response was inhibited by a CC chemokine receptor 5 (CCR5)-specific antagonist, indicating that CCR5 was in large part responsible. These results indicate that gp120-elicited TNF-alpha production by macrophages involves chemokine receptor-mediated PI-3K and MAPK activation, that PI-3K is an upstream regulator of MAPK in this pathway, and that p38 and ERK-1/2 independently regulate TNF-alpha production. These gp120-triggered signaling pathways may be responsible for inappropriate production of proinflammatory cytokines by macrophages, which are believed to play a role in immunopathogenesis and in neurological sequelae of AIDS.
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PMID:HIV-1 gp120-induced TNF-{alpha} production by primary human macrophages is mediated by phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein (MAP) kinase pathways. 1608 99

The human immunodeficiency virus type 1 (HIV-1) infects cells within mucosal tissues, including those of the female reproductive tract (FRT). The mechanism of viral transmission within the FRT and the mode of viral spread to the periphery are not completely understood. We performed phenotypical analyses and infectivity studies of primary FRT cells to identify potential targets of infection within the FRT. Our findings indicate that expression of HIV-1 receptors and coreceptors in the FRT varies as a function of menstrual-cycle stage, suggesting that sex hormone levels may influence a woman's susceptibility to infection by HIV-1. Moreover, HIV-1 strains that utilize the CXCR4 chemokine receptor for infectivity are able to undergo reverse transcription, integration, viral DNA transcription, and viral release, whereas viral strains that utilize CCR5 do not undergo these early replicative events, and are only released unmodified from these cells. This indicates that several mechanisms for viral infection and transmission are present throughout the FRT.
Curr HIV/AIDS Rep 2005 Feb
PMID:HIV-1 infection of the female reproductive tract. 1609 Dec 47

There is a growing interest in the role of chemokines and their receptors in the determination of mast cell tissue localization and how chemokines regulate mast cell function. At least nine chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CX3CR1, CCR1, CCR3, CCR4 and CCR5) have been described to be expressed by human mast cells of different origins. Seven chemokines (CXCL1, CXCL5, CXCL8, CXCL14, CX3CL1, CCL5 and CCL11) have been shown to act on some of these receptors and to induce mast cell migration. Mast cells have a unique expression pattern of CCR3, CXCR1 and CXCR2. These receptors are mainly expressed intracellularly on cytoplasmic membranes. Upon an allergic activation, CCR3 expression is increased on the cell surface and the cell becomes vulnerable for CCL11 treatment. Chemokines do not induce mast cell degranulation but CXCL14 causes secretion of de novo synthesized CXCL8. Because of the expression of CCR3, CCR5 and CXCR4 on mast cell progenitors, these cells are susceptible to HIV infection and mast cells might therefore be a persistent HIV reservoir in AIDS. In this review, we summarize the knowledge about chemokine receptor expression and function on mast cells.
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PMID:Chemokine receptor expression by mast cells. 1610 68

Extracellular Tat protein of HIV-1 activates virus replication in HIV-infected cells and induces a variety of host factors in the uninfected cells, some of which play a critical role in the progression of HIV infection. The cysteine-rich and arginine-rich basic domains represent key components of the HIV-Tat protein for pathogenic effects of the full-length Tat protein and, therefore, could be ideal candidates for the development of a therapeutic AIDS vaccine. The present study describes selective modifications of the side-chain functional groups of cysteine and arginine amino acids of these HIV-Tat peptides to minimize the pathogenic effects of these peptides while maintaining natural peptide linkages. Modification of cysteine by introducing either a methyl or t-butyl group in the free sulfhydryl group and replacing the guanidine group with a urea linkage in the side chain of arginine in the cysteine-rich and arginine-rich Tat peptide sequences completely blocked the ability of these peptides to induce HIV replication, chemokine receptor CCR-5 expression, and NF-kappaB activity in monocytes. Such modifications also inhibited angiogenesis and migration of Kaposi's sarcoma cells normally induced by Tat peptides. Such chemical modifications of the cysteine-rich and arginine-rich peptides did not affect their reactivity with antibodies against the full-length Tat protein. With an estimated 40 million HIV-positive individuals worldwide and approximately 4 million new infections emerging every year, a synthetic subunit HIV-Tat vaccine comprised of functionally inactive Tat domains could provide a safe, effective, and economical therapeutic vaccine to reduce the progression of HIV disease.
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PMID:Selective side-chain modification of cysteine and arginine residues blocks pathogenic activity of HIV-1-Tat functional peptides. 1625 45

Encephalitis and dementia associated with acquired immunodeficiency syndrome (AIDS) are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood-brain barrier (BBB) disruption, and eventual loss of neurons. Little is known about whether human immunodeficiency virus 1 (HIV-1) infection of leukocytes affects their ability to transmigrate in response to chemokines and to alter BBB integrity. We now demonstrate that HIV infection of human leukocytes results in their increased transmigration across our tissue culture model of the human BBB in response to the chemokine CCL2, as well as in disruption of the BBB, as evidenced by enhanced permeability, reduction of tight junction proteins, and expression of matrix metalloproteinases (MMP)-2 and MMP-9. HIV-infected cells added to our model did not transmigrate in the absence of CCL2, nor did this condition alter BBB integrity. The chemokines CXCL10/interferon-gamma-inducible protein of 10 kDa, CCL3/macrophage inflammatory protein-1alpha, or CCL5/RANTES (regulated on activation normal T-cell expressed and secreted) did not enhance HIV-infected leukocyte transmigration or BBB permeability. The increased capacity of HIV-infected leukocytes to transmigrate in response to CCL2 correlated with their increased expression of CCR2, the chemokine receptor for CCL2. These data suggest that CCL2, but not other chemokines, plays a key role in infiltration of HIV-infected leukocytes into the CNS and the subsequent pathology characteristic of NeuroAIDS.
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PMID:CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. 1643 95

The unexpected encounter, 10 years ago, between human immunodeficiency virus (HIV) and the chemokine system has dramatically advanced our understanding of the pathogenesis of AIDS, opening new perspectives for the development of effective prophylactic and therapeutic measures. To initiate infection, the HIV-1 external envelope glycoprotein, gp120, sequentially interacts with two cellular receptors, CD4 and a chemokine receptor (or coreceptor) like CCR5 or CXCR4. This peculiar two-stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. The differential use of CCR5 and CXCR4 defines three HIV-1 biological variants (R5, R5X4, X4), which vary in their prevalence during the disease course. The evolutionary choice of HIV-1 to exploit chemokine receptors as cellular entry gateways has turned their chemokine ligands into endogenous antiviral factors that variably modulate viral transmission, disease progression and vaccine responses. Likewise, the natural history of HIV-1 infection is influenced by specific polymorphisms of chemokine and chemokine-receptor genes. The imminent clinical availability of coreceptor-targeted viral entry inhibitors raises new hope for bridging the gap towards a definitive cure of HIV infection.
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PMID:HIV and the chemokine system: 10 years later. 1643 64

In the immature hippocampus, the giant depolarizing potentials (GDPs) are recurrent network-driven synaptic events generated by gamma-aminobutyric acid (GABA), which in neonatal life is depolarizing and excitatory. The GDPs enable a high degree of synchrony in immature neurons and participate in activity-dependent growth and synapse formation. To understand how human immunodeficiency virus type one (HIV-1) infection in the immature brain impairs brain growth and development, we studied the effects of HIV-1 envelope glycoprotein, gp120, a viral toxin shed in abundance by infected cells, on spontaneous occurring GDPs recorded in the CA3 pyramidal cells in neonatal (P2-P6) Sprague-Dawley rat hippocampal slices using whole-cell patch technique. Bath application of gp120 produced a sustained enhancement of GDP frequency in a concentration-dependent manner without affecting passive membrane properties, suggesting that the site of action is most likely on neural network, other than on the recorded neurons. The gp120-induced enhancement of GDPs was blocked by T140, a highly specific antagonist for the chemokine receptor, CXCR4, indicating the involvement of CXCR4 in the gp120-induced increase of GDPs. Bath application of stromal cell-derived factor-1alpha (SDF-1alpha), the only CXCR4 ligand, mimicked the effects of gp120 on GDPs, supporting the engagement of CXCR4 receptors in the gp120-induced increase of GDP occurrence. Further studies revealed the involvement of protein kinase A/C in the gp120-induced enhancement of GDPs. These results demonstrate that gp120 enhances GDPs in the neonatal rat hippocampus. This enhancement may cause an excessive increase in intracellular calcium and resultant neuronal injury, leading to retardation of the brain and behavioural development as seen in paediatric AIDS patients.
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PMID:HIV-1 gp120 enhances giant depolarizing potentials via chemokine receptor CXCR4 in neonatal rat hippocampus. 1655 76


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