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) replicates more efficiently in Mycobacterium tuberculosis (MTB)-infected macrophages than in uninfected controls. We investigated whether this may be partly explained by changes in expression of CCR5 in the course of mycobacterial infection, as this molecule has been shown to be a coreceptor for HIV entry. Since the lung is the preferential organ of HIV replication in the course of tuberculosis, we preliminarily analyzed beta-chemokine receptor expression in alveolar macrophages from patients with active tuberculosis, using flow cytometry based on an MIP-1alpha ligand-biotin/avidin-FITC detection system. Increased MIP-1alpha receptor (MIP-1alphaR) expression in alveolar macrophages from infected patients was observed whereas no detectable expression could be revealed in uninfected controls. Since MIP-la can also bind CCR1 and CCR4, the presence of CCR5 mRNA was investigated in bronchoalveolar lavage (BAL) cells and detected in alveolar macrophages from tuberculosis patients only. The study was then extended to in vitro MTB-infected macrophages. Monocyte-derived macrophages (MDMs) were left to differentiate for 7 days before MTB H37Rv infection, and CCR5 expression was monitored, by using a specific monoclonal antibody, on days 1, 6, and 11 after infection. Increased CCR5 expression in MTB-infected macrophages was observed, with a peak on day 6 (64% in MTB-infected versus 33% in control cultures) and a decrease by day 11 (25% in MTB infected versus 13% in control cultures). These results show that CCR5 expression is enhanced in the course of in vitro MTB infection and during active pulmonary tuberculosis.
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PMID:Expression of CCR5 is increased in human monocyte-derived macrophages and alveolar macrophages in the course of in vivo and in vitro Mycobacterium tuberculosis infection. 1040 23

Fifty percent of individuals infected with human immunodeficiency virus type 1 (HIV-1) progress to AIDS in the presence of only non-syncytium-inducing (NSI) variants. These rapidly replicating NSI isolates are associated with a high viral load. The question of whether disease progression in the absence of syncytium-inducing (SI) HIV-1 variants is associated with an expansion of the coreceptor repertoire of NSI HIV-1 variants was studied. Biological HIV-1 clones were isolated both early and late in infection from progressors and long-term survivors with wild-type or mutant CCR5 or CCR2b genotypes and analyzed for their capacity to use CCR1, CCR2b, CCR3, CCR5, and CXCR4 on U87 cells coexpressing CD4. All HIV-1 clones were restricted to the use of CCR5. Absent replication of all HIV-1 clones in peripheral blood mononuclear cells from a CCR5 Delta32 homozygous blood donor confirmed this result. These findings indicate that an expanded coreceptor repertoire of HIV-1 is not a prerequisite for a progressive clinical course of HIV-1 infection.
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PMID:Adaptation to promiscuous usage of chemokine receptors is not a prerequisite for human immunodeficiency virus type 1 disease progression. 1047 37

Chemokine receptors serve as portals of entry for certain intracellular pathogens, most notably human immunodeficiency virus (HIV). Myxoma virus is a member of the poxvirus family that induces a lethal systemic disease in rabbits, but no poxvirus receptor has ever been defined. Rodent fibroblasts (3T3) that cannot be infected with myxoma virus could be made fully permissive for myxoma virus infection by expression of any one of several human chemokine receptors, including CCR1, CCR5, and CXCR4. Conversely, infection of 3T3-CCR5 cells can be inhibited by RANTES, anti-CCR5 polyclonal antibody, or herbimycin A but not by monoclonal antibodies that block HIV-1 infection or by pertussis toxin. These findings suggest that poxviruses, like HIV, are able to use chemokine receptors to infect specific cell subtypes, notably migratory leukocytes, but that their mechanisms of receptor interactions are distinct.
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PMID:Use of chemokine receptors by poxviruses. 1058 63

RANTES (regulated on activation normal T cell expressed) has been found at elevated levels in biological fluids from patients with a wide range of allergic and autoimmune diseases and is able to attract several subtypes of leukocytes including eosinophils and monocytes into inflamed tissue. Amino-terminal modifications of RANTES produce receptor antagonists which are candidates for blocking this cellular recruitment. Met-RANTES has been shown to modulate inflammation in vivo, while AOP-RANTES is a potent inhibitor of R5 human immunodeficiency virus type 1 (HIV-1) strains and has been shown to down-modulate CCR5 and prevent recycling of the receptor. We have studied the effect of AOP-RANTES in eosinophil activation and have found that it is able to efficiently elicit eosinophil effector functions through CCR3, as measured by the release of reactive oxygen species and calcium mobilization, whereas Met-RANTES is inactive in these assays. AOP-RANTES is found to inhibit CCR3-mediated HIV-1 infection with moderate potency, in contrast to its potent inhibition of CCR5-mediated HIV-1 infection. Furthermore, we have investigated the abilities of these modified proteins to down-modulate CCR1 and CCR3 from the surface of monocytes and eosinophils. We show here that AOP-RANTES is much less effective than RANTES in down-modulation of CCR1. Surprisingly, recycling of CCR1 was minimal after incubation with RANTES while there was complete recycling with AOP-RANTES. In the case of CCR3, no significant difference was found between RANTES and AOP-RANTES in down-modulation and recycling. It therefore appears that trafficking of RANTES receptors follows different patterns, which opens up potential new targets for therapeutic intervention.
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PMID:Differential activation of CC chemokine receptors by AOP-RANTES. 1071 92

We describe a small molecule chemokine receptor antagonist, UCB35625 (the trans-isomer J113863 published by Banyu Pharmaceutical Co., patent WO98/04554), which is a potent, selective inhibitor of CCR1 and CCR3. Nanomolar concentrations of UCB35625 were sufficient to inhibit eosinophil shape change responses to MIP-1alpha, MCP-4, and eotaxin, while greater concentrations could inhibit the chemokine-induced internalization of both CCR1 and CCR3. UCB35625 also inhibited the CCR3-mediated entry of the human immunodeficiency virus-1 primary isolate 89.6 into the glial cell line, NP-2 (IC(50) = 57 nm). Chemotaxis of transfected cells expressing either CCR1 or CCR3 was inhibited by nanomolar concentrations of the compound (IC(50) values of CCR1-MIP-1alpha = 9.6 nm, CCR3-eotaxin = 93.7 nm). However, competitive ligand binding assays on the same transfectants revealed that considerably larger concentrations of UCB35625 were needed for effective ligand displacement than were needed for the inhibition of receptor function. Thus, it appears that the compound may interact with a region present in both receptors that inhibits the conformational change necessary to initiate intracellular signaling. By virtue of its potency at the two major eosinophil chemokine receptors, UCB35625 is a prototypic therapy for the treatment of eosinophil-mediated inflammatory disorders, such as asthma and as an inhibitor of CCR3-mediated human immunodeficiency virus-1 entry.
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PMID:A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. 1085 42

Chemokines are proinflammatory cytokines that play a role in leukocyte migration and activation. Recent reports showed that RANTES (regulated on activation normal T-cell expressed and secreted chemokine), eotaxin, macrophage-derived chemokine (MDC), and stromal cell-derived factor-1 (SDF-1) are NH(2)-terminally truncated by the lymphocyte surface glycoprotein and protease CD26/dipeptidyl peptidase IV (CD26/DPP IV). Removal of the NH(2)-terminal dipeptide resulted in impaired inflammatory properties of RANTES, eotaxin, MDC, and SDF-1. The potential CD26/DPP IV substrate macrophage inflammatory protein-1beta (MIP-1beta) and the related chemokine, LD78alpha (ie, one of the MIP-1alpha isoforms), were not affected by this protease. However, CD26/DPP IV cleaved LD78beta, a most potent CCR5 binding chemokine and inhibitor of macrophage tropic human immunodeficiency virus-1 (HIV-1) infection, into LD78beta(3-70). Naturally truncated LD78beta(3-70), but not truncated MIP-1beta, was recovered as an abundant chemokine form from peripheral blood mononuclear cells. In contrast to all other chemokines processed by CD26/DPP IV, LD78beta(3-70) had increased chemotactic activity in comparison to intact LD78beta. With a minimal effective concentration of 30 pmol/L, LD78beta(3-70) became the most efficient monocyte chemoattractant. LD78beta(3-70) retained its high capacity to induce an intracellular calcium increase in CCR5-transfected cells. Moreover, on CCR1 transfectants, truncated LD78beta(3-70) was 30-fold more potent than intact LD78beta. Thus, CD26/DPP IV can exert not only a negative but also a positive feedback during inflammation by increasing the specific activity of LD78beta. CD26/DPP IV-cleaved LD78beta(3-70) is the most potent CCR1 and CCR5 agonist that retains strong anti-HIV-1 activity, indicating the importance of the chemokine-protease interaction in normal and pathologic conditions. (Blood. 2000;96:1674-1680)
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PMID:Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78beta into a most efficient monocyte attractant and CCR1 agonist. 1096 62

To enter its target cells, human immunodeficiency virus (HIV) must interact with CD4 and one of a family of chemokine receptors. CCR5 is widely used by the virus in this context, and its ligands can prevent HIV entry. Amino-terminal modified chemokine variants, in particular AOP-RANTES (aminooxypentane-linked regulated on activation normal T cell expressed and secreted), exhibit enhanced HIV entry inhibition. We have previously demonstrated that a non-allelic isoform of macrophage inflammatory protein (MIP)-1alpha, termed MIP-1alphaP, is the most active naturally occurring inhibitor of HIV entry known. Here we report the properties of a variant of MIP-1alphaP with an AOP group on the amino terminus. We show that, like RANTES, the addition of AOP to MIP-1alphaP enhances its interactions with CCR1 and CCR5, allows more effective internalization of CCR5, and increases the ligand's potency as an inhibitor of HIV entry through CCR5. Importantly, AOP-MIP-1alphaP is about 10-fold more active than AOP-RANTES at inhibiting HIV entry, making it the most effective chemokine-based inhibitor of HIV entry through CCR5 described to date. Surprisingly, the enhanced receptor interactions of AOP-MIP-1alphaP do not translate into increased chemotaxis or coupling to calcium ion fluxes, suggesting that this protein should be viewed as a partial, rather than a full, agonist for CCR1 and CCR5.
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PMID:Aminooxypentane addition to the chemokine macrophage inflammatory protein-1alpha P increases receptor affinities and HIV inhibition. 1100 16

The CXC chemokine receptor CXCR4 was the first molecule identified as a coreceptor working in conjunction with CD4 to mediate cellular entry for the human immunodeficiency virus (HIV-1). Since that original discovery, 11 other seven-mtransmembrane domain molecules, many of which are chemokine receptors, have been shown to facilitate HIV entry into cells. These include CCR5, CCR3, CCR2, CCR1, CCR8, CX3CR1, STRL33 (BONZO), GPR15 (BOB), GPR1, US28, and APJ. In studies done by this and other labs, CCR3, CCR5, and CXCR4 have been identified in CNS microglia and several laboratories, including ours, have shown that CXCR4 is expressed in neurons. Neuronal expression of CCR2, CCR3, and CCR5 has been less consistent. We performed a semiquantitative immunohistochemical analysis of the expression of CCR2, CCR3, CCR5, and CXCR4 in 23 regions of the brain and in two sections of the spinal cord. Hippocampal neurons were positive for CCR2, CCR3, and CXCR4, but not for CCR5. In other regions of the brain, neurons, and glial cells reacted with anti-CCR2, anti-CCR3, and anti-CXCR4 antibodies, whereas only glial cells (primarily microglia) were positive for CCR5. The areas of highest expression, however, seem to be subcortical regions and the limbic system. The limbic system plays a key role in memory, and the presence of CXCR4-which can bind the viral envelope protein gp120-min a subset of neurons from this system may play a role in the development of HIV-related dementia.
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PMID:Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. 1111 60

CC chemokine receptor 5 (CCR5) is a high-affinity receptor for macrophage inflammatory protein (MIP)-1beta and functions as the major coreceptor for entry of macrophage-tropic (M-tropic) human immunodeficiency virus type 1 (HIV-1). To evaluate the role of transmembrane domains (TM) in the receptor function of CCR5, the seventh transmembrane domain (TM7) was examined in a series of chimeric receptor constructs including CCR5TM (CCR5 backbone/CCR5 TM7 replaced with CCR1 TM7) and mutants of CCR5TM. The CCR5TM chimera exhibited a dramatic reduction in receptor activation, as well as little or no MIP-1beta binding. Further mutational analysis revealed that Met 287 in TM7 of CCR5 is a critical molecular determinant for both MIP-1beta binding and receptor activation. Interestingly, all of the chimeric/mutated receptors were biologically active in an HIV-1 coreceptor fusion assay, demonstrating that chemokine binding is independent of HIV-1 coreceptor activity.
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PMID:The seventh transmembrane domain of cc chemokine receptor 5 is critical for MIP-1beta binding and receptor activation: role of MET 287. 1123 3

Both simian and human immunodeficiency viruses (SIV and HIV) utilize chemokine receptors, with or without CD4, as portals for entry into susceptible cells. In this report, we present the cloning and comparison of 11 rhesus macaque chemokine receptors and receptor-like proteins (CCR1, CCR2b, CCR3, CCR5, CCR8, CXCR4, STRL33, GPR1, GPR15, APJ, and CRAM-A/B), the human counterparts of which have been previously shown to be utilized by SIV for entry.
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PMID:Identification and comparison of eleven rhesus macaque chemokine receptors. 1146 84


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