Showing papers on "Chemokine receptor CCR5 published in 2002"
TL;DR: The polymorphism MDR1 3435 C/T predicts immune recovery after initiation of antiretroviral treatment, which suggests that P-glycoprotein has an important role in admittance of antifiltration drugs to restricted compartments in vivo.
673 citations
TL;DR: It is shown that DC-SIGN mediates rapid internalization of intact HIV into a low pH nonlysosomal compartment and reduces viral uptake and abrogated the trans-enhancement of T cell infection.
533 citations
TL;DR: It is concluded that glioma cells express a predominant chemokine receptor, CXCR4, and that this functions to regulate survival in part through activating pathways such as Akt.
387 citations
TL;DR: It is demonstrated, for the first time, that Gro-alpha was able to induce interferon-gamma secretion from transduced T cells, thereby extending the knowledge of other potential functions of CXCR2 and the feasibility of redirecting the migration properties of T cells toward chemokines secreted by tumors.
Abstract: T-cell-based immunotherapies provide a promising means of cancer treatment although durable antitumor responses are infrequent. A potential reason for these shortcomings may lie in the observed lack of trafficking of specific T cells to tumor. Our increasing knowledge of the process of trafficking involving adhesion molecules and chemokines affords us the opportunity to intervene and correct deficiencies in this process. Chemokines can be expressed by a range of tumors and may serve as suitable targets for directing specific T cells toward tumor. We initially sought to identify which chemokines were produced by a range of human tumor cell lines, and which chemokines and chemokine receptors were expressed by cultured T cells. We identified two chemokines: Growth-Regulated Oncogene-α (Gro-α; CXCL1) and Regulated on Activation Normal T Cell-Expressed and Secreted (RANTES; CCL5), to be secreted by several human tumor cell lines. Expression was also detected in fine-needle aspirates of melanoma from patients. ...
260 citations
TL;DR: The data indicate that constitutive receptor homo-oligomerization has a biologically relevant significance and might be involved in the process of receptor biosynthesis.
223 citations
TL;DR: The reduced ability of cord DCs to attain a fully mature adult phenotype, and to activate naive CD4+ T cells to produce IFN‐γ, suggests that they are intrinsically preprogrammed against the generation of Th‐1 immune responses.
Abstract: Dendritic cells (DCs) were derived from human peripheral blood monocytes or cord blood monocytes cultured in the presence of IL-4 and GM-CSF. Adult and cord DCs were observed to have comparable immature phenotypes. However, the increase in surface expression of HLA-DR and CD86 after addition of LPS was significantly attenuated in cord DCs, with CD25 and CD83 expression also markedly reduced. Cord DCs were also unable to produce IL-12p70, failed to down-regulate expression of the chemokine receptor CCR5 and induced lower levels of IFN-gamma production from allogeneic naive CD4+ T cells than their adult counterparts. In contrast, the kinetics of the production of TNF-alpha and IL-10 in response to LPS stimulation was comparable to adult DCs. The reduced ability of cord DCs to attain a fully mature adult phenotype, and to activate naive CD4+ T cells to produce IFN-gamma, suggests that they are intrinsically preprogrammed against the generation of Th-1 immune responses.
206 citations
TL;DR: Using inhibitors of vesicle transport in the cell, it was found that the CCR5 recycling pathway is independent of the Golgi apparatus and late endosomes and Protein synthesis is not involved in receptor recovery, suggesting it seems likely that after internalization, C CR5 is directed to early endosome and subsequently recycled to the cell surface.
164 citations
TL;DR: It is found that cholesterol extraction by hydroxypropyl-beta-cyclodextrin (BCD) significantly reduced the binding and signaling of macrophage inflammatory protein 1 beta (MIP-1 beta) using CCR5-expressing CEM-NKR T cells, demonstrating that cholesterol and lipid rafts are important for the maintenance of the C CR5 conformation and are necessary for both the binding of this chemokine receptor.
133 citations
TL;DR: The results suggest that oligomerization of chemokine receptor CCR5 and opioid receptors on the cell membrane of human or monkey lymphocytes may modulate receptor functions.
131 citations
TL;DR: Opiates enhance HIV R5 strain infection of macrophages through the downregulation of β-chemokine production and upregulation of CCR5 receptor expression and may have an important role in HIV immunopathogenesis.
Abstract: Background Injection drug use remains a significant risk for acquiring HIV infection. The mechanisms by which morphine enhances HIV infection of human immune cells are largely unknown. Objective In this study, we sought to determine the possible mechanisms by which morphine upregulates HIV infection of human blood monocyte-derived macrophages (MDM). Methods In this study, MDM were infected with the R5, X4, and R5X4 HIV strains. HIV replication was determined by performing reverse transcriptase activity assays. HIV receptors were determined by performing reverse transcriptase polymerase chain reactions and flow cytometry assays. β-chemokines were analyzed by performing enzyme-linked immunosorbent assays. In addition, HIV R5 strain and murine leukemia virus envelope-pseudotyped HIV infection was performed to determine whether morphine affects HIV infection of macrophages at entry level. Results Morphine significantly enhanced HIV R5 strain infection of MDM but had little effect on X4 strain infection. The macrophage-tropic R5 strain envelope-pseudotyped HIV infection was markedly increased by morphine, whereas murine leukemia virus envelope-pseudotyped HIV infection was not significantly affected. Furthermore, morphine significantly upregulated CCR5 receptor expression and inhibited the endogenous production of β-chemokines in MDM. The opioid receptor antagonist naltrexone blocked the effects of morphine on the production of β-chemokines. Conclusion Opiates enhance HIV R5 strain infection of macrophages through the downregulation of β-chemokine production and upregulation of CCR5 receptor expression and may have an important role in HIV immunopathogenesis.
117 citations
TL;DR: In this study, insight is gained into the mechanism(s) of neurotoxicity elicited by the viral glycoprotein using the human neuroblastoma CHP100 cell line as an experimental model and suggests that the neuronal injury observed in HIV‐1 infection could be due to direct (or indirect) interactions between the viral protein gp120 and chemokine and/or NMDA receptors.
Abstract: To infect target cells, the human immunodeficiency virus (HIV) type I (HIV-1) must engage not only the well-known CD4 molecule, but it also requires one of several recently described coreceptors. In particular, the CXCR4 (LESTR/fusin) receptor allows fusion and entry of T-tropic strains of HIV, whereas CCR5 is the major coreceptor used by primary HIV-1 strains that infect macrophages and CD4(+) T-helper cells (M-tropic viruses). In addition, the alpha chemokine SDF1alpha and the beta chemokines MIP1alpha, MIP1beta, and RANTES, natural ligands of CXCR4 and CCR5, respectively, are potent soluble inhibitors of HIV infection by blocking the binding between the viral envelope glycoprotein gp120 and the coreceptors. Approximately two-thirds of individuals with acquired immunodeficiency syndrome (AIDS) show neurologic complications, which are referred to a syndrome called AIDS dementia complex or HIV-1-associated cognitive/motor complex. The HIV-1 coat glycoprotein gp120 has been proposed as the major etiologic agent for neuronal damage, mediating both direct and indirect effects on the CNS. Furthermore, recent findings showing the presence of chemokine receptors on the surface of different cell types resident in the CNS raise the possibility that the association of gp120 with these receptors may contribute to the pathogenesis of neurological dysfunction. Here, we address the possible role of alpha and beta chemokines in inhibiting gp120-mediated neurotoxicity using the human neuroblastoma CHP100 cell line as an experimental model. We have previously shown that, in CHP100 cells, picomolar concentrations of gp120 produce a significant increase in cell death, which seems to proceed through a Ca(2+) - and NMDA receptor-dependent cascade. In this study, we gained insight into the mechanism(s) of neurotoxicity elicited by the viral glycoprotein. We found that CHP100 cells constitutively express both CXCR4 and CCR5 receptors and that stimulation with phorbol 12-myristate 13-acetate down-regulates their expression, thus preventing gp120-induced cell death. Furthermore, all the natural ligands of these receptors exerted protective effects against gp120-mediated neuronal damage, although with different efficiencies. These findings, together with our previous reports, suggest that the neuronal injury observed in HIV-1 infection could be due to direct (or indirect) interactions between the viral protein gp120 and chemokine and/or NMDA receptors.
TL;DR: Results indicate that glial cells in culture functionally express the chemokine receptor CXCR3, which might contribute to an intercellular signalling system in the CNS related to pathological conditions.
TL;DR: Modified chemokines, monoclonal antibodies and small chemical antagonists, as well as a number of gene therapy approaches have been developed in this frame, some of which lead to nonfunctional receptors or otherwise influence AIDS progression.
Abstract: Chemokines and chemokine receptors play a crucial role in the trafficking of leukocyte populations across the body, and are involved in the development of a large variety of human diseases. CCR5 is the main coreceptor used by macrophage (M)-tropic strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2, which are responsible for viral transmission. CCR5 therefore plays an essential role in HIV pathogenesis. A number of inflammatory CC-chemokines, including MIP-1 alpha, MIP-1 beta, RANTES, MCP-2, and HCC-1[9-74] act as CCR5 agonists, while MCP-3 is a natural antagonist of the receptor. CCR5 is mainly expressed in memory T-cells, macrophages, and immature dendritic cells, and is upregulated by proinflammatory cytokines. It is coupled to the Gi class of heterotrimeric G-proteins, and inhibits cAMP production, stimulates Ca2+ release, and activates PI3-kinase and MAP kinases, as well as other tyrosine kinase cascades. A mutant allele of CCR5, CCR5 delta 32 is frequent in populations of European origin, and encodes a nonfunctional truncated protein that is not transported to the cell surface. Homozygotes for the delta 32 allele exhibit a strong, although incomplete, resistance to HIV infection, whereas heterozygotes display delayed progression to acquired immunodeficiency syndrome (AIDS). Many other alleles, affecting the primary structure of CCR5 or its promoter have been described, some of which lead to nonfunctional receptors or otherwise influence AIDS progression. CCR5 is considered as a drug target in the field of HIV, but also in a growing number of inflammatory diseases. Modified chemokines, monoclonal antibodies and small chemical antagonists, as well as a number of gene therapy approaches have been developed in this frame.
TL;DR: The high number of CX3CR1-positive inflammatory cells in various disease entities is consistent with its having a role in the accumulation of intrarenal inflammatory cells, but does not provide evidence of specificity of leukocytes bearing this receptor for specific types of injury.
TL;DR: Advances in HIV immunology research are currently being applied in the development of prophylactic and therapeuticvaccines and cytotoxic T cells in the control of HIV disease.
Abstract: Great progress has been made with respect to our understanding of the immunopathogenesis of AIDS and the infectious agent, HIV, that causes the disease. HIV, a human retrovirus with tropism for CD4(+) T cells and monocytes, induces a decrease of T-cell counts, T-cell dysfunction, and, ultimately, immunodeficiency. HIV also causes B-cell dysfunction characterized by polyclonal activation, hypergammaglobulinemia, and lack of specific antibody responses. Chemokine receptors-mainly CCR5 and CXCR4-have been found to be necessary for viral entry into the host cell, a step that can be inhibited by chemokine-related molecules that are ligands for those receptors. After HIV infection, a strong cellular immunity develops and partially controls viral replication. It can take several years for HIV infection to become clinically evident. Studies in long-term nonprogressors have shown the determinant roles of both helper and cytotoxic T cells in the control of HIV disease. Advances in HIV immunology research are currently being applied in the development of prophylactic and therapeutic vaccines.
TL;DR: Transgenic rats expressing the appropriate human receptor complex are promising candidates for a small animal model of HIV-1 infection.
Abstract: The development of a permissive small animal model for the study of human immunodeficiency virus type (HIV)-1 pathogenesis and the testing of antiviral strategies has been hampered by the inability of HIV-1 to infect primary rodent cells productively. In this study, we explored transgenic rats expressing the HIV-1 receptor complex as a susceptible host. Rats transgenic for human CD4 (hCD4) and the human chemokine receptor CCR5 (hCCR5) were generated that express the transgenes in CD4+ T lymphocytes, macrophages, and microglia. In ex vivo cultures, CD4+ T lymphocytes, macrophages, and microglia from hCD4/hCCR5 transgenic rats were highly susceptible to infection by HIV-1 R5 viruses leading to expression of abundant levels of early HIV-1 gene products comparable to those found in human reference cultures. Primary rat macrophages and microglia, but not lymphocytes, from double-transgenic rats could be productively infected by various recombinant and primary R5 strains of HIV-1. Moreover, after systemic challenge with HIV-1, lymphatic organs from hCD4/hCCR5 transgenic rats contained episomal 2–long terminal repeat (LTR) circles, integrated provirus, and early viral gene products, demonstrating susceptibility to HIV-1 in vivo. Transgenic rats also displayed a low-level plasma viremia early in infection. Thus, transgenic rats expressing the appropriate human receptor complex are promising candidates for a small animal model of HIV-1 infection.
TL;DR: M7-CCR5 is a useful tool for discriminating coreceptor internalization from binding site masking in the evaluation of small molecule inhibitors of HIV-1 entry and was surprisingly desensitized as efficiently as wild type, suggesting that desensitization does not require cytoplasmic tail phosphorylation.
TL;DR: An overview of the chemokine system is provided and the current literature implicating chemokines in veterinary pathophysiology is critically evaluated to highlight promising areas for further research and discuss how and why chemokin antagonists are viewed as next generation anti-inflammatory drugs for the 21st century.
TL;DR: Results demonstrate that both CCR1 and CCR4 are functional receptors on human mast cells with capacity to mediate migration towards CCL5.
TL;DR: It is reported that MIP-3α/CCL20-induced calcium flux and chemotaxis can be enhanced significantly on peripheral blood and tonsillar B cells after activation by cross-linking surface Ag receptors, and this data establish CCR6 as an efficacious receptor on human B cells.
Abstract: CCR6 is the only known receptor for the chemokine macrophage-inflammatory protein (MIP)-3α/CC chemokine ligand (CCL)20. We have shown previously that CCR6 is expressed on peripheral blood B cells, but CCR6 activity on these cells is low in in vitro assays. We report that MIP-3α/CCL20-induced calcium flux and chemotaxis can be enhanced significantly on peripheral blood and tonsillar B cells after activation by cross-linking surface Ag receptors. Of particular interest is the fact that the enhanced activity on B cells was not associated with an increase in CCR6 expression as assessed by levels of receptor mRNA, surface staining, or MIP-3α/CCL20 binding sites, or by a change in the affinity of the receptor for ligand. These data convincingly demonstrate that responses to a chemokine can be regulated solely by changes in the downstream pathways for signal transduction resulting from Ag receptor activation, and establish CCR6 as an efficacious receptor on human B cells.
TL;DR: The findings suggest that these chemokines may be responsible for modulating the process of infectious disease such as marginal periodontitis.
Patent•
08 Feb 2002TL;DR: In this article, a novel human protein called Human G-protein Chemokine Receptor (CCR5) HDGNR10, and isolated polynucleotides encoding this protein are described.
Abstract: The present invention relates to a novel human protein called Human G-protein Chemokine Receptor (CCR5) HDGNR10, and isolated polynucleotides encoding this protein. The invention is also directed to human antibodies that bind Human G-protein Chemokine Receptor (CCR5) HDGNR10 and to polynucleotides encoding those antibodies. Also provided are vectors, host cells, antibodies, and recombinant methods for producing Human G-protein Chemokine Receptor (CCR5) HDGNR10 and human anti-Human G-protein Chemokine Receptor (CCR5) HDGNR10 antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing and treating diseases, disorders, and/or conditions related to this novel human protein and these novel human antibodies.
TL;DR: Topical microbicides that interfere with HIV infection of Langerhans cells represent an attractive strategy for blocking sexual transmission of virus and dendritic cells have been targeted both ex vivo and in vivo to initiate and enhance HIV-specific immunity.
TL;DR: It is concluded that reduced CCR5 gene dosage rather than receptor sequestration is the major determinant of reduced C CR5 expression in cells from ccr5Δ32 heterozygotes.
TL;DR: Data indicate that chemokine receptor blockade with Met-RANTES does not affect leukocyte trafficking in chronic-relapsing EAE, and further analysis of the effects of chemokin receptor blockade may need to focus on leukocytes activation within the affected CNS as well as trafficking events.
TL;DR: Immunoneutralization of RANTES/CCL5 in sensitized CCR5+/+ and CCR 5‐/‐ mice for 12 days after the conidia challenge significantly reduced the peribronchial inflammation and airway hyperresponsiveness in comparison with control wild‐type and knockout mice at this time.
Abstract: SPECIFIC AIMSIn the present study, we explore the role of CC chemokine receptor 5 (CCR5) and RANTES/CCL5 in a murine model of chronic fungal asthma induced by an intrapulmonary challenge with Aspergillus fumigatus conidia.PRINCIPAL FINDINGS1. CCR5−/− mice limit the development of fungal asthma and only transiently express airway hyperresponsiveness (day 12) after fungal challengeAirway hyperresponsiveness was significantly decreased after conidia challenge in CCR5−/− mice, except at day 12, at which time the response to methacholine was comparable to control mice (Fig. 1⤻ ). A deficit in eosinophil chemoattractants, C10/CCL6 and eotaxin/CCL11, was noted in the CCR5 knockout strain at days 2 and 12, highlighting the importance of the CCR5 receptor in multiple facets of eosinophil recruitment. Control mice displayed obvious perivascular and peribronchial inflammation, while the inflammation in the CCR5-deficient mice was predominantly perivascular. The peribronchial inflammation that was noted in the CCR5−/...
TL;DR: Human cytomegalovirus encodes the G protein-coupled chemokine receptor homologue US28 that binds several CC chemokines and sequesters extracellular chemokites from the environment of infected cells and may provide a pathogenic mechanism for a potential decoy function of the virally encoded receptor.
TL;DR: By modulation of CXCR4 function, signaling through CCR5 may influence B lymphopoiesis by affecting the migration and maturation of B-cell progenitors in the bone marrow microenvironment.
TL;DR: The results reveal that in primary isolated brain MVECs viral attachment is mediated by a possible previously unknown receptor(s) or by cooperative activity of various receptors, and suggests a CD4-independent HIV/SIV entry/infection of these cells, which are the major cells constituting the human blood-brain barrier.
TL;DR: Results demonstrated that genital chlamydial infection is associated with a significant induction of chemokines and chemokine receptors that are involved in the recruitment of Th1 cells into the site of infection.
Abstract: Current design strategies for vaccines against certain microbial pathogens, including Chlamydia trachomatis, require the induction and targeting of specific immune effectors to the local sites of infection known as the mucosal effector sites. Chemokines and their receptors are important mediators of leukocyte trafficking and of the controlled recruitment of specific leukocyte clonotypes during host defense against infections and during inflammation. We analyzed the dynamics of chemokine and chemokine receptor expression in genital mucosae during genital chlamydial infection in a murine model to determine how these molecular entities influence the development of immunity and the clearance of infection. A time course study revealed an increase of up to threefold in the levels of expression of RANTES, monocyte chemotactic protein 1 (MCP-1), gamma-interferon-inducible protein 10 (IP-10), macrophage inflammatory protein 1α (MIP-1α), and intercellular adhesion molecule type 1 (ICAM-1) after genital infection with the C. trachomatis agent of mouse pneumonitis. Peak levels of expression of RANTES, MCP-1, and MIP-1α occurred by day 7 after primary infection, while those of IP-10 and ICAM-1 peaked by day 21. Expression levels of these molecules decreased by day 42 after primary infection, by which time all animals had resolved the infection, suggesting an infection-driven regulation of expression. A rapid upregulation of expression of these molecules was observed after secondary infection. The presence of cells bearing the chemokine receptors CCR5 and CXCR3, known to be preferentially expressed on Th1 and dendritic cells, was also synchronous with the kinetics of immune induction in the genital tract and clearance of infection. Results demonstrated that genital chlamydial infection is associated with a significant induction of chemokines and chemokine receptors that are involved in the recruitment of Th1 cells into the site of infection. Future studies will focus on how selective modulation of chemokines and their receptors can be used to optimize long-term immunity against Chlamydia.