|
| ||
|
|
||
CCR5
Kinds of CCR5 Terms modified by CCR5 Selected AbstractsIntrasplenic trafficking of natural killer cells is redirected by chemokines upon inflammationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008Claude Grégoire Abstract The spleen is a major homing site for NK cells. How they traffic to and within this site in homeostatic or inflammatory conditions is, however, mostly unknown. Here we show that NK cells enter the spleen through the marginal sinus and home to the red pulp via a pertussis toxin-insensitive mechanism. Upon inflammation induced by poly(I:C) injection or mouse cytomegalovirus infection, many NK cells left the red pulp while others transiently entered the white pulp, predominantly the T cell area. This migration was dependent on both CXCR3 and CCL5, suggesting a synergy between CXCR3 and CCR5, and followed the path lined by fibroblastic reticular cells. Thus, the entry of NK cells in the white pulp is limited by the expression of pro-inflammatory chemokines. This phenomenon ensures the segregation of NK cells outside of the white pulp and might contribute to the control of immunopathology. [source] Interaction between the CCR5 chemokine receptors and microbial HSP70EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Trevor Whittall Abstract Evidence is presented that the microbial 70-kD heat shock protein (HSP70) binds to CCR5 chemokine receptors in CCR5-transfected cell lines and in primary human cells. Significant CCR5-mediated calcium mobilization was stimulated by HSP70 and inhibited with TAK,779, which is a specific CCR5 antagonist. HSP70-mediated activation of the p38 MAPK phosphorylation signaling pathway was also demonstrated in CCR5-transfected HEK 293 cells. Direct binding of three extracellular peptides of CCR5 to HSP70 was demonstrated by surface plasmon resonance. Functional evidence of an interaction between HSP70, CCR5 and CD40 was shown by enhanced production of CCL5 by HEK 293 cells transfected with both CD40 and CCR5. Primary monocyte-derived immature DC stimulated with HSP70 produced IL-12 p40, which showed dose-dependent inhibition of >90% on treatment with both TAK 779 and anti-CD40 mAb. Stimulation of IL-12 p40 or TNF-, by HSP70 was related to the differential cell surface expression of CCR5 in primary human immature and mature DC, and those with the homozygous ,,32 CCR5 mutation. These findings may be of significance in the interaction between HSP70 and immune responses of CCR5+ T cells in HIV-1 infection, as well as in inflammatory bowel disease. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636551 [source] Intestinal double-positive CD4+CD8+ T,cells are highly activated memory cells with an increased capacity to produce cytokinesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2006Bapi Pahar Dr. Abstract Peripheral blood and intestinal CD4+CD8+ double-positive (DP) T,cells have been described in several species including humans, but their function and immunophenotypic characteristics are still not clearly understood. Here we demonstrate that DP T,cells are abundant in the intestinal lamina propria of normal rhesus macaques (Macaca mulatta). Moreover, DP T,cells have a memory phenotype and are capable of producing different and/or higher levels of cytokines and chemokines in response to mitogen stimulation compared to CD4+ single-positive T,cells. Intestinal DP T,cells are also highly activated and have higher expression of CCR5, which makes them preferred targets for simian immunodeficiency virus/HIV infection. Increased levels of CD69, CD25 and HLA-DR, and lower CD62L expression were found on intestinal DP T,cells populations compared to CD4+ single-positive T,cells. Collectively, these findings demonstrate that intestinal and peripheral blood DP T,cells are effector cells and may be important in regulating immune responses, which distinguishes them from the immature DP cells found in the thymus. Finally, these intestinal DP T,cells may be important target cells for HIV infection and replication due to their activation, memory phenotype and high expression of CCR5. [source] Phenotypic classification of human CD8+ T,cells reflecting their function: inverse correlation between quantitative expression of CD27 and cytotoxic effector functionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2004Hiroko Tomiyama Abstract Phenotypic classification of human CD8+ T,cells using three cell surface markers, CD27, CD28 and CD45RA, was recently suggested to be useful for identification of naive, memory and effector CD8+ T,cells. However, it still remains unclear whether such classification precisely reflects functional classification of CD8+ T,cells. To clarify this, we characterized each CD27CD28CD45RA subset of total and human cytomegalovirus (HCMV)-specific CD8+ T,cells by analyzing the expression of perforin and two chemokine receptors, CCR5 and CCR7, as well as their function. An inverse correlation between perforin and CD27 expression was found in all four CD28CD45RA subsets. Therefore, to achieve a phenotypic classification of CD8+ T,cells that moreprecisely reflects their function, the CD27+ subset was divided into CD27low and CD27high subsets based on the expression level of CD27. Functional and flow cytometric analyses of CD27CD28CD45RA subsets showed that this phenotypic classification reflects functional classification of CD8+ T,cells. HCMV-specific CD8+ T,cells from healthy HCMV-seropositive individuals were predominantly found in effector and memory/effector subsets, indicating that HCMV-specific effector CD8+ T,cells are actively induced by HCMV replication in healthy HCMV carriers. Phenotypic analyses of CD8+ T,cells using this classification will enable the characterization of antigen-specific CD8+ T,cells. [source] Functional reconstitution of the HIV receptors CCR5 and CD4 in liposomesFEBS JOURNAL, Issue 21 2002François Devesa Reconstitution of membrane proteins allows their study in a membrane environment that can be manipulated at will. Because membrane proteins have diverse biophysical properties, reconstitution methods have so far been developed for individual proteins on an ad hoc basis. We developed a postinsertion reconstitution method for CCR5, a G protein coupled receptor, with seven transmembrane ,,helices and small ecto- and endodomains. A His6 -tagged version of CCR5 was expressed in mammalian cells, purified using the detergent N -dodecyl-,- d -maltoside (DDM) and reconstituted into preformed liposomal membranes saturated with DDM, removing the detergent with hydrophobic polystyrene beads. We then attempted to incorporate CD4, a protein with a single transmembrane helix and a large hydrophilic ectodomain into liposomal membranes, together with CCR5. Surprisingly, reconstitution of this protein was also achieved by the method. Both proteins were found to be present together in individual liposomes. The reconstituted CCR5 was recognized by several monoclonal antibodies, recognized its natural ligand, and CD4 bound a soluble form of gp120, a subunit of the HIV fusion protein that uses CD4 as a receptor. Moreover, cells expressing the entire fusion protein of HIV bound to the liposomes, indicating that the proteins were intact and that most of them were oriented right side out. Thus, functional coreconstitution of two widely different proteins can be achieved by this method, suggesting that it might be useful for other proteins. [source] Simvastatin affects cell motility and actin cytoskeleton distribution of microgliaGLIA, Issue 2 2006Hedwich F. Kuipers Abstract Statin treatment is proposed to be a new potential therapy for multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. The effects of statin treatment on brain cells, however, are hardly understood. We therefore evaluated the effects of simvastatin treatment on the migratory capacity of brain microglial cells, key elements in the pathogenesis of MS. It is shown that exposure of human and murine microglial cells to simvastatin reduced cell surface expression of the chemokine receptors CCR5 and CXCR3. In addition, simvastatin treatment specifically abolished chemokine-induced microglial cell motility, altered actin cytoskeleton distribution, and led to changes in intracellular vesicles. These data clearly show that simvastatin inhibits several immunological properties of microglia, which may provide a rationale for statin treatment in MS. © 2005 Wiley-Liss, Inc. [source] RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytesGLIA, Issue 1 2002Yi Luo Abstract Cultured mouse astrocytes respond to the CC chemokine RANTES by production of chemokine and cytokine transcripts. Stimulation of astrocytes with 1 nM RANTES or 3,10 nM of the structurally related chemokines (eotaxin, macrophage inflammatory protein-1, and -, [MIP-1,, MIP-1,]) induced transcripts for KC, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-, (TNF-,), MIP-1,, MIP-2, and RANTES in a chemokine and cell-specific fashion. Synthesis of chemokine (KC and MCP-1) and cytokine (TNF-,) proteins was also demonstrated. RANTES-mediated chemokine synthesis was specifically inhibited by pertussis toxin, indicating that G-protein-coupled chemokine receptors participated in astrocyte signaling. Astrocytes expressed CCR1 and CCR5 (the redundant RANTES receptors). Astrocytes derived from mice with targeted mutations of either CCR1 or CCR5 respond after RANTES stimulation, suggesting multiple chemokine receptors may separately mediate RANTES responsiveness in astrocytes. Preliminary data suggest activation of the MAP kinase pathway is also critical for RANTES-mediated signaling in astrocytes. Treatment with RANTES specifically modulated astrocyte receptors upregulating intercellular adhesion molecule 1 (ICAM-1) and downregulating CX3CR1 expression. Thus, after chemokine treatment, astrocytes release proinflammatory mediators and reprogram their surface molecules. The combined effects of RANTES may serve to amplify inflammatory responses within the central nervous system. GLIA 39:19,30, 2002. © 2002 Wiley-Liss, Inc. [source] Isolated human astrocytes are not susceptible to infection by M- and T-tropic HIV-1 strains despite functional expression of the chemokine receptors CCR5 and CXCR4 ,GLIA, Issue 3 2001Agnès Boutet Abstract Within the brain, HIV-1 targets the microglia and astrocytes. Previous studies have reported that viral entry into astrocytes is independent of CD4, in contrast to microglia. We aimed to determine whether chemokine receptors play a role in mediating CD4-independent HIV-1 entry into astrocytes. We found that embryonic astrocytes and microglial cells express CCR5, CCR3, and CXCR4 transcripts. Intracellular calcium levels in astrocytes were found to increase following application of RANTES, MIP-1, (CCR5-agonist), SDF-1, (CXCR4-agonist), but not eotaxin (CCR3-agonist). In microglial cells, eotaxin was also able to modulate internal calcium homeostasis. CD4 was not present at the cell surface of purified astrocytes but CD4 mRNA could be detected by RT-PCR. Neither HIV-19533 (R5 isolate) nor HIV-1LAI (X4 isolate) penetrated into purified astrocytes. In contrast, mixed CNS cell cultures were infected by HIV-19533 and this was inhibited by anti-CD4 mAb in 4/4 tested cultures and by anti-CCR5 mAb in 2/4. Thus, the HIV-1 R5 strain requires CD4 to penetrate into brain cells, suggesting that CCR5 cannot be used as the primary receptor for M-tropic HIV-1 strains in astrocytes. Moreover, inconstant inhibition of HIV-1 entry by anti-CCR5 mAb supports the existence of alternative coreceptors for penetration of M-tropic isolates into brain cells. GLIA 34:165,177, 2001. © 2001 Wiley-Liss, Inc. [source] CCR5 deficiency exacerbates T-cell,mediated hepatitis in mice,HEPATOLOGY, Issue 4 2005Christophe Moreno Experimental T-cell,mediated hepatitis induced by concanavalin A (Con A) involves the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands (CCL3, CCL4, and CCL5) regulate leukocyte chemotaxis and activation, we investigated the role of CCR5 during Con A,induced liver injury. Serum levels of CCR5 ligands and their hepatic transcript levels were significantly increased after Con A injection, whereas CCR5+ liver mononuclear cells were recruited to the liver. CCR5-deficient (CCR5,/,) mice disclosed increased mortality and liver injury following Con A administration compared with wild-type mice. CCR5,/, mice also exhibited increased production of interleukin 4, tumor necrosis factor ,, CCL3, CCL4, and CCL5, and a prominent liver mononuclear cell infiltrate, among which many cells were CCR1+. In vivo neutralization of CCR5 ligands in CCR5,/, mice afforded a protection against hepatitis only when CCL5 was neutralized. In conclusion, CCR5 deficiency exacerbates T-cell,mediated hepatitis, and leads to increased levels of CCR5 ligands and a more pronounced liver mononuclear infiltrate, suggesting that CCR5 expression can modulate severity of immunomediated liver injury. (HEPATOLOGY 2005;42:854,862.) [source] Comparison of two genotypic algorithms to determine HIV-1 tropism,HIV MEDICINE, Issue 1 2008C Soulié Objectives One or both of two co-receptors, CCR5 (R5) and CXCR4 (X4), are used by HIV-1 to enter into host cells. The glycoprotein 120 (gp120) V3 sequence is correlated with the R5 and X4 phenotype. CCR5 inhibitors are specifically active against R5 viruses, suggesting the need to determine tropism before the use of these antagonists. A comparison of the position-specific scoring matrices (PSSM) and Geno2pheno algorithms based on the V3 loop gp120 sequences and previously described to be correlated to the R5 or X4 phenotype was carried out. Methods V3 envelope (env) genes from 83 plasma samples were amplified and sequenced, and 69 sequences were analysed with the PSSM and Geno2pheno algorithms. Results These two algorithms were concordant in 86.5% of cases. The Geno2pheno algorithm gave a tropism result more frequently than the PSSM algorithm, but R5X4 or X4 viruses were less frequently detected by the Geno2pheno algorithm. R5X4 or X4 tropism was predicted in 29.9% of samples. There was more R5X4 co-receptor use in the antiretroviral-treated group than in the antiretroviral-naïve group. Conclusions It is advisable to run a validated co-receptor use prediction tool before using co-receptor antagonists. If genotyping methods are considered, the PSSM and Geno2pheno algorithms are complementary and both are necessary. The association between predicted co-receptor use and virological response to co-receptor antagonists needs to be thoroughly evaluated. [source] Improved virological response to highly active antiretroviral therapy in HIV-1-infected patients carrying the CCR5 ,32 deletionHIV MEDICINE, Issue 4 2007JJ Laurichesse Background Patients heterozygous for the C-C chemokine receptor 5 (CCR5) ,32 deletion spontaneously progress less rapidly to AIDS and death than do wild-type patients. We investigated whether the CCR5 ,32 deletion has an impact on immunological, virological and clinical responses to highly active antiretroviral therapy (HAART) in HIV-1-infected patients. Patients and methods We included in the study 565 HIV-1-infected patients from the French HIV-1 infected cohort with documented date of serconversion (SEROCO)/haemophiliacs HIV-1 infected (HEMOCO) cohorts, who started HAART after 1996. We investigated virological responses to HAART at 6 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection or a 2 log HIV-1 RNA decrease) and at 12 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection) and clinical response to HAART by Kaplan,Meier survival curves, with AIDS and death as outcomes. Results The ,32 heterozygous patients (n=83; 15%) had a better virological response to HAART than wild-type patients (73 vs 53% at 6 months, P=0.01; and 60 vs 44% at 12 months, P=0.01). This better virological response was still observed after adjustment for antiretroviral status (whether or not patients were naïve to antiretroviral therapy), year of HAART initiation, number of new antiretroviral drugs and baseline viral load. There was no statistical difference between heterozygous patients and wild-type patients in terms of survival and AIDS-free survival. Conclusions CCR5 ,32 heterozygous patients were more likely to have a virological response to HAART than wild-type patients at 6 and 12 months. However, this virological response did not produce better immunological and clinical responses. The long-term impact of the ,32 deletion on survival in HIV-1-infected treated patients should be investigated in a meta-analysis. [source] Differential regulation of SOCS-1 signalling in B and T lymphocytes by hepatitis C virus core proteinIMMUNOLOGY, Issue 2 2008Zhi Qiang Yao Summary Hepatitis C virus (HCV) infection is characterized by a strong propensity toward chronicity, autoimmune phenomena and lymphomagenesis, supporting a role for lymphocyte dysregulation during persistent viral infection. We have shown that HCV core protein inhibits T-cell functions through interaction with a complement receptor, gC1qR. Here, we further report that B cells also express gC1qR that can be bound by HCV core protein. Importantly, using flow cytometry, we demonstrated differential regulation of B and T lymphocytes by the HCV core,gC1qR interaction, with down-regulation of CD69 activation in T cells but up-regulation of CD69 activation and cell proliferation in B cells. HCV core treatment led to decreased interferon-, production in CD8+ T cells but to increased immunoglobulin M and immunoglobulin G production as well as cell surface expression of costimulatory and chemokine receptors, including CD86 (B7-2), CD154 (CD40L) and CD195 (CCR5), in CD20+ B cells. Finally, we showed down-regulation of suppressor of cytokine signalling-1 (SOCS-1) using real-time reverse transcription,polymerase chain reaction, accompanied by up-regulation of signal transducer and activator of transcription-1 (STAT1) phosphorylation in B cells in response to HCV core protein, with the opposite pattern observed in HCV core-treated T cells. This study demonstrates differential regulation of B and T lymphocytes by HCV core and supports a mechanism by which lymphocyte dysregulation occurs in the course of persistent HCV infection. [source] Expression of GM1, a marker of lipid rafts, defines two subsets of human monocytes with differential endocytic capacity and lipopolysaccharide responsivenessIMMUNOLOGY, Issue 4 2007M. Maximina Bertha Moreno-Altamirano Summary Monocytes constitute 5,10% of total human peripheral blood leucocytes and remain in circulation for several days before replenishing the tissue macrophage populations. Monocytes display heterogeneity in size, granularity and nuclear morphology, and in the expression of cell membrane molecules, such as CD14, CD16, CD32, CD64, major histocompatibility complex class II, CCR2, CCR5, among others. This has led to the suggestion that individual monocyte/macrophage populations have specialized functions within their microenvironments. This study provides evidence for the occurrence of two peripheral blood monocyte subpopulations on the basis of their differential expression of GM1, a sphingolipid found mostly in lipid rafts, a CD14+ GM1low population and a CD14+ GM1high population comprising about 97·5% and 2·5% of total CD14+ cells, respectively. GM1 expression correlates with functional differences in terms of endocytic activity, susceptibility to mycobacterial infection, and response to lipopolysaccharide (LPS) (modulation of Toll-like receptor-4 expression). CD14+ GM1low cells proved to be less endocytic and more responsive to LPS, whereas CD14+ GM1high cells are more endocytic and less responsive to LPS. In addition, during monocyte to macrophage differentiation in vitro, the percentage of CD14+ GM1high cells increases from about 2·5% at day 1 to more than 50% at day 7 of culture. These results suggest that GM1low and GM1high monocytes in peripheral blood, represent either different stages of maturation or different subsets with specialized activities. The expression of CD16 on GM1high favours the first possibility and, on the other hand that up-regulation of GM1 expression and probably lipid rafts function is involved in the monocyte to macrophage differentiation process. [source] Activation of human macrophages by allogeneic islets preparations: inhibition by AOP-RANTES and heparinoidsIMMUNOLOGY, Issue 4 2004Séverine Sigrist Summary During transplantation, pancreatic islets release chemokines which promote macrophage attraction, hampering engraftment of islets. The aim of this study was to modulate chemotaxis and the immune response of human macrophages induced by islets. Human monocyte-derived macrophages of healthy subjects were exposed to supernatants of human islets. Chemotaxis, tumour necrosis factor-, (TNF-,) and interleukin-1, (IL-1,) release were evaluated. To modulate migration, human macrophages were incubated in the presence of aminooxypentane-regulated on activation, normal, T-cell expressed, and secreted (AOP-RANTES), a potent antagonist of CCR5. Chemotactic activity of islets supernatant was modulated by the addition of heparin or heparinoids [pentosan and calix[8S]arene (C8S)]. AOP-RANTES significantly reduced, in a dose-dependent manner, macrophage chemotaxis and cytokine release induced by islets supernatant. The chemotactic index was reduced from 3·05 ± 0·27 to 0·71 ± 12, TNF-, from 1205 ± 52 to 202 ± 12 pg/ml, and IL-1, from 234 ± 12 to 10 ± 6 pg/ml. The trapping of chemokines by heparinoids reduced the chemotactic activity of islets supernatant from 3·05 ± 0·27 to 1·2 ± 0·1 with heparin or pentosan and to 1·72 ± 0·22 with C8S, and also decreased the TNF-, release by human macrophages from 1205 ± 35 to 1000 ± 26 (C8S), 250 ± 21 (heparin) and 320 ± 19 (pentosan) pg/ml, and IL-1, from 234 ± 13 to 151 ± 5 (C8S), 50 ± 3 (heparin) and 57 ± 4 (pentosan) pg/ml. In conclusion, AOP-RANTES and heparinoids inhibit human macrophage activation and migration induced by islets supernatant. [source] CD1d-restricted natural killer T cells are potent targets for human immunodeficiency virus infectionIMMUNOLOGY, Issue 1 2003Richardson Fleuridor Summary Invariant human natural killer T cells (NKT) express a restricted T-cell receptor (TCR) V,24V,11 repertoire. These cells share both phenotypic and functional similarities between NK and T cells. Given the emerging role of NKT cells as critical cells in bridging the gap between innate and adaptive immunity, we examined their susceptibility to productive human immunodeficiency virus (HIV) infection by T-tropic, M-tropic, and primary isolates of HIV. We generated three human NKT cell clones (CA5, CA29, and CA31). Phenotypic characterization of these V,24+ V,11+ clones indicated that they were predominately positive for CD4, CD161, HLA-DR, CD38, CD45RO, and CD95 expression. The NKT cell clones expressed significantly more surface CCR5 molecules/cell and lower CXCR4 molecules/cell than phytohaemagglutinin-stimulated peripheral blood mononuclear cells (PBMC). Consistent with the surface expression of CCR5 and CXCR4, the NKT clones were also selectively susceptible to HIV M-tropic, T-tropic, and primary isolate infection, as evaluated by both HIV p24 enzyme-linked immunosorbent assay and intracellular staining of HIV proteins. The amount of p24 production was dependent on the NKT clone studied and the HIV strain used. Clones CA29 and CA31 were also susceptible to HIV IIIB infection. The virions produced by these clones were able to productively infect PHA-stimulated PBMCs with the same kinetics as for primary infection of CD4+ blast. Collectively, this data demonstrates that NKT cells can be a target for productive HIV infection but with a lag in the time to peak p24 production. [source] Oral biopsies from patients with orofacial granulomatosis with histology resembling Crohn's disease have a prominent Th1 environmentINFLAMMATORY BOWEL DISEASES, Issue 4 2007Jona Freysdottir BSc Abstract Background: Orofacial granulomatosis (OFG) is an idiopathic inflammatory disorder of children and young adults whose clinical symptoms include swelling of the lips or face, mucosal nodularity (cobblestoning), mucosal tags, hyperplasia of the gingivae, and aphthous oral ulcers. Whether some OFG patients with clinical and histological characteristics resembling Crohn's disease (CD) are a special group (oral CD) or true CD patients with symptoms reaching all the way to the oral mucosa remains to be determined. Methods: In this study oral biopsies from 10 patients with OFG were analyzed for the presence of T cells, T-cell subsets, B cells, and macrophages, as well as cytokines (IL-4, IL-10, IFN-,, IL-12, and TNF-,), chemokines (RANTES and MIP-1,), and chemokine receptors (CCR3, CCR5, and CXCR3). For comparison, oral tissues from 7 patients with other granulomatous diseases were included. Results: Compared with the non-OFG group, the OFG group had raised levels of CD4+ T cells, IFN-,, IL-10, and RANTES but reduced levels of CD68+ macrophages outside the granulomas, whereas within the granulomas the levels of CD3+ and CD4+ T cells and of IFN-, were raised, but the levels of IL-4 were decreased. These data are indicative of a Th1 environment within the oral OFG tissues, which resembles that already observed in gut CD tissues. Conclusions: Therefore, it can be concluded that some OFG patients have both histopathological and immunopathological features that resemble those observed in CD patients. (Inflamm Bowel Dis 2006) [source] Extensive gene conversion between CCR2 and CCR5 in domestic cat (Felis catus)INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 5 2007P. J. Esteves Summary Homogenization of the CC-motif chemokine receptors CCR2 and CCR5 of cat (Felis catus) is documented and shown to be the outcome of gene conversion within the feline lineage. All regions were concerned, except the three extracellular protein domains (N- and C-tails, and ECL2), suggesting that structural differentiation at these domains could be related to pathogen susceptibility. [source] The CCR5,32 allele is associated with reduced liver inflammation in hepatitis C virus infectionINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2004O. Wald Summary CCR5,32 is a deletion mutation in the chemokine receptor CCR5. Liver inflammatory activity was found to be significantly reduced (P = 0.005) in Jewish Israeli patients infected with the hepatitis C virus (HCV) carrying the CCR5,32 allele. The CCR5,32 allele does not alter susceptibility to HCV infection; however, it may play a role in the progression and outcome of the disease. [source] Analysis of the CC chemokine receptor 5 (CCR5) ,32 polymorphism in Behçet's diseaseINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 1 2004X. Yang Summary Chemokines are important determinants of the early inflammatory response. The CC chemokine receptor 5 (CCR5) ,32 variant results in a non-functional form of the chemokine receptor, and has been implicated in a variety of immune-mediated diseases. To investigate its role in the pathogenesis of Behçet's disease, we studied 350 patients and 519 healthy controls from three ethnic groups. While significant inter-ethnic variation in allele frequency was observed, no association was identified with disease, even when data were stratified by the known susceptibility gene HLA-B*51. [source] Further support for the association of CCR5 allelic variants with asthma susceptibilityINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2002R. McGinnis Summary English and German nuclear families containing multiple asthmatic children and asthmatic parents were analysed to retest a recently reported association between resistance to asthma and the ,32 allele of chemokine receptor 5 (CCR5). Analysis of the families by the transmission-disequilibrium test (TDT) revealed a non-significant trend in the English families that provided marginal confirmation of the association (P < 0.125), but no similar trend was observed in the German families. Case,control comparison of ,32 allele and genotype frequencies in asthmatic vs. non-asthmatic parents revealed a significantly lower frequency of ,32 in asthmatic English parents (P < 0.009) and a similar but non-significant trend in German parents (P < 0.265). Taken together, the pattern of results provides confirmation for the previously observed ,32,asthma association and indicates that susceptibility to asthma may be influenced by CCR5 or another gene in chromosomal region 3p21. [source] Constitutive association of cell surface CCR5 and CXCR4 in the presence of CD4,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2004Dr. Jinhai Wang Abstract Chemokine receptors CCR5 and CXCR4 are the major coreceptors of HIV-1 infection and also play fundamental roles in leukocyte trafficking, metastasis, angiogenesis, and embyogenesis. Here, we show that transfection of CCR5 into CXCR4 and CD4 expressing 3T3 cells enhances the cell surface level of CXCR4. In CCR5 high expressing cells, cell surface level of CXCR4 was incompletely modulated in the presence of the CXCR4 ligand CXCL12/SDF-1,. CCR5 was resistant to ligand-dependent modulation with the CCR5 ligand CCL5/RANTES. Confocal laser microscopy revealed that CCR5 was colocalized with CXCR4 on the cell surface. In CD4 expressing CCR5 and CXCR4 double positive NIH 3T3 cells, immunoprecipitation followed by Western blot analysis revealed that CCR5 was associated with CXCR4 and CD4. CXCR4 and CCR5 were not co-immunoprecipitated in cells expressing CCR5 and CXCR4 but without CD4 expression. Compared to NIH 3T3CD4 cells expressing CXCR4, the entry of an HIV-1 X4 isolate (HCF) into NIH 3T3CD4 expressing both CXCR4 and CCR5 was reduced. Our data indicate that chemokine receptors interact with each other, which may modulate chemokine,chemokine receptor interactions and HIV-1 coreceptor functions. Published 2004 Wiley-Liss, Inc. [source] The chemokine system and CCR5 antagonists: potential in HIV treatment and other novel therapiesJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2009H. Dhami PharmD (Student) Summary Since the recognition of human acquired immune deficiency syndrome, numerous classes of pharmacologic therapeutics have been developed to manage the disease. Current therapy includes co-administration of combinations of drugs classified by their mechanism of action as ,transcriptase inhibitors', ,protease inhibitors', ,integrase inhibitors' and the more recent ,fusion inhibitors'. This review focuses on the chemokine system and the recognition of chemokine receptors as targets for anti-human immunodeficiency virus (HIV) therapy. The FDA-approved chemokine (C,C motif) receptor 5 (CCR5) antagonist maraviroc (Selzentry®) is discussed in detail, along with another compound vicriviroc, currently in clinical trials. The mechanism of action, pharmacokinetics, toxicity and current status of research on CCR5 antagonists is described. Further, potential therapeutic uses of these agents other than anti-HIV therapy are discussed. [source] Differential expression of CCR5 and CRTH2 on infiltrated cells in colonic mucosa of patients with ulcerative colitisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2003KOJI MATSUZAKI Abstract Background and Aim:, The pathogenesis of ulcerative colitis (UC) is unclear, but abnormal infiltration of T lymphocytes in the colonic mucosa has been implicated in the mucosal tissue damage. The abnormal cytokine production because of a T helper (h)1/Th2 imbalance may play an important role in continuing inflammation in the colonic mucosa. In the present study, the expression of chemokine receptor 5 (CCR5) as a Th1 marker and a chemoattractant receptor-homologs molecule expressed on Th2 cells (CRTH2) were investigated in order to analyze impaired Th1/Th2 responses in the colonic mucosa of UC patients. Methods:, Tissue samples were obtained by colonic biopsies from patients with UC or colonic polyps, with informed consent. Immunohistochemical analysis was performed on periodate, lysine-paraformaldehyde-fixed serial cryostat sections using the labeled streptavidin biotin method. Monoclonal antibodies against CD4, CCR5 or CRTH2 were used as primary antibodies. The number of cells expressing CD4, CCR5 or CRTH2 per unit area was calculated by using an image analyzer. Results:, In the patients with UC, the numbers of CD4- and CCR5-positive cells were significantly increased in inflamed mucosa, and appeared to be correlated with the disease activity. The infiltration of CRTH2-positive cells was predominantly observed in the mildly inflamed or the margin of inflamed mucosa of UC patients. Conclusion:, There is a possibility that Th1 responses significantly occur in colonic mucosa with severe inflammation, while Th2 responses mainly occur with mild inflammation in UC patients. The Th1/Th2 imbalance in colonic mucosa may be related to the disease progression of UC. [source] Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese populationJOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Ding-Qiang Chen Abstract A number of genetic loci have been proposed to be associated with persistent hepatitis B virus (HBV) infection. This study aimed to evaluate the association and interaction of susceptible genes with HBV persistence in a Chinese population. A total of 17 polymorphisms in 9 candidate genes were studied in 361 Chinese chronic hepatitis B patients and 304 patients who recovered spontaneously. Distributions of susceptible polymorphisms were examined in healthy Chinese and Caucasian populations. Gene,gene interactions were tested by the multifactor dimensionality reduction (MDR) method. The TNF ,308 G/G genotype and G allele, IL-10RB codon 47 A allele, and MCP-1 ,2518 G/G genotype and G allele were more frequent in patients than controls (P,<,0.01, after multiple corrections Pc,<,0.05), while the frequencies of TNF ,308 A/G genotype and IL-10 ,592 A/A genotype were significantly higher in controls than in the patient group (Pc,<,0.05). The frequencies of the risk allele MCP-1 ,2518 G and CTLA4 6230 G were much higher in Chinese than in the Caucasian groups (P,<,0.001). An interaction between CCR5 ,2459, TNFA ,863, IL-10RB codon 47, and MCP-1 ,2518 was detected by MDR (P,=,0.001). The results indicate that genetic determinants may affect the outcome of HBV infection in both independent and synergic manners. J. Med. Virol. 82:371,378, 2010. © 2010 Wiley-Liss, Inc. [source] Do human polyoma viruses and human immunodeficiency virus share common co-receptors?JOURNAL OF MEDICAL VIROLOGY, Issue 1 2010Kalin Borissov Abstract Host and/or viral factors involved in human polyomavirus (HPoV) infection in persons living with HIV remain unknown. A hypothesis is outlined suggesting the importance of the co-receptors CCR5, CCR2, and CXCR4 not only for HIV, but also for HPoV. Functionally capable receptors coded by wild-type (wt) genotypes could facilitate internalization of HPoV in the cell resulting in brain and/or kidney infection/s in HIV infected individuals. Forty-nine Bulgarians with HIV, all treated by HAART, without neurological and/or kidney disorders, were tested for JCV and BKV and genotyped for CCR5 (CCR5del32), CCR2 (CCR2-64I), and CXCR4 (SDF1-3,A). In 27/49 (55.1%) individuals a co-infection with HPoV was identified,BKV in 12/49 (24.5%), JCV,in another 12/49 (24.5%), and both viruses,in 3/49 (6.1%). A high frequency of wt CCR5 was found in patients with HPoV (91.7% for BKV and JCV and in 100% with both viruses). V/V of CCR2 was presented in 75% for BKV and JCV and in 66.7% for BKV plus JCV. SDF1-3,G/G predominated in JCV infected patients (75%), while G/A and A/A genotypes were more frequent in patients with BKV (41.7%). Also, 21/22 (95.4%) persons without HPoV infection were heterozygous for SDF1 and CCR2. The number of individuals bearing wt of all co-receptors in the group of persons not infected with HPoV was lower (P,=,0.03) than that with polymorphism/s in one or two genes (SDF1 and CCR2) in the same group. The results suggest a probable role of co-receptors used by HIV to facilitate infection with HPoV. J. Med. Virol. 82:8,13, 2010. © 2009 Wiley-Liss, Inc. [source] Molecular characterization of the env gene of two CCR5/CXCR4-independent human immunodeficiency 2 primary isolates,JOURNAL OF MEDICAL VIROLOGY, Issue 11 2009Quirina Santos-Costa Abstract Human immunodeficiency virus 2 (HIV-2) infection is characterized by a slower disease progression and lower transmission rates. The molecular features that could be assigned as directly involved in this in vivo phenotype remain essentially unknown, and the importance of HIV-2 as a model to understand pathogenicity of HIV infection has been frequently underestimated. The early events of the HIV replication cycle involve the interaction between viral envelope glycoproteins and cellular receptors: the CD4 molecule and a chemokine receptor, usually CCR5 or CXCR4. Despite the importance of these two chemokine receptors in human immunodeficiency virus 1 (HIV-1) entry into cells, we have previously shown that in some HIV-2 asymptomatic individuals, a viral population exists that is unable to use both CCR5 and CXCR4. The goal of the present study was to investigate whether possible regions in the env gene of these viruses might account for this phenotype. From the molecular characterization of these env genes we could not detect any correlation between V3 loop sequence and viral phenotype. In contrast, it reveals the existence of remarkable differences in the V1/V2 and C5 regions of the surface glycoprotein, including the loss of a putative glycosilation site. Moreover, in the transmembrane glycoprotein some unique sequence signatures could be detected in the central ectodomain and second heptad repeat (HR2). Some of the mutations affect well-conserved residues, and may affect the conformation and/or the dynamics of envelope glycoproteins complex, including the SU,TM association and the modulation of viral entry function. J. Med. Virol. 81:1869,1881, 2009. © 2009 Wiley-Liss, Inc. [source] Association of IL-4 589 C/T promoter and IL-4R,I50V receptor polymorphism with susceptibility to HIV-1 infection in North IndiansJOURNAL OF MEDICAL VIROLOGY, Issue 6 2009Animesh Chatterjee Abstract The clinical course and outcome of HIV-1 infection are highly variable among individuals. Interleukin 4 (IL-4) is a key T helper 2 cytokine with various immune-modulating functions including induction of immunoglobulin E (IgE) production in B cells, downregulation of CCR5 and upregulation of CXCR4, the main co-receptors for HIV. Our objective is to investigate whether single-nucleotide polymorphisms (SNPs) in the IL-4 promoter 589 C/T and IL-4 R, I50V affect the susceptibility to HIV infection and its progression to AIDS in North Indian individuals. The study population consisted of 180 HIV-1 seropositive (HSP) stratified on the basis of disease severity (stage I, II, III), 50 HIV-1 exposed seronegative (HES), and 305 HIV-1 seronegative (HSN) individuals. The subjects were genotyped for IL-4 589 C/T promoter polymorphism and IL-4 R, I50V by polymerase chain reaction restriction fragment length polymorphism. The results showed that IL-4 589 C/T was not associated with the risk of HIV infection and disease progression. However, the IL-4R, I50 allele and genotype was significantly increased in HSP compared to HSN and HSP and was associated with risk of HIV infection. The frequency of IL-4R, I50 allele in the HSP group was higher than in HSN (76.11 vs. 64.75%; P,=,0.000; OR,=,1.734) and HES (76.11% vs. 62.00%; P,=,0.007; OR,=,1.953). Homozygous IL-4R, I50I genotype was significantly increased in HSP group compared with HSN (58.88% vs. 44.26%; P,=,0.002; OR,=,1.804) and HES (58.88% vs. 42.00%; P,=,0.038; OR,=,1.978). The present study for the first time suggests an association of IL-4R, I50 allele with increased likelihood of HIV-1 infection in North Indian population. Further studies are required to confirm these findings and understand the effect of IL-4R, polymorphism on the outcome of HIV-1 infection. J. Med. Virol. 81:959,965, 2009. © 2009 Wiley-Liss, Inc. [source] Characterization of a chemokine receptor CCR5-negative T cell line and its use in determining human immunodeficiency virus type 1 phenotypeJOURNAL OF MEDICAL VIROLOGY, Issue 2 2008Dorothea Binninger-Schinzel Abstract A human CD4-positive T cell line from a donor homozygous negative for the chemokine receptor CCR5 was established, characterized, and used for determining the coreceptor usage of human immunodeficiency virus type 1 (HIV-1) isolates. Clones of this IL-2 dependent human T-cell lymphotropic virus type 1 (HTLV-I) immortalized cell line, named IsnoR5 clones 1 and 2, are susceptible to infection by HIV-1 isolates that use CXCR4 as a coreceptor but resistant to infection by CCR5 tropic HIV-1 viruses. HIV-1 isolates whose replication is inhibited in IsnoR5 cells in the presence of the bicyclam AMD 3100, a CXCR4 specific inhibitor, utilize a coreceptor distinct from CCR5 and CXCR4. Using a panel of primary HIV-1 isolates we have shown that a single T cell line is sufficient to discriminate between use of CCR5, CXCR4 or an alternative coreceptor. As IsnoR5 clone 1 cells revealed the existence of even minor populations of CXCR4-using virus variants, they could be useful for the early identification of changes in coreceptor usage in HIV infected individuals facilitating the timely introduction of appropriate clinical treatments. J. Med. Virol. 80:192,200, 2008. © 2007 Wiley-Liss, Inc. [source] Prevalence of X4 tropic HIV-1 variants in patients with differences in disease stage and exposure to antiretroviral therapyJOURNAL OF MEDICAL VIROLOGY, Issue 8 2007Eva Poveda Abstract Viral tropism plays an important role in HIV pathogenesis. However, its correlation with the clinical outcome and following exposure to antiretroviral drugs are still unclear. HIV-1 co-receptor usage was examined in 206 infected individuals: 67 seroconverters, 52 chronically drug-naïve, and 87 antiretroviral-experienced patients. The V3 loop was sequenced from plasma HIV-RNA and co-receptor usage was inferred using a phenotype predictor software (http://genomiac2.ucsd.edu:8080/wetcat/v3.html), which classifies V3 sequences as R5 or X4. The overall prevalence of X4 viruses was 26.2%, with significant differences among groups: 13.4% in seroconverters, 25% in drug-naïve, and 36.8% in antiretroviral- experienced patients (P,=,0.001). The presence of X4 variants in the latter group was associated with higher viral load (P,=,0.002) but not with lower CD4 counts. There was no association between HIV tropism and gender, transmission route or age. Neither with the CCR5 ,32 genotype. Moreover, no association was found between HIV-1 tropism and drug resistance mutations nor with failure to regimens based on either protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Finally, no significant association was found between IL-7 plasma levels with HIV-1 tropism. In summary, X4 viruses are particularly frequent among antiretroviral-experienced patients with high viral loads, irrespective of the CD4 count. Thus, CCR5 antagonists should be used with special caution in this subset of patients. J. Med. Virol. 79: 1040,1046, 2007. © 2007 Wiley-Liss, Inc. [source] Chemokine receptors and neurotrophic factors: Potential therapy against aids dementia?JOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2008Italo Mocchetti Abstract Chemokine receptors, in particular, CXCR4 and CCR5, mediate human immunodeficiency virus type 1 (HIV-1) infection of immunocompetent cells and the apoptosis of these cells. However, the virus does not infect neurons. Yet through a variety of mechanisms, HIV promotes glial cell activation, synaptodendritic alterations, and neuronal loss that ultimately lead to motor and cognitive impairment. Chemokines and chemokine receptors are abundant in the adult central nervous system and play a role in neuronal apoptosis evoked by HIV proteins. Thus, reducing the availability of chemokine receptors may prevent the neuronal degeneration seen in HIV-positive patients. In this article, we present and discuss a recent experimental approach aimed at testing effective neuroprotective therapies against HIV-mediated neuronal degeneration. © 2007 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||