Showing papers on "Chemokine receptor CCR5 published in 2003"
TL;DR: IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.
Abstract: Selective skewing of autoreactive interferon-gamma (IFN-gamma)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2-0.5 microg rhuIL-4 than at < or =0.1 microg rhuIL-4 (P = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ Th1 cells; and the IFN-gamma/IL-4 ratio. In the circulation, 0.2-0.5 microg/kg rhuIL-4 increased the number of IL-4+CD4+ T cells two- to three-fold. Thus, IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.
429 citations
TL;DR: Gut Peyer's patches are required to activate anti-host CTL responses in a well characterized murine acute graft-versus-host reaction (a-GVHR) model, involving transfer of parent lymphocytes into F1 hybrid recipients, and blockade of CTL generation in PPs might offer new strategies for circumventing a-GVHD.
Abstract: Acute graft-versus-host disease (a-GVHD) is initiated primarily by immunologically competent cytotoxic T cells (CTLs) that express anti-host specificities. However, the host lymphoid compartment in which these precursor CTLs are initially stimulated remains unclear. Here we show that gut Peyer's patches (PPs) are required to activate anti-host CTL responses in a well characterized murine acute graft-versus-host reaction (a-GVHR) model, involving transfer of parent lymphocytes into F1 hybrid recipients. The a-GVHR was prevented when recruitment of donor T cells into PP was interrupted either by disrupting the gene encoding chemokine receptor CCR5 or by blocking integrin alpha(4)beta(7)-MAdCAM-1 (mucosal vascular addressin) interactions. Mice deficient for PPs failed to develop a-GVHD in two models of disease induction. Thus, blockade of CTL generation in PPs might offer new strategies for circumventing a-GVHD.
296 citations
Journal Article•
TL;DR: The results provide direct evidence that macrophages contribute to tumor development and are the first indication that chemokine receptor antagonists may provide novel strategies in cancer prevention and treatment.
Abstract: The leukocyte infiltrate of human and murine epithelial cancers is regulated by chemokine production in the tumor microenvironment. In this article, we tested the hypothesis that chemokine receptor antagonists may have anticancer activity by inhibiting this infiltrate. We first characterized CC chemokines, chemokine receptors, and the leukocyte infiltrate in the 410.4 murine model of breast cancer. We found that CCL5 (RANTES) was produced by the tumor cells, and its receptors, CCR1 and CCR5, were expressed by the leukocyte infiltrate. As Met-CCL5 is an antagonist of CCR1 and CCR5 with activity in models of inflammatory disease, we tested its activity against 410.4 tumors. After 5 weeks of daily treatment with Met-CCL5, the volume and weight of 410.4 tumors was significantly decreased compared with control-treated tumors. Met-CCL5 was also active against established tumors. The total cell number obtained after collagenase digestion was decreased in Met-CCL5-treated tumors as was the proportion of infiltrating macrophages. Furthermore, chemokine antagonist treatment increased stromal development and necrosis. Our results provide direct evidence that macrophages contribute to tumor development and are the first indication that chemokine receptor antagonists may provide novel strategies in cancer prevention and treatment.
264 citations
TL;DR: This review will address specific aspects related to chemokine-T cell interactions and the molecular signaling mechanisms that influence T cell function in an inflammatory immune response.
259 citations
TL;DR: Shikonin, as a naturally occurring, low-molecular-weight pan-chemokine receptor inhibitor, constitutes a basis for the development of novel anti-HIV therapeutic agents.
Abstract: Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). G protein-coupled chemokine receptors are used by HIV-1 as coreceptors to enter the host cells. In this study, we assessed the effects of shikonin on chemokine receptor function and HIV-1 replication. The results showed that, at nanomolar concentrations, shikonin inhibited monocyte chemotaxis and calcium flux in response to a variety of CC chemokines (CCL2 [monocyte chemoattractant protein 1], CCL3 [macrophage inflammatory protein 1alpha], and CCL5 [regulated upon activation, normal T-cell expressed and secreted protein]), the CXC chemokine (CXCL12 [stromal cell-derived factor 1alpha]), and classic chemoattractants (formylmethionyl-leucine-phenylalanine and complement fraction C5a). Shikonin down-regulated surface expression of CCR5, a primary HIV-1 coreceptor, on macrophages to a greater degree than the other receptors (CCR1, CCR2, CXCR4, and the formyl peptide receptor) did. CCR5 mRNA expression was also down-regulated by the compound. Additionally, shikonin inhibited the replication of a multidrug-resistant strain and pediatric clinical isolates of HIV in human peripheral blood mononuclear cells, with 50% inhibitory concentrations (IC(50)s) ranging from 96 to 366 nM. Shikonin also effectively inhibited the replication of the HIV Ba-L isolate in monocytes/macrophages, with an IC(50) of 470 nM. Our results suggest that the anti-HIV and anti-inflammatory activities of shikonin may be related to its interference with chemokine receptor expression and function. Therefore, shikonin, as a naturally occurring, low-molecular-weight pan-chemokine receptor inhibitor, constitutes a basis for the development of novel anti-HIV therapeutic agents.
202 citations
TL;DR: A possible role of the polymorphisms CCR5‐Δ32, RANTES −403, and MCP‐2 Q46K in the outcome of HCV infection is suggested.
199 citations
TL;DR: This review focuses on the overall expression of chemokine receptors on cells of myeloid lineage and considers the mechanisms of entry of R5‐, X4‐ and dual‐tropic strains of HIV‐1 into these cells.
Abstract: Monocytes, macrophages and dendritic cells play an important role in the initial infection and contribute to its pathogenesis throughout the course of infection. Myeloid cells express CD4 and chemokine receptors known for HIV-1 fusion and entry. The beta-chemokine receptor, CCR5, is the major co-receptor in conjunction with CD4 for macrophage (M)-tropic or (R5) isolates of HIV-1, whereas the alpha-chemokine receptor, CXCR4, facilitates entry of T-tropic or (X4) HIV-1 strains. Cells of myeloid lineage may be infected predominantly with R5- strains, although infection with dual-tropic isolates of HIV-1 (exhibiting the capacity to use CCR-5 and/or CXCR-4 for entry) or some strains of X4- isolates has also been reported. The expression of chemokine receptors, HIV-1 infection and replication is under continuous regulation by a complex cytokine network produced by a variety of cells. The effects of cytokines/chemokines on HIV-1 replication in cells of myeloid lineage can be inhibitory (IFN-alpha, IFN-beta, IFN-gamma, GM-CSF, IL-10, IL-13 and IL-16 and beta-chemokines), stimulatory (M-CSF, TNF-alpha, TNF-beta, IL-1, IL-6) or bifunction al, that is both inhibitory and stimulatory (IL-4). This review focuses on the overall expression of chemokine receptors on cells of myeloid lineage and considers the mechanisms of entry of R5-, X4- and dual-tropic strains of HIV-1 into these cells. The effects of cytokines/chemokines on viral entry and productive HIV-1 infection are also reviewed.
183 citations
TL;DR: Results indicate that the early stages of plaque formation in this model of lipid-mediated atherogenesis do not depend on CCR5, and there is no evidence for expression of prominent markers of T and B lymphocytes.
164 citations
TL;DR: Analyzing the biological function of the U12 gene revealed that U12 activates distinct transmembrane signaling pathways that may mediate biological functions by binding with a β-chemokine, ELC/MIP-3β.
Abstract: Human herpesvirus 6 (HHV- 6), which belongs to the betaherpesvirus subfamily and infects mainly T cells in vitro, causes acute and latent infections HHV- 6 contains two genes (U12 and U51) that encode putative homologs of cellular G-protein-coupled receptors (GCR), while three other betaherpesviruses, human cytomegalovirus, murine cytomegalovirus, and human herpesvirus 7, have three, one, and two GCR-homologous genes, respectively The U12 gene is expressed late in infection from a spliced mRNA The U12 gene was cloned, and the protein was expressed in cells and analyzed for its biological characteristics U12 functionally encoded a calcium-mobilizing receptor for beta-chemokines such as regulated upon activation, normal T expressed and secreted (RANTES), macrophage inflammatory proteins 1alpha and 1beta (MIP-1alpha and MIP-1beta) and monocyte chemoattractant protein 1 but not for the alpha-chemokine interleukin-8, suggesting that the chemokine selectivity of the U12 product was distinct from that of the known mammalian chemokine receptors These findings suggested that the product of U12 may play an important role in the pathogenesis of HHV- 6 through transmembrane signaling by binding with beta-chemokines
158 citations
TL;DR: The inhibitory effect against X4 viral replication by KRH-1636 was clearly reproduced in the human peripheral blood lymphocyte/severe combined immunodeficiency mouse system and this compound was absorbed into the blood after intraduodenal administration as judged by anti-HIV-1 activity and liquid chromatography MS in the plasma.
Abstract: A low molecular weight nonpeptide compound, KRH-1636, efficiently blocked replication of various T cell line-tropic (X4) HIV type 1 (HIV-1) in MT-4 cells and peripheral blood mononuclear cells through the inhibition of viral entry and membrane fusion via the CXC chemokine receptor (CXCR)4 coreceptor but not via CC chemokine receptor 5. It also inhibited binding of the CXC chemokine, stromal cell-derived factor 1α, to CXCR4 specifically and subsequent signal transduction. KRH-1636 prevented monoclonal antibodies from binding to CXCR4 without down-modulation of the coreceptor. The inhibitory effect against X4 viral replication by KRH-1636 was clearly reproduced in the human peripheral blood lymphocyte/severe combined immunodeficiency mouse system. Furthermore, this compound was absorbed into the blood after intraduodenal administration as judged by anti-HIV-1 activity and liquid chromatography MS in the plasma. Thus, KRH-1636 seems to be a promising agent for the treatment of HIV-1 infection.
158 citations
TL;DR: Dysregulation of macrophage function by gp120/chemokine receptor signaling may contribute to local inflammation and injury and further recruit additional inflammatory and/or target cells, which may enhance or suppress HIV‐1 replication.
Abstract: Macrophages are major targets for in- fection by human immunodeficiency virus type 1 (HIV-1). In addition to their role as productive viral reservoirs, inappropriate activation of in- fected and uninfected macrophages appears to contribute to pathogenesis. HIV-1 infection re- quires initial interactions between the viral enve- lope surface glycoprotein gp120, the cell-surface protein CD4, and a chemokine receptor CCR5 or CXCR4. Besides their role in HIV-1 entry, CCR5 and CXCR4 are G protein-coupled receptors that can activate multiple intracellular signaling path- ways. HIV-1 gp120 has been shown to activate signaling pathways through the chemokine recep- tors in several cell types including lymphocytes, neurons, and astrocytes. In some cell types, these consequences may cause cellular injury. In this review, we highlight our data demonstrating di- verse signaling events that occur in primary human macrophages in response to gp120/chemokine re- ceptor interactions. These responses include K, Cl - , and nonselective cation currents, intracellular Ca 2 increases, and activation of several kinases including the focal adhesion-related tyrosine ki- nase Pyk2, mitogen-activated protein kinases (MAPK), and phosphoinositol-3 kinase. Activation of the MAPK leads to gp120-induced expression of chemokines such as monocyte chemoattractant protein-1 and macrophage-inflammatory pro- tein-1 and the proinflammatory cytokine tumor necrosis factor . These responses establish a com- plex cytokine network, which may enhance or sup- press HIV-1 replication. In addition, dysregulation of macrophage function by gp120/chemokine re- ceptor signaling may contribute to local inflamma- tion and injury and further recruit additional in- flammatory and/or target cells. Targeting these cel- lular signaling pathways may have benefit in controlling inflammatory sequelae of HIV infection such as in neurological disease. J. Leukoc. Biol. 74: 676-682; 2003.
TL;DR: It is found that activation of the chemokine receptor CCR5 regulates p53 transcriptional activity in breast cancer cells through pertussis toxin–, JAK2-, and p38 mitogen–activated protein kinase–dependent mechanisms.
Abstract: Chemokines are implicated in tumor pathogenesis, although it is unclear whether they affect human cancer progression positively or negatively. We found that activation of the chemokine receptor CCR5 regulates p53 transcriptional activity in breast cancer cells through pertussis toxin–, JAK2-, and p38 mitogen–activated protein kinase–dependent mechanisms. CCR5 blockade significantly enhanced proliferation of xenografts from tumor cells bearing wild-type p53, but did not affect proliferation of tumor xenografts bearing a p53 mutation. In parallel, data obtained in a primary breast cancer clinical series showed that disease-free survival was shorter in individuals bearing the CCR5Δ32 allele than in CCR5 wild-type patients, but only for those whose tumors expressed wild-type p53. These findings suggest that CCR5 activity influences human breast cancer progression in a p53-dependent manner.
TL;DR: It is demonstrated that IP-10 stimulates HIV-1 replication in monocyte-derived macrophages and peripheral blood lymphocytes and that blocking the interaction betweenIP-10 and CXCR3 represents a possible new target for anti-retroviral therapy.
TL;DR: It is shown that the robustness of the chemokine system, in its most prominent role, is evidenced by the apparent health of mostChemokine or chemokines receptor knockout mice, but when more specialized disease models are tested, a specific role for individual receptors and their ligands can be demonstrated.
Abstract: Publisher Summary Chemokines act in a network, constituted by many overlapping interactions between ligands and their receptors. Multiple chemokines can recognize the same receptor, and one chemokine can bind to several receptors. This complex organization guarantees a solid defense system that assures protection, even if one of the links in the web is affected. This robustness of the chemokine system, in its most prominent role, is evidenced by the apparent health of most chemokine or chemokine receptor knockout mice. However, when more specialized disease models are tested, a specific role for individual receptors and their ligands can be demonstrated.
TL;DR: It is demonstrated that the CXCR3 ligands inhibit CCR3‐mediated functional responses of both human eosinophils and C CR3 transfectants induced by all three eotaxins, with CXCL11 being the most efficacious antagonist.
Abstract: The chemokine receptor CXCR3 is predominantly expressed on T lymphocytes, and its agonists CXCL9, CXCL10 and CXCL11 are IFN-gamma-inducible chemokines that promote Th1 responses In contrast, the CCR3 agonists CCL11, CCL24 and CCL26 are involved in the recruitment of cells such as eosinophils and basophils during Th2 responses Here, we report that although CCL11, CCL24 and CCL26 are neither agonists nor antagonists of CXCR3, CCL11 binds with high affinity to CXCR3 This suggests that, in vivo, CXCR3 may act as a decoy receptor, sequestering locally produced CCL11 We also demonstrate that the CXCR3 ligands inhibit CCR3-mediated functional responses of both human eosinophils and CCR3 transfectants induced by all three eotaxins, with CXCL11 being the most efficacious antagonist The examination of CCR3-CCR1 chimeric constructs revealed that CCL11 and CXCL11 share overlapping binding sites contained within the CCR3 extracellular loops, a region that was previously shown to be essential for effective receptor-activation Hence, eosinophil responses mediated by chemokines acting at CCR3 may be regulated by two distinct mechanisms: the antagonistic effects of CXCR3 ligands and the sequestration of CCL11 by CXCR3-expressing cells Such interplay may serve to finely tune inflammatory responses in vivo
TL;DR: It is suggested that CX CR4-tropic viruses are present within the quasispecies of patients infected with subtype C virus and that antiretroviral treatment may create an environment for the emergence of CXCR4 tropism.
Abstract: Human immunodeficiency virus type 1 (HIV-1) subtype C viruses have been found to almost exclusively use the chemokine receptor CCR5 as a coreceptor for entry, even in patients with advanced AIDS. We have characterized subtype C virus isolates from 28 patients from Harare, Zimbabwe, 20 of whom were receiving antiretroviral treatment. Virus from 10 of the treated patients induced syncytium formation (SI virus) when cultured with MT2 cells. Only non-syncytium-inducing (NSI) virus was cultured from the peripheral blood mononuclear cells of the eight patients who had not received treatment. The majority of these subtype C SI viruses were capable of using both CCR5 and CXCR4 as coreceptors for viral entry, and the consensus V3 loop sequences from the SI viruses displayed a high net charge compared to those of NSI viruses. While those on treatment had reverse transcriptase (RT) and protease mutations, there was no clear association between RT and protease drug resistance mutations and coreceptor tropism. These results suggest that CXCR4-tropic viruses are present within the quasispecies of patients infected with subtype C virus and that antiretroviral treatment may create an environment for the emergence of CXCR4 tropism.
TL;DR: It is determined that IL-16 preferentially induces a migratory response in Th1 cells, and CD4+CCR5+ cells are prevalent at sites of inflammation, this intimate functional relationship likely plays a pivotal role for the recruitment and activation of Th 1 cells.
Abstract: IL-16 binds to CD4 and induces a migratory response in CD4(+) T cells. Although it has been assumed that CD4 is the sole receptor and that IL-16 induces a comparable migratory response in all CD4(+) T cells, this has not been investigated. In this study, we determined that IL-16 preferentially induces a migratory response in Th1 cells. Because chemokine receptor CCR5 is expressed predominantly in Th1 cells and is physically associated with CD4, we investigated whether IL-16/CD4 stimulation was enhanced in the presence of CCR5. Using T cells from CCR5(null) mice, we determined that IL-16-induced migration was significantly greater in the presence of CCR5. The presence of CCR5 significantly increased IL-16 binding vs CD4 alone; however, IL-16 could not bind to CCR5 alone. Because CD4(+)CCR5(+) cells are prevalent at sites of inflammation, this intimate functional relationship likely plays a pivotal role for the recruitment and activation of Th1 cells.
TL;DR: It is concluded that CpG-DNA can aggravate preexisting GN via a shift toward a Th1 response but also by a novel pathway involving TLR9-mediated chemokine and Chemokine receptor expression by macrophages, which may contribute to the enhanced glomerular macrophage recruitment and activation.
Abstract: Immune complex glomerulonephritis (GN) often deteriorates during infection with viruses and bacteria that, in contrast to mammals, have DNA that contains many unmethylated CpG motifs. Balb/c mice with horse apoferritin-induced GN (HAF-GN) were treated with either saline, CpG-oligodeoxynucleotides (ODN), or control GpC-ODN. Only CpG-ODN exacerbated HAF-GN with an increase of glomerular macrophages, which was associated with massive albuminuria and increased renal MCP-1/CCL2, RANTES/CCL5, CCR1, CCR2, and CCR5 mRNA expression. CpG-ODN induced a Th1 response as indicated by serum anti-HAF IgG(2a) titers, mesangial IgG(2a) deposits, and splenocyte IFN-gamma secretion. Messenger RNA for the CpG-DNA receptor Toll-like reeptor 9 (TLR9) was present in kidneys with HAF-GN but not in normal kidneys. The source of TLR9 mRNA in HAF-GN could be infiltrating macrophages or intrinsic renal cells, e.g., mesangial cells; but, in vitro, only murine J774 macrophages expressed TLR9. In J774 cells, CpG-ODN induced the chemokines MCP-1/CCL2 and RANTES/CCL5 and the chemokine receptors CCR1 and CCR5. It is concluded that CpG-DNA can aggravate preexisting GN via a shift toward a Th1 response but also by a novel pathway involving TLR9-mediated chemokine and chemokine receptor expression by macrophages, which may contribute to the enhanced glomerular macrophage recruitment and activation. This mechanism may be relevant during infection-triggered exacerbation of human immune-complex GN and other immune-mediated diseases in general.
TL;DR: The studies show that inhibition of the PI3-kinase signaling pathway suppresses virus infection post-viral entry and post-reverse transcription but prior to HIV gene expression, which has implications for anti-HIV therapeutics that target cellular signaling machinery.
Abstract: Human immunodeficiency virus type 1 (HIV-1) can activate multiple signaling pathways within a target cell to facilitate viral entry and replication. A number of signal transduction pathways may be activated during engagement of the HIV-1 envelope with CD4 and/or the chemokine coreceptor. Binding to CD4 causes phosphorylation of receptor tyrosine kinases such as p56Lck, which activate the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3-kinase) pathways and indirectly activate calcium channels (6, 15, 33, 34, 38). The chemokine receptor is coupled to G-proteins, which, depending on the subunit composition, can activate adenyl cyclase, protein tyrosine kinases such as Pyk2, and phospholipase C, which catalyzes the formation of inositol 1,4,5-triphosphate, subsequently opening calcium channels on the endoplasmic reticulum (reviewed in references 18 and 37). Because these pathways ultimately regulate functions such as cytoskeletal rearrangement, cell survival, differentiation, and activation of transcription, HIV gp120-induced signal transduction may facilitate virus infection.
Previously, HIV signaling through the chemokine receptor has been considered dispensable for infection. Under conditions where signaling through the CCR5 receptor is blocked either by mutagenesis or G-protein inactivation with pertussis toxin, tumor cells are still capable of supporting viral entry and replication (3, 21). However, the phenotypes and functions of these tumor cell lines differ from those of the primary targets of HIV infection in vivo, primary macrophages and CD4+ lymphocytes, so the requirements for infection differ substantially. Only a relatively small fraction of T cells are productively infected in HIV-positive patients despite the presence of the relevant receptors, and activation of CD4+ T cells is critical for efficient viral reverse transcription and replication in these cells (29). Although HIV-1 entry can occur in quiescent T cells, there is a preintegration postentry block in replication (8). In addition, signaling through chemokine receptors by their natural ligands can enhance or suppress HIV replication in T cells and macrophages (12, 27, 28). Recent studies suggest that signal transduction by HIV envelope glycoprotein gp120 may affect host cell susceptibility to virus entry and infection in primary cells (2, 4, 10, 11, 23).
In the case of HIV-1, only viruses competent to induce signaling through the CCR5 coreceptor are able to establish productive infection within macrophages (4). Primary viral isolates and laboratory-adapted strains with gp120 envelopes that do not induce calcium mobilization enter macrophages but are unable to complete replication. This postentry block can be overcome by stimulating signaling through CCR5 with its natural ligand, MIP-1α. In addition, perturbation of coreceptor signaling with pertussis toxin markedly decreases infection of peripheral blood mononuclear cells with CXCR4-utilizing (X4) and CCR5-utilizing (R5) HIV-1 viruses (2, 23). It has been proposed that coreceptor function is important for both entry and postentry events during HIV infection (9). A role for the Raf/MEK/ERK pathway has been demonstrated for nuclear import of the HIV reverse transcriptase complex (7) and in NF-κB-driven transcription from the HIV long terminal repeat promoter (34).
The role of PI3-kinase signal transduction in HIV infection has not been fully studied. PI3-kinases are a cellular family of heterodimeric enzymes that consist of a regulatory subunit (p85) activated by tyrosine phosphorylation, which recruits inositol phospholipids, which are phosphorylated by the catalytic subunit (p110). These lipids serve as second messengers which regulate the phosphorylation of other kinases such as Akt/PKB, cyclic AMP-dependent protein kinase A, some protein kinase C isoforms, and the ribosomal S6 kinases p70 and p85 (reviewed in reference 13). Because PI3-kinase controls the activation of many different pathways, it is a critical mediator of various cellular processes such as cell migration, survival, and changes in morphology. The ability of PI3-kinase to regulate multiple cellular pathways, coupled with the need for HIV to induce an environment favorable for viral replication, prompted us to examine the role of PI3-kinase signaling in HIV-1 infection of CD4+ T cells and macrophages.
TL;DR: This review addresses key pharmacology and virology issues relevant in discovery and development of CCR5 antagonists as anti-HIV drugs, such as target validation, receptor internalization, allosterism, viral resistance and tropism.
TL;DR: Evidence supporting a key role for CCR2 in the pathogenesis of atherosclerosis, infections with intracellular pathogens, and regulation of the type I adaptive immune response is summarized.
Abstract: Infiltration of tissues by monocyte-derived macrophages is a prominent component of a wide-range of diseases, including atherosclerosis, glomerulonephritis, encephalitis, infectious diseases, and virtually all syndromes characterized by chronic inflammation. The molecular signals responsible for this directed migration are incompletely understood, but members of the chemokine family, especially the monocyte chemoattractant proteins (MCPs) (MCP-1 to MCP-5) are emerging as key players. Cells that respond to the MCPs do so because they express chemokine receptor 2 (CCR2), the cognate receptor. This review will summarize evidence supporting a key role for CCR2 in the pathogenesis of atherosclerosis, infections with intracellular pathogens, and regulation of the type I adaptive immune response.
TL;DR: This review discusses the various points of intervention that can be addressed to provide anti-inflammatory and anti-HIV infectivity therapeutics and summarizes the status of the approaches that have been undertaken to produce therapeutics that block chemokine action.
TL;DR: The data support a multi‐site model for CXCR3 interactions with its agonists, in which several extracellular domains of CX CR3 contribute to ligand binding and the induction of receptor activation.
Abstract: CXCR3 is a chemokine receptor predominantly expressed on T lymphocytes, and binds the chemokines CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC). Here, we have investigated the role of the extracellular domains of CXCR3 in ligand selectivity and receptor activation by assessing the ligand binding and chemotactic responses of chimeric CXCR3/CXCR1 constructs. Our data reveal that the secondextracellular loop of CXCR3 is essential for receptor activation in response to all CXCR3 ligands. In contrast, the N terminus and first extracellular loop of CXCR3 play some role in CXCL10- and CXCL11-mediated activation but are dispensable for CXCL9-induced signaling. The third extracellular loop of CXCR3 is important only for CXCL9- and CXCL10-induced chemotaxis. Binding studies suggest that the CXCR3 ligands bind to distinct sites composed of multiple domains of CXCR3 and that high-affinity binding and receptor activation are disparate functions. Collectively, our data support a multi-site model for CXCR3 interactions with its agonists, in which several extracellular domains of CXCR3 contribute to ligand binding and the induction of receptor activation. The development of antagonists targeting the second extracellular loop of CXCR3 should impede receptor activation and aid the treatment of several human inflammatory disorders.
TL;DR: Through in vitro infection of peripheral blood mononuclear cells obtained from healthy Caucasian blood donors with macrophage-tropic HIV-1 isolates, low, medium, and high viral propagation in association with G/G, A/ G, and A/A promoter genotypes are observed.
TL;DR: Morphine enhances the susceptibility of neonatal MDM to HIV infection, and may have a cofactor role in perinatal HIV transmission and infection.
Abstract: Perinatal transmission of HIV accounts for almost all new HIV infections in children. There is an increased risk of perinatal transmission of HIV with maternal illicit substance abuse. Little is known about neonatal immune system alteration and subsequent susceptibility to HIV infection after morphine exposure. We investigated the effects of morphine on HIV infection of neonatal monocyte-derived macrophages (MDM). Morphine significantly enhanced HIV infection of neonatal MDM. Morphine-induced HIV replication in neonatal MDM was completely suppressed by naltrexone, the opioid receptor antagonist. Morphine significantly up-regulated CCR5 receptor expression and inhibited the endogenous production of macrophage inflammatory protein-1β in neonatal MDM. Thus, morphine, most likely through alteration of β-chemokines and CCR5 receptor expression, enhances the susceptibility of neonatal MDM to HIV infection, and may have a cofactor role in perinatal HIV transmission and infection.
TL;DR: Results from both a case-control and family-based genetic-association analysis show that the -2459G and -2554T variants are associated with severe RSV bronchiolitis, and it is proposed that these CCR5 variants influence the inflammatory response, and these data provide further evidence of the important role that host genetic variability plays in the determination of disease severity.
Abstract: Respiratory syncytial virus (RSV) bronchiolitis is characterized by intense inflammation of the airways, and high levels of proinflammatory cytokines and chemokines can be found in respiratory secretions of affected infants. Important among these chemokines are RANTES (regulated on activation, normal T cell-expressed and -secreted) and macrophage inflammatory-protein alpha, MIP-1alpha, both of which show correlation with severe RSV bronchiolitis. It is not clear whether high levels of these chemokines are important in disease pathogenesis, and this study addresses this question by studying genetic variants of their major receptor, CC chemokine receptor 5. Results from both a case-control and family-based genetic-association analysis show that the -2459G and -2554T variants are associated with severe RSV bronchiolitis (P=.01). It is proposed that these CCR5 variants influence the inflammatory response, and these data provide further evidence of the important role that host genetic variability plays in the determination of disease severity in RSV bronchiolitis.
TL;DR: It is shown that in mice in which the CCL2 gene was disrupted, low‐dose aerosol infection with Mycobacterium tuberculosis resulted in fewer macrophages entering the lungs, but only a minor and transient increase in bacterial load in the lungs; these mice were still able to establish a state of chronic disease.
Abstract: Chemokines play an important role in the development of immunity to tuberculosis. Chemokine ligand 2 (CCL2, JE, monocyte chemoattractant protein-1) is thought to be primarily responsible for recruiting monocytes, dendritic cells, natural killer cells and activated T cells, all of which play critical roles in the effective control of tuberculosis infection in mice. We show here that in mice in which the CCL2 gene was disrupted, low-dose aerosol infection with Mycobacterium tuberculosis resulted in fewer macrophages entering the lungs, but only a minor and transient increase in bacterial load in the lungs; these mice were still able to establish a state of chronic disease. Such animals showed similar numbers of activated T cells as wild-type mice, as determined by their expression of the CD44hi CD62lo phenotype, but a transient reduction in cells secreting interferon-gamma. These data indicate that the primary deficiency in mice unable to produce CCL2 is a transient failure to focus antigen-specific T lymphocytes into the infected lung, whereas other elements of the acquired host response are compensated for by different ligands interacting with the chemokine receptor CCR2.
TL;DR: Whether the quaternary opioid antagonist methylnaltrexone (MNTX), now in phase III clinical trials for opioid-induced constipation, reverses the opioid-mediated enhancement of HIV infection of macrophages at clinically relevant doses is determined.
Abstract: Opioid abuse has been postulated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) infection and AIDS. We and others have recently demonstrated that opioid enhances HIV infection of human macrophages through modulation of β-chemokines and the CCR5 receptor and that this effect is reversed by naltrexone, a tertiary opioid antagonist. Tertiary opioid antagonists cannot be used in opioid-dependent patients because they precipitate withdrawal or reversal of analgesia. We determined whether the quaternary opioid antagonist methylnaltrexone (MNTX), now in phase III clinical trials for opioid-induced constipation, reverses the opioid-mediated enhancement of HIV infection of macrophages at clinically relevant doses. MNTX completely abrogated morphine-induced HIV Bal strain infection of macrophages. MNTX also inhibited the R5 strain (ADA) envelope-pseudotyped HIV replication induced by morphine. Furthermore, MNTX abolished morphine-mediated up-regulation of CCR5 receptor expression. The ability of MNTX to block opioid-induced CCR5 expression and HIV replication at clinically relevant doses may have additional benefit for opioid abusers with HIV infection, or patients with AIDS pain receiving opioids.
TL;DR: A complex network of interactions involving immune mediators produced by monocytes/macrophages and other cell types as a direct/indirect consequence of HIV infection is operative at all stages of the disease and may profoundly influence the extent of viral replication, dissemination, and pathogenesis.
Abstract: Monocytes/macrophages are cells of the innate arm of the immune system and exert important regulatory effects on adaptive immune response. These cells also represent major targets of HIV infection and one of the main reservoirs. Notably, macrophage-tropic viruses are responsible for the initial infection, predominate in the asymptomatic phase, and persist throughout infection, even after the emergence of dual-tropic and T-tropic variants. Functional impairment of HIV-infected macrophages plays an important role in the immune dysregulation typical of AIDS. Recent studies have underlined the pivotal role of chemokines, cytokines, and their receptors in HIV pathogenesis. It is becoming increasingly apparent that the expression level of chemokine receptors, serving as HIV coreceptors, influences the susceptibility of a CD4+ cell to viral infection and to certain HIV envelope-induced alterations in cellular functions. Numerous pathogens, including HIV, can stimulate the production of chemokines and cytokines, which in turn can modulate coreceptor availability, resulting in differential replication potential for R5 and X4 strains, depending on the microenvironment milieu. Thus, a complex network of interactions involving immune mediators produced by monocytes/macrophages and other cell types as a direct/indirect consequence of HIV infection is operative at all stages of the disease and may profoundly influence the extent of viral replication, dissemination, and pathogenesis.
TL;DR: The data indicate that CXCR4 affects cell-cycle proteins in neurons and raise the possibility that chemokines may contribute to neuronal survival by repressing the activity of E2F-dependent apoptotic genes and maintaining neurons in a highly differentiated and quiescent state.
Abstract: Neurons express a variety of chemokine receptors that regulate neuronal signaling and survival, including CXCR4 and CCR5, the two major human immunodeficiency virus (HIV) coreceptors. However, the role of chemokine receptors in HIV neuropathology and neuroinflammatory disorders is still unclear. This study aims to determine whether chemokine receptors regulate the activity of cell-cycle proteins in neurons and evaluate the possibility that alterations of these proteins are involved in HIV neuropathogenesis. The authors studied the effect of the chemokine stromal cell-derived factor (SDF)-1α, the natural CXCR4 ligand, and an X4-using variant of gp120 on the activity of cell-cycle proteins involved in neuronal apoptosis and differentiation, such as Rb and E2F-1. Changes in expression, localization, and phosphorylation/activation of Rb and E2F-1 induced by SDF-1α (20 nM) gp120IIIB (200 pM) were analyzed in primary cultures of rat neurons and in a human cell line expressing recombinant CXCR4. The data indicate that changes in the nuclear and cytosolic levels of Rb—which result in the functional loss of this protein—are associated with apoptosis in hippocampal or cerebellar granule neurons and in cell lines. SDF-1α, which is able to rescue these neurons from apoptosis, induces a time-dependent increase of total Rb expression while decreasing the nuclear content of phosphorylated (Ser780/Ser795) Rb and the transcriptional activity of E2F-1. The HIV envelope protein gp120IIIB exerts opposite effects at the nuclear level. These data indicate that CXCR4 affects cell-cycle proteins in neurons and raise the possibility that chemokines may contribute to neuronal survival by repressing the activity of E2F-dependent apoptotic genes and maintaining neurons in a highly differentiated and quiescent state. This state may be altered during neuroinflammatory conditions and/or by HIV-derived proteins.