UMLS:C0019693 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A genetic defect in a CC-chemokine receptor (CCR)-5, the principal coreceptor for the macrophage-tropic HIV type 1 (HIV-1), recently was found to naturally protect CCR-5-defective, but healthy, individuals from HIV-1 infection. In this study, we mimic the natural resistance of the CCR-5-defective individuals by designing a strategy to phenotypically knock out CCR-5. The inactivation of the CCR-5 coreceptor is accomplished by targeting a modified CC-chemokine to the endoplasmic reticulum to block the surface expression of newly synthesized CCR-5. The lymphocytes transduced to express the intracellular chemokine, termed "intrakine," were found to be viable and resistant to macrophage-tropic HIV-1 infection. Thus, this gene-based intrakine strategy targeted at the conserved cellular receptor for the prevention of HIV-1 entry should have significant advantages over currently described approaches for HIV-1 therapy.
...
PMID:Phenotypic knockout of HIV type 1 chemokine coreceptor CCR-5 by intrakines as potential therapeutic approach for HIV-1 infection. 932 50

Entry of the type 1 human immunodeficiency virus into most cells requires the presence of the CD4 protein in combination with one of several recently described co-receptors. CXCR-4 (fusin) was the first identified, and it serves as co-receptor for T-cell-line tropic (T-tropic) HIV-1 isolates. To determine the expression of CXCR-4 in the brain, a major target of HIV pathology, we used immunohistochemistry and reverse transcriptase polymerase chain reaction with CXCR-4-specific antibodies and probes. We found that CXCR-4 was expressed in several cell types in brain, but notably in neurons and microglia, a finding that was replicated in tissue culture. The study of the expression of CXCR-4 in the brain, which may be one of many chemokine receptors in the central nervous system, may provide further insight into the interactions between brain cells, pathogens, and the immune system, and help understand the pathogenesis of HIV dementia.
...
PMID:CXCR-4 (Fusin), a co-receptor for the type 1 human immunodeficiency virus (HIV-1), is expressed in the human brain in a variety of cell types, including microglia and neurons. 932 37

beta-Chemokines and their receptors mediate the trafficking and activation of a variety of leukocytes including the lymphocyte and macrophage. An array of no less than eight beta-chemokine receptors has been identified, four of which are capable of recognizing the chemokines MIP1alpha and RANTES. Genetic deletion of one of the MIP1alpha and RANTES receptors, CCR5, is associated with protection from infection with HIV-1 in humans, while deletion of the ligand MIP1alpha protects against Coxsackie virus-associated myocarditis. In this report we show that the deletion of another receptor for MIP1alpha and RANTES, the CCR1 receptor, is associated with protection from pulmonary inflammation secondary to acute pancreatitis in the mouse. The protection from lung injury is associated with decreased levels of TNF-alpha in a temporal sequence indicating that the activation of the CCR1 receptor is an early event in the systemic inflammatory response syndrome.
...
PMID:Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. 932 66

CCR5 is a chemokine receptor expressed by T cells and macrophages, which also functions as the principal coreceptor for macrophage (M)-tropic strains of HIV-1. To understand the molecular basis of the binding of chemokines and HIV-1 to CCR5, we developed a number of mAbs that inhibit the various interactions of CCR5, and mapped the binding sites of these mAbs using a panel of CCR5/CCR2b chimeras. One mAb termed 2D7 completely blocked the binding and chemotaxis of the three natural chemokine ligands of CCR5, RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta, to CCR5 transfectants. This mAb was a genuine antagonist of CCR5, since it failed to stimulate an increase in intracellular calcium concentration in the CCR5 transfectants, but blocked calcium responses elicited by RANTES, MIP-1alpha, or MIP-1beta. This mAb inhibited most of the RANTES and MIP-1alpha chemotactic responses of activated T cells, but not of monocytes, suggesting differential usage of chemokine receptors by these two cell types. The 2D7 binding site mapped to the second extracellular loop of CCR5, whereas a group of mAbs that failed to block chemokine binding all mapped to the NH2-terminal region of CCR5. Efficient inhibition of an M-tropic HIV-1-derived envelope glycoprotein gp120 binding to CCR5 could be achieved with mAbs recognizing either the second extracellular loop or the NH2-terminal region, although the former showed superior inhibition. Additionally, 2D7 efficiently blocked the infectivity of several M-tropic and dual-tropic HIV-1 strains in vitro. These results suggest a complicated pattern of HIV-1 gp120 binding to different regions of CCR5, but a relatively simple pattern for chemokine binding. We conclude that the second extracellular loop of CCR5 is an ideal target site for the development of inhibitors of either chemokine or HIV-1 binding to CCR5.
...
PMID:Interaction of chemokine receptor CCR5 with its ligands: multiple domains for HIV-1 gp120 binding and a single domain for chemokine binding. 933 77

CXC-chemokine receptor (CXCR)-4/fusin, a newly discovered co-receptor for T-cell line (T)-tropic HIV-1 virus, plays a critical role in T-tropic virus fusion and entry into permissive cells. The occurrence of T-tropic HIV viruses is associated with CD4-positive cell decline and progression to AIDS, suggesting that the T-tropic HIV-1 contributes to AIDS pathogenesis. In this study, we used a novel strategy to inactivate CXCR-4 by targeting a modified CXC-chemokine to the endoplasmic reticulum (ER) to block the surface expression of newly synthesized CXCR-4. The genetically modified lymphocytes expressing this intracellular chemokine, termed "intrakine", are immune to T-tropic virus infection and appear to retain normal biological features. Thus, this genetic intrakine strategy is uniquely targeted at the conserved cellular receptor for the prevention of HIV-1 entry and may be developed into an effective treatment for HIV-1 infection and AIDS.
...
PMID:Inactivation of HIV-1 chemokine co-receptor CXCR-4 by a novel intrakine strategy. 933 10

The chemokine receptors CCR-5 and CXCR-4, and possibly CCR-3, are the principal human immunodeficiency virus type 1 (HIV-1) coreceptors, apparently interacting with HIV-1 envelope, in association with CD4. Cell lines coexpressing CD4 and these chemokine receptors were infected with a panel of seven primary HIV-2 isolates passaged in peripheral blood mononuclear cells (PBMC) and three laboratory HIV-2 strains passaged in T-cell lines. The CCR-5, CCR-3, and CXCR-4 coreceptors could all be used by HIV-2. The ability to use CXCR-4 represents a major difference between HIV-2 and the closely related simian immunodeficiency viruses. Most HIV-2 strains using CCR-5 could also use CCR-3, sometimes with similar efficiencies. As observed for HIV-1, the usage of CCR-5 or CCR-3 was observed principally for HIV-2 strains derived from asymptomatic individuals, while HIV-2 strains derived from AIDS patients used CXCR-4. However, there were several exceptions, and the patterns of coreceptor usage seemed more complex for HIV-2 than for HIV-1. The two T-tropic HIV-2 strains tested used CXCR-4 and not CCR-5, while T-tropic HIV-1 can generally use both. Moreover, among five primary HIV-2 strains all unable to use CXCR-4, three could replicate in CCR-5-negative PBMC, which has not been reported for HIV-1. These observations suggest that the CCR-5 coreceptor is less important for HIV-2 than for HIV-1 and indicate that HIV-2 can use other cell entry pathways and probably other coreceptors. One HIV-2 isolate replicating in normal or CCR-5-negative PBMC failed to infect CXCR-4+ cells or the U87MG-CD4 and sMAGI cell lines, which are permissive to infection by HIV-2 but not by HIV-1. This suggests the existence of several HIV-2-specific coreceptors, which are differentially expressed in cell lines and PBMC.
...
PMID:Usage of the coreceptors CCR-5, CCR-3, and CXCR-4 by primary and cell line-adapted human immunodeficiency virus type 2. 934 75

The CC chemokine receptors CCR5, CCR2, and CCR3 and the CXC chemokine receptor CXCR4 have been implicated as CD4-associated cofactors in the entry of primary and cell line-adapted human immunodeficiency virus type 1 (HIV-1) strains. CXCR4 is also a receptor for T-cell-line-adapted, CD4-independent strains of HIV-2. With the exception of this latter example, little has been reported on the entry cofactors used by HIV-2 strains. Here we show that a CD4-dependent, T-cell-line-adapted HIV-2 strain uses CXCR4 and, to a lesser extent, CCR3 for fusion with and infectious entry into cells. In a cell-to-cell fusion assay, the envelope protein of this virus can utilize a wider repertoire of chemokine receptors to induce fusion. These include CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4. Kinetic analysis indicated that cell lines expressing the receptors that support infection, CXCR4 and CCR3, form syncytia more rapidly than do cell lines expressing the other receptors. Nevertheless, although less efficient, fusion with CXCR2 expressing cells was specific, since it was inhibited by antibodies against CXCR2. The extensive use of chemokine receptors in cell-to-cell fusion has implications for understanding the molecular basis of CD4-chemokine receptor-induced lentivirus fusion and may have relevance for syncytium formation and the direct cell-to-cell transfer of virus in vivo.
...
PMID:Promiscuous use of CC and CXC chemokine receptors in cell-to-cell fusion mediated by a human immunodeficiency virus type 2 envelope protein. 934 97

CCR5, a receptor for the CC chemokines RANTES, Mip1alpha, and Mip1beta, has been identified as a coreceptor for infections by macrophage-tropic isolates of human immunodeficiency virus type 1 (HIV-1). To study its structure and function, we isolated cDNA clones of human, African green monkey (AGM), and NIH/Swiss mouse CCR5s, and we quantitatively analyzed infections by macrophage-tropic HIV-1 and SIVmac251 after transfecting human HeLa-CD4 cells with the CCR5 expression vectors. The AGM and NIH/Swiss mouse CCR5 proteins are 97.7 to 98.3% and 79.8% identical to the human protein, respectively. In addition, we analyzed site-directed mutants and chimeras of these CCR5s. Cell surface expression of CCR5 proteins was monitored by using a specific rabbit antiserum and by binding the chemokine [125I]Mip1beta. Our major results were as follows. (i) Two distinct AGM CCR5 sequences were reproducibly found in DNA from CV-1 cells. The AGM clone 1 CCR5 protein differs from that of clone 2 by two substitutions, Y14N in the amino-terminal extracellular region and L352F at the carboxyl terminus. Interestingly, AGM clone 1 CCR5 was inactive as a coreceptor for all tested macrophage-tropic isolates of HIV-1, whereas AGM clone 2 CCR5 was active. As shown by chimera studies and site-directed mutagenesis, the Y14N substitution in AGM clone 1 CCR5 was solely responsible for blocking HIV-1 infections. In contrast, both AGM CCR5 clones were active coreceptors for SIVmac251. Studies of DNA samples from other AGMs indicated frequent additional CCR5 polymorphisms, and we cloned an AGM clone 2 variant with a Q93R substitution in the extracellular loop 1 from one heterozygote. This variant CCR5 was active as a coreceptor for SIVmac251 but was only weakly active for macrophage-tropic isolates of HIV-1. In addition, SIVmac251 appeared to be dependent on the extracellular amino terminus and loop 2 regions of human CCR5 for maximal infection. Our results suggest major differences in the interactions of SIVmac251 and macrophage-tropic HIV-1 isolates with 19, N13, and Y14 in the amino terminus; with Q93 in extracellular loop 1; and with extracellular loop 2 of human CCR5. (ii) The NIH/Swiss mouse CCR5 protein differs at multiple positions from sequences recently reported for other inbred strains of mice. This CCR5 was inactive as a coreceptor for HIV-1 and SIVmac251. Studies of chimeras that contained different portions of NIH/Swiss mouse CCR5 substituted into human CCR5, as well as the reciprocal chimeras, indicated that the amino-terminal region and extracellular loops 1 and 2 of human CCR5 contribute to its coreceptor activity for macrophage-tropic isolates of HIV-1. Specific differences with previous CCR5 chimera results occurred because the NIH/Swiss mouse CCR5 contains a unique substitution corresponding to P183L in extracellular loop 2 that is nonpermissive for coreceptor activity. We conclude that diverse CCR5 sequences occur in AGMs and mice, that SIVmac251 and macrophage-tropic HIV-1 isolates interact differently with specific CCR5 amino acids, and that multiple regions of human CCR5 contribute to its coreceptor functions. In addition, we have identified naturally occurring amino acid polymorphisms in three extracellular regions of CCR5 (Y14N, Q93R, and P183L) that do not interfere with cell surface expression or Mip1beta binding but prevent infections by macrophage-tropic isolates of HIV-1. In contrast to previous evidence, these results suggest that CCR5 contains critical sites that are essential for HIV-1 infections.
...
PMID:Polymorphisms in the CCR5 genes of African green monkeys and mice implicate specific amino acids in infections by simian and human immunodeficiency viruses. 934 22

Chemokines are cytokines that activate and induce the migration of leukocytes. Stroma-derived factor-1 (SDF-1) is a novel chemokine that blocks the entry of T-tropic HIV-1 mediated by fusin/CXCR4/LESTR (leukocyte-derived seven-transmembrane domain receptor). In this work we demonstrate that SDF-1 triggers increases in intracellular calcium and inhibits the proliferation of myeloid progenitor cell line 32D. By contrast, SDF-1 neither triggers a calcium response nor affects the proliferation of the myeloid progenitor cell line 32D-GR that is deficient in CXCR4. Responsiveness to SDF-1 was rescued by transfection of 32D-GR cells with a cDNA encoding the human CXCR4. The data indicate that SDF-1 induces myelosuppression by activation of CXCR4. The constitutive production of SDF-1 by bone marrow stromal cells argues for a major role of SDF-1 on the regulation of myelopoiesis.
...
PMID:Activation of HIV-1 coreceptor (CXCR4) mediates myelosuppression. 934 84

The chemokine receptor CXCR4 is required, together with CD4, for entry by some isolates of HIV-1, particularly those that emerge late in infection. The use of CXCR4 by these viruses likely has profound effects on viral host range and correlates with the evolution of immunodeficiency. Stromal cell-derived factor-1 (SDF-1), the ligand for CXCR4, can inhibit infection by CXCR4-dependent viruses. To understand the mechanism of this inhibition, we used a monoclonal antibody that is specific for CXCR4 to analyze the effects of phorbol esters and SDF-1 on surface expression of CXCR4. On human T cell lines SupT1 and BC7, CXCR4 undergoes slow constitutive internalization (1.0% of the cell surface pool/min). Addition of phorbol esters increased this endocytosis rate >6-fold and reduced cell surface CXCR4 expression by 60 to 90% over 120 min. CXCR4 was internalized through coated pits and coated vesicles and subsequently localized in endosomal compartments from where it could recycle to the cell surface after removal of the phorbol ester. SDF-1 also induced the rapid down modulation (half time approximately 5 min) of CXCR4. Using mink lung epithelial cells expressing CXCR4 and a COOH-terminal deletion mutant of CXCR4, we found that an intact cytoplasmic COOH-terminal domain was required for both PMA and ligand-induced CXCR4 endocytosis. However, experiments using inhibitors of protein kinase C indicated that SDF-1 and phorbol esters trigger down modulation through different cellular mechanisms. SDF-1 inhibited HIV-1 infection of mink cells expressing CD4 and CXCR4. The inhibition of infection was less efficient for CXCR4 lacking the COOH-terminal domain, suggesting at least in part that SDF-1 inhibition of virus infection was mediated through ligand-induced internalization of CXCR4. Significantly, ligand induced internalization of CXCR4 but not CD4, suggesting that CXCR4 and CD4 do not normally physically interact on the cell surface. Together these studies indicate that endocytosis can regulate the cell-surface expression of CXCR4 and that SDF-1-mediated down regulation of cell-surface coreceptor expression contributes to chemokine-mediated inhibition of HIV infection.
...
PMID:Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. 934 82

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>