UMLS:C0019693 - FACTA Search

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

We demonstrate that human immunodeficiency virus HIV-1(LAI) envelope glycoprotein 120 (gp120(LAi)) specifically interacts with several membrane ligands on lymphoid CEM or monocytic U937 cells in addition to its previously identified receptor, CD4, and CXCR4, its coreceptor. In its native state, gp120(LAI) is able to elicit specific multimolecular complexes with these membrane ligands at the surface of the cells; most of the interactions are abolished by mannan or heparin but not by dextran. Similarly, stromal cell-derived factor (SDF)-1alpha interacts not only with CXCR4 expressed by CXCR4(+) CD4(+) U937, CEM, and HOS-CD4(+) CXCR4(+) cells but also with CD4 expressed by intact U937, CEM, and HOS-CD4(+) CXCR4(+/-) cells or electroblotted onto Immobilon. SDF-1alpha binding to CD4(+) CXCR4(+/-) cells, or soluble CD4 electroblotted onto Immobilon, is significantly inhibited by sCD4, whereas truncated sCD4 lacking D3 and D4 domains had no significant effect, which indicates that SDF-1 binds to CD4 but at regions different from the HIV-gp120-binding site. Heparin and mannan also inhibit SDF-1alpha binding to intact CD4(+) CXCR4(+/-) cells, and electroblotted soluble CD4. Heparitinase treatment of such cells reduced SDF-1alpha binding. These data demonstrate that glycans and glycosaminoglycans are directly or indirectly involved in the interactions of HIV-1 gp120(LAI) and of SDF-1alpha with membrane ligands of CD4(+) CXCR4(+) cells and thus could play a role both in HIV-1 infection and in the physiology of SDF-1alpha.
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PMID:Glycans and proteoglycans are involved in the interactions of human immunodeficiency virus type 1 envelope glycoprotein and of SDF-1alpha with membrane ligands of CD4(+) CXCR4(+) cells. 1060 Jun 6

CD34(+) cells are nonpermissive to infection by HIV strains X4 and R5, despite the fact that many CD34(+) cells express high levels of the viral receptor protein CD4 and the coreceptor CXCR4 on their surface. In these cells, the co-receptor CCR5 protein, which, like CXCR4, is a chemokine receptor, is detected mainly intracellularly. We hypothesized that CD34(+) cells secrete CCR5-binding chemokines and that these factors interfere with HIV R5 interactions with these cells, possibly by binding CCR5 or by inducing its internalization. We found that human CD34(+) cells and CD34(+)KIT(+) cells, which are enriched in myeloid progenitor cells, expressed and secreted the CCR5 ligands RANTES, MIP-1alpha, and MIP-1beta and that IFN-gamma stimulated expression of these chemokines. In contrast, SDF-1, a CXCR4 ligand, was not detectable in the CD34(+)KIT(+) cells, even by RT-PCR. Conditioned media from CD34(+) cell culture significantly protected the T lymphocyte cell line PB-1 from infection by R5 but not X4 strains of HIV. Interestingly, the secretion of endogenous chemokines decreased with the maturation of CD34(+) cells, although ex vivo, expanded megakaryoblasts still secreted a significant amount of RANTES. Synthesis of CCR5-binding chemokines by human CD34(+) cells and megakaryoblasts therefore largely determines the susceptibility of these cells to infection by R5 HIV strains. We postulate that therapeutic agents that induce the endogenous synthesis of chemokines in human hematopoietic cells may protect these cells from HIV infection.
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PMID:Bone marrow CD34(+) cells and megakaryoblasts secrete beta-chemokines that block infection of hematopoietic cells by M-tropic R5 HIV. 1060 28

It has been shown that deletion of the chemokine receptor, CXCR4, causes disordered angiogenesis in mouse models. In the present studies, we examined the distribution and trafficking of CXCR4 in human endothelial cells, tested their responses to the CXCR4 ligand, SDF-1, and asked whether endothelial cell CXCR4 can serve as a cell surface receptor for the binding of viruses. The results show that CXCR4 is present on endothelial cells from coronary arteries, iliac arteries and umbilical veins (HUVEC), but expression was heterogeneous, with some cells expressing CXCR4 on their surface, while others did not. Addition of SDF-1 caused a rapid decrease in CXCR4 surface expression. It also caused CXCR4-mediated activation of MAPK, release of PGI(2), endothelial migration, and the formation of capillary-like structures by endothelial cells in culture. Co-culture of HUVEC with lymphoid cells that were chronically infected with a CD4-independent/CXCR4-tropic variant of HIV-2 resulted in the formation of multinucleated syncytia. Formation of the syncytia was inhibited by each of several different CXCR4 antibodies. Thus, our findings indicate: (1) that CXCR4 is widely expressed on human endothelial cells; (2) the CXCR4 ligand, SDF-1, can evoke a wide variety of responses from human endothelial cells; and (3) CXCR4 on endothelial cells can serve as a receptor for isolates of HIV that can utilize chemokine receptors in the absence of CD4.
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PMID:CXCR4 on human endothelial cells can serve as both a mediator of biological responses and as a receptor for HIV-2. 1065 92

The effects of chemokine and chemokine receptor genetic polymorphisms such as stromal derived factor 1 (SDF1-3'A), CCR2-64I, and CCR5-delta32 associated with HIV-1 transmission and/or rate of disease progression in infected study subjects remain highly controversial and have been analyzed primarily only in adults. We have investigated whether these polymorphisms may provide similar beneficial effects in children exposed to HIV-1 perinatally. The prevalence of CCR2-64I allele was significantly increased (p = .03) and the CCR2-64I genotype distribution was not in Hardy-Weinberg equilibrium, among HIV-1-exposed uninfected infants. Moreover, in the HIV-1-infected group, a delay to AIDS progression was observed among carriers of CCR2-64I allele. This is the first report that suggests a protective role of CCR2-64I allele in mother-to-infant HIV-1 transmission and documents a delay in disease progression, after the child has been infected with HIV-1. However, SDFI-3'A and CCR5-delta32 alleles did not modify the rate of HIV-1 transmission or disease progression in HIV-1-infected children.
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PMID:Protective effect of CCR2-64I and not of CCR5-delta32 and SDF1-3'A in pediatric HIV-1 infection. 1070 56

In order to better define the role of HIV-related chemokines in human erythropoiesis we studied: A) the expression of chemokine receptors, both on human CD34(+) cells which include erythroid progenitors and on more mature erythroid cells; B) the functionality of these receptors by calcium flux, chemotaxis assay and phosphorylation of mitogen-activated protein kinases (MAPK) p42/44 (ERK1/ERK2) and AKT, and finally C) the influence of chemokines on BFU-E formation. We found that HIV-related chemokine receptor CXCR4, but not CCR5, is detectable on human CD34(+) BFU-E cells. CXCR4 surface expression decreased during erythroid maturation, although CXCR4 mRNA was still present in cells isolated from differentiated erythroid colonies. SDF-1, a CXCR4 ligand, induced calcium flux and phosphorylation of MAPK (p42/44) and AKT in CD34(+)KIT(+) bone marrow mononuclear cells which contain BFU-E, as well as chemotactic activity of both human CD34(+) BFU-E progenitors and erythroid cells isolated from day 2-6 BFU-E colonies. Responsiveness to SDF-1 decreased when the cells differentiated to the point of surface expression of the erythroid-specific marker Glycophorin-A. In contrast, the CCR5 ligands (macrophage inflammatory protein-1alpha [MIP-1alpha], MIP-1beta, and RANTES) did not activate calcium flux, MAPK and AKT phosphorylation or chemotaxis of CD34(+)KIT(+) cells or cells isolated from the BFU-E colonies. Interestingly, none of the chemokines tested in this study had any effect on BFU-E colony formation. In conclusion, only CXCR4 is functional, and its specific ligand SDF-1 may therefore play an important role in the homing and/or retention of early erythroid precursors in the bone marrow environment.
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PMID:The role of HIV-related chemokine receptors and chemokines in human erythropoiesis in vitro. 1074 85

Factors accounting for long-term nonprogression may include infection with an attenuated strain of human immunodeficiency virus type 1 (HIV-1), genetic polymorphisms in the host, and virus-specific immune responses. In this study, we examined eight individuals with nonprogressing or slowly progressing HIV-1 infection, none of whom were homozygous for host-specific polymorphisms (CCR5-Delta32, CCR2-64I, and SDF-1-3'A) which have been associated with slower disease progression. HIV-1 was recovered from seven of the eight, and recovered virus was used for sequencing the full-length HIV-1 genome; full-length HIV-1 genome sequences from the eighth were determined following amplification of viral sequences directly from peripheral blood mononuclear cells (PBMC). Longitudinal studies of one individual with HIV-1 that consistently exhibited a slow/low growth phenotype revealed a single amino acid deletion in a conserved region of the gp41 transmembrane protein that was not seen in any of 131 envelope sequences in the Los Alamos HIV-1 sequence database. Genetic analysis also revealed that five of the eight individuals harbored HIV-1 with unusual 1- or 2-amino-acid deletions in the Gag sequence compared to subgroup B Gag consensus sequences. These deletions in Gag have either never been observed previously or are extremely rare in the database. Three individuals had deletions in Nef, and one had a 4-amino-acid insertion in Vpu. The unusual polymorphisms in Gag, Env, and Nef described here were also found in stored PBMC samples taken 3 to 11 years prior to, or in one case 4 years subsequent to, the time of sampling for the original sequencing. In all, seven of the eight individuals exhibited one or more unusual polymorphisms; a total of 13 unusual polymorphisms were documented in these seven individuals. These polymorphisms may have been present from the time of initial infection or may have appeared in response to immune surveillance or other selective pressures. Our results indicate that unusual, difficult-to-revert polymorphisms in HIV-1 can be found associated with slow progression or nonprogression in a majority of such cases.
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PMID:Unusual polymorphisms in human immunodeficiency virus type 1 associated with nonprogressive infection. 1075 51

Genetic polymorphisms in chemokine and chemokine receptor genes influence susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and disease progression, but little is known regarding the association between these allelic variations and the ability of the host to transmit virus. In this study, we show that the maternal heterozygous SDF1 genotype (SDF1 3'A/wt) is associated with perinatal transmission of HIV-1 (risk ratio [RR], 1.8; 95% confidence interval [CI], 1.0 to 3.3) and particularly postnatal breastmilk transmission (RR, 3.1; 95% CI, 1.1 to 8.6). In contrast, the infant SDF1 genotype had no effect on mother-to-infant transmission. These data suggest that SDF1, which is a ligand for the T-tropic HIV-1 coreceptor CXCR4, may affect the ability of a mother to transmit the virus to her infant. This suggests that a genetic polymorphism in a gene encoding a chemokine receptor ligand may be associated with increased infectivity of the index case and highlights the importance of considering transmission as well as clinical outcome in designing chemokine-based therapies for HIV-1.
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PMID:Maternal SDF1 3'A polymorphism is associated with increased perinatal human immunodeficiency virus type 1 transmission. 1082 84

CXCR4 is a G-coupled receptor for the stromal cell-derived factor (SDF-1) chemokine, and a CD4-associated human immunodeficiency virus type 1 (HIV-1) coreceptor. These functions were studied in a panel of CXCR4 mutants bearing deletions in the NH(2)-terminal extracellular domain (NT) or substitutions in the NT, the extracellular loops (ECL), or the transmembrane domains (TMs). The coreceptor activity of CXCR4 was markedly impaired by mutations of two Tyr residues in NT (Y7A/Y12A) or at a single Asp residue in ECL2 (D193A), ECL3 (D262A), or TMII (D97N). These acidic residues could engage electrostatical interactions with basic residues of the HIV-1 envelope protein gp120, known to contribute to the selectivity for CXCR4. The ability of CXCR4 mutants to bind SDF-1 and mediate cell signal was consistent with the two-site model of chemokine-receptor interaction. Site I involved in SDF-1 binding but not signaling was located in NT with particular importance of Glu(14) and/or Glu(15) and Tyr(21). Residues required for both SDF-1 binding and signaling, and thus probably part of site II, were identified in ECL2 (Asp(187)), TMII (Asp(97)), and TMVII (Glu(288)). The first residues () of NT also seem required for SDF-1 binding and signaling. A deletion in the third intracellular loop abolished signaling, probably by disrupting the coupling with G proteins. The identification of CXCR4 residues involved in the interaction with both SDF-1 and HIV-1 may account for the signaling activity of gp120 and has implications for the development of antiviral compounds.
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PMID:Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities. 1082 58

HIV-1 encephalitis occurs in up to one-third of HIV-1-infected individuals. The mechanisms through which this pathology develops are thought to involve viral passage across the blood-brain barrier (BBB), as well as entry of HIV-infected and/or uninfected inflammatory cells into the central nervous system (CNS). Viral proteins and cytokines may also contribute to the pathogenesis of encephalitis. We show that the chemokines SDF-1 and MCP-1 induce transmigration of uninfected human lymphocytes and monocytes across our model of the BBB, a co-culture of human fetal astrocytes and endothelial cells. We also demonstrate that the HIV-1 protein Tat induces adhesion molecule expression and chemokine production by human fetal astrocytes and microglia, which could further contribute to leukocyte entry into the CNS. Finally, our data indicate that inflammatory cytokines modulate the expression of CXCR4, a co-receptor for HIV-1, on human fetal astrocytes, suggesting that these cytokines may potentially modulate the infectability of astrocytes by HIV-1. These findings support the hypothesis that there may be several different mechanisms that contribute to the development and progression of HIV-1 encephalitis.
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PMID:Mechanisms of leukocyte trafficking into the CNS. 1087 69

Chemokines constitute a large and still growing family of structurally-related small (8-10 kDa) cytokines that have chemotactic activity for leukocytes. Recently, some receptors for chemokines were reported to be used as a co-receptor by HIV at infection. In addition to their well-established role in inflammatory response and recently-reported role as a co-receptor for HIV, recent data suggest that chemokines and their receptors physiologically and pathologically play crucial roles as the mediators for intercellular communication among the cells intrinsic to and recruited into the brain; i.e., neurons, astrocytes, microglia, endothelial cells and leukocytes. Some chemokines such as SDF-1 and fractalkine are constitutively produced in the brain, implicating that they have an important role in maintenance of CNS homeostasis or determination of the patterning of neurons and/or glial cells in developing brain and normal adult brain. Chemokines such as MCP-1, MIP-1 alpha and CINC were shown to be induced by various neuroinflammatory stimuli, suggesting that they are involved in various neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, stroke and AIDS dementia syndrome. Chemokines and their receptors are potential targets for therapeutic intervention in neurodegenerative diseases.
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PMID:[Chemokines as mediators for intercellular communication in the brain]. 1087 3

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