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

The chemokine receptor CCR5 has been found to play a key role in early infection with macrophage-tropic isolates of HIV-1 and CCR5 deficiency is associated with a relative resistance to HIV-1 infection. In this context, we studied the regulation of CCR5 gene expression by cytokines, and in particular, interleukin (IL)-10 in human monocytes. CCR5 mRNA was rapidly up-regulated by exposure of monocytes to graded concentrations of IL-10, with near maximal stimulation with 10 ng/ml. The effect was rapid, being detectable as early as 1 h and maximal between 2 and 4 h of treatment. Pretreatment of monocytes with actinomycin D prevented the IL-10-induced effect, suggesting a transcriptional mechanism for CCR5 up-regulation by IL-10. Protein expression of CCR5 was also enhanced by IL-10, as indicated by a 3-fold increase in anti-CCR5 antibody labeling of monocytes treated for 20 h with IL-10. Increased surface expression of CCR5 persisted at 48 h of treatment. Moreover, IL-10-treated monocytes responded with augmented intracellular Ca++ mobilization and enhanced (3-4-fold) chemotaxis in response to the CCR5 ligand MIP-1beta(25 ng/ml). Taken together, our data indicate that IL-10 can modulate CCR5 expression and function. This can constitute a potentially important regulatory mechanism which can affect not only responses during inflammation, but also susceptibility to HIV-1 infection.
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PMID:IL-10 up-regulates CCR5 gene expression in human monocytes. 1039 58

HIV-1 enters target cells mainly via binding to CD4 and its coreceptors. The presence of HIV-1 in CD4- cells suggests, however, that there exist other mechanisms for viral entry. Here it is reported that HIV-1 DNA may be transferred from one cell to another by uptake of apoptotic bodies in a CD4-independent way. This was investigated by coculturing CD4-, chemokine receptor CCR5- and CXCR4- human fetal fibroblasts with apoptotic HIV-1-infected HuT78 cells or apoptotic PBMC isolated from HIV-1-infected patients. After 2 wk of coculture, fibroblasts contained HIV-1 DNA and expressed HIV-1 proteins p24 and gp120. Transfer of HIV-1 DNA was verified by coculturing fibroblasts with apoptotic bodies derived from cells infected with a defective HIV-1 virus. These cells contain one integrated copy of a reverse transcriptase (RT)-negative HIV-1 strain (8E5/LAV RT- cells) and consequently cannot produce free virus. Intracellular HIV-1 gag DNA was detected in both fibroblasts and dendritic cells after coculture with apoptotic 8E5/LAV RT- cells. Transfer of viral DNA after uptake of apoptotic bodies may explain HIV-1 infection of CD4- cells in vivo and furthermore may be relevant for Ag presentation.
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PMID:Functional gene transfer of HIV DNA by an HIV receptor-independent mechanism. 1039 65

Human immunodeficiency virus type 1 (HIV-1) non-syncytium-inducing (NSI) strains predominantly use the chemokine receptor CCR5, while syncytium-inducing (SI) strains use CXCR4. In vitro, SI isolates infect and replicate in a range of CD4(+) CXCR4(+) T-cell lines, whereas NSI isolates usually do not. Here we describe three NSI strains that are able to infect two CD4(+) T-cell lines, Molt4 and SupT1. For one strain, a variant of JRCSF selected in vitro, replication on Molt4 was previously shown to be conferred by a single amino-acid change in the V1 loop (M.T. Boyd et al., J. Virol. 67:3649-3652, 1993). On CD4(+) cell lines expressing different coreceptors, these strains use CCR5 predominantly and do not replicate in CCR5-negative peripheral blood mononuclear cells derived from individuals homozygous for Delta32 CCR5. Furthermore, infection of Molt4 and SupT1 by each of these three strains is potently inhibited by ligands for CCR5, including 2D7, a monoclonal antibody specific for CCR5. CCR5 mRNA was present in both Molt4 and SupT1 by reverse transcription-PCR, although CCR5 protein could not be detected either on the cell surface or in intracellular vesicles. The expanded tropism of the three strains shown here is therefore not due to adaptation to a new coreceptor but due to the capacity to exploit extremely low levels of CCR5 on Molt4 and SupT1 cells. This novel tropism observed for a subset of primary HIV-1 isolates may represent an extended tropism to new CD4(+) cell types in vivo.
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PMID:Expanded tropism of primary human immunodeficiency virus type 1 R5 strains to CD4(+) T-cell lines determined by the capacity to exploit low concentrations of CCR5. 1043 77

Memory T cells that home to inflamed tissues typically express the beta-chemokine receptor CCR5 and exhibit a Th1 cytokine profile. The migration of these cells into the genital tract following antigenic exposure has particular relevance to acquisition of HIV-1 infection, because CCR5 functions as the coreceptor for most sexually transmitted HIV-1 strains. We recently established methodology to purify and culture mononuclear cells from the female reproductive tract, and here we analyzed the phenotype, CCR5 expression, and cytokine production of cervicovaginal T cells in up to 16 donors. The proportion of mucosal T cells expressing CCR5 was markedly expanded as compared with peripheral blood (mean 88% vs 24% in 13 donors), but the receptor density on individual CCR5+ T cells was only slightly increased (mean 5837 vs 4191 MEPE (molecules of equivalent PE) units in 6 of 7 donors). Intracellular costaining for IL-2, IFN-gamma, IL-4, and IL-5 revealed a Th1-type pattern in cervical T cells, with significantly higher percentages of IL-2- and IFN-gamma-producing T cells in the mucosa than in blood (mean 67% vs 29%). Coexpression of surface CCR5 with intracellular IL-2 and IFN-gamma was observed only among T cells in the mucosa, but not among those in circulation. Thus, we postulate that T cell homing to the genital mucosa leads to differentiation into the combined CCR5+ Th1 phenotype. Moreover, the predominance of CCR5+ Th1-type T cells in normal cervical mucosa provides targets accessible for the efficient transmission of macrophage-tropic HIV-1 variants in women following sexual exposure.
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PMID:Coexpression of CCR5 and IL-2 in human genital but not blood T cells: implications for the ontogeny of the CCR5+ Th1 phenotype. 1043 76

The chemokine receptor CCR5 has been shown to be a major coreceptor for HIV-1. The chemokines that bind to this receptor (MIP-1alpha, MIP-1beta, and RANTES) are potent inhibitors of HIV replication and may play an important role in the pathophysiology of HIV disease. We investigated the effect of potent antiretroviral therapy (ritonavir and saquinavir) on the production of MIP-1alpha, MIP-1beta, and RANTES in 19 HIV-infected patients who had sustained decreases in plasma HIV RNA levels (<200 copies/ml). Chemokine concentrations were measured in serum, plasma, and PHA-stimulated PBMCs at baseline and 24 and 48 weeks after initiating therapy. MIP-1alpha, MIP-1beta, and RANTES levels in serum and plasma did not significantly change in the 48-week period. In contrast, MIP-1alpha and MIP-1beta secreted by PHA-stimulated PBMCs increased at 24 weeks, with this increase sustained at 48 weeks, whereas no significant change was observed in PHA-induced RANTES production. A significant positive correlation was found between the changes in PHA-induced chemokine production and baseline CD4+ T cell counts. These data demonstrate that sustained suppression of viral replication by potent antiretroviral therapy has a potentially beneficial effect on chemokine production and early initiation of this therapy appears to confer a more favorable chemokine profile.
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PMID:Sustained suppression of plasma HIV RNA is associated with an increase in the production of mitogen-induced MIP-1alpha and MIP-1beta. 1046 27

Infection of target cells by HIV-1 requires initial binding interactions between the viral envelope glycoprotein gp120, the cell surface protein CD4, and one of the members of the seven-transmembrane G protein-coupled chemokine receptor family. Most primary isolates (R5 strains) use chemokine receptor CCR5, but some primary syncytium-inducing, as well as T cell line-adapted, strains (X4 strains) use the CXCR4 receptor. Signaling from both CCR5 and CXCR4 is mediated by pertussis toxin (PTX)-sensitive G(i) proteins and is not required for HIV-1 entry. Here, we show that the PTX holotoxin as well as its binding subunit, B-oligomer, which lacks G(i)-inhibitory activity, blocked entry of R5 but not X4 strains into primary T lymphocytes. Interestingly, B-oligomer inhibited virus production by peripheral blood mononuclear cell cultures infected with either R5 or X4 strains, indicating that it can affect HIV-1 replication at both entry and post-entry levels. T cells treated with B-oligomer did not initiate signal transduction in response to macrophage inflammatory protein (MIP)-1beta or RANTES (regulated upon activation, normal T cell expressed and secreted); however, cell surface expression of CCR5 and binding of MIP-1beta or HIV-1 to such cells were not impaired. The inhibitory effect of B-oligomer on signaling from CCR5 and on entry of R5 HIV-1 strains was reversed by protein kinase C (PKC) inhibitors, indicating that B-oligomer activity is mediated by signaling events that involve PKC. B-oligomer also blocked cocapping of CCR5 and CD4 induced by R5 HIV-1 in primary T cells, but did not affect cocapping of CXCR4 and CD4 after inoculation of the cultures with X4 HIV-1. These results suggest that the B-oligomer of PTX cross-deactivates CCR5 to impair its function as a coreceptor for HIV-1.
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PMID:The B-oligomer of pertussis toxin deactivates CC chemokine receptor 5 and blocks entry of M-tropic HIV-1 strains. 1047 44

Human immunodeficiency virus type 1 (HIV-1) infection of CD4(+) lymphocytes and macrophages involves interaction of the surface subunit of the envelope protein (gp120) with coreceptors. Isolates have been found with specific tropism for macrophages and/or T-cell lines, through the utilization of chemokine receptor CCR5 (R5) or CXCR4 (X4). The third hypervariable loop (V3 loop) of gp120 is the major determinant of tropism. Using chimeric envelopes between HXB2 (X4) and ADA (R5), we found that the C-terminal half of the V3 loop was sufficient to confer on HXB2 the ability to infect CCR5-expressing cells. A sequence motif was identified at positions 289 to 292 allowing 30% of wild-type levels of infection, whereas full activity was achieved with the conversion of Lys to Glu at position 287 in addition to the above motif. Moreover, V3 loops from either SF2 (X4R5) or SF162 (R5) also allowed infection of CCR5-expressing cells, supporting the importance of V3 loops in influencing CCR5 utilization. The effects of amino acid changes at position 287 on the level of infection via CCR5 showed that negatively charged residues (Glu and Asp) were optimal for efficient interaction whereas only bulky hydrophobic residues drastically reduced infection. In addition, sequences at the N terminus of the V3 loop independently modulated the level of infection via CCR5. This study also examined the susceptibility of chimeric envelopes to neutralization by anticoreceptor antibodies and suggested the presence of differential interaction between the chimeric envelopes and CCR5. These findings highlight the critical residues in the V3 loop that mediate HIV-1 infection.
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PMID:Analysis of the critical domain in the V3 loop of human immunodeficiency virus type 1 gp120 involved in CCR5 utilization. 1048 72

The chemokine receptor CCR5 can serve as a coreceptor for M-tropic HIV-1 infection and both M-tropic and T-tropic SIV infection. We sequenced the entire CCR5 gene from 10 nonhuman primates: Pongo pygmaeus, Hylobates leucogenys, Trachypithecus francoisi, Trachypithecus phayrei, Pygathrix nemaeus, Rhinopithecus roxellanae, Rhinopithecus bieti, Rhinopithecus avunculus, Macaca assamensis, and Macaca arctoides. When compared with CCR5 sequences from humans and other primates, our results demonstrate that: (1) nucleotide and amino acid sequences of CCR5 among primates are highly homologous, with variations slightly concentrated on the amino and carboxyl termini; and (2) site Asp13, which is critical for CD4-independent binding of SIV gp120 to Macaca mulatta CCR5, was also present in all other nonhuman primates tested here, suggesting that those nonhuman primate CCR5s might also bind SIV gp120 without the presence of CD4. The topologies of CCR5 gene trees constructed here conflict with the putative opinion that the snub-nosed langurs compose a monophyletic group, suggesting that the CCR5 gene may not be a good genetic marker for low-level phylogenetic analysis. The evolutionary rate of CCR5 was calculated, and our results suggest a slowdown in primates after they diverged from rodents. The synonymous mutation rate of CCR5 in primates is constant, about 1.1 x 10(-9) synonymous mutations per site per year. Comparisons of Ka and Ks suggest that the CCR5 genes have undergone negative or purifying selection. Ka/Ks ratios from cercopithecines and colobines are significantly different, implying that selective pressures have played different roles in the two lineages.
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PMID:Sequence evolution of the CCR5 chemokine receptor gene in primates. 1048 70

Seven-transmembrane segment, G protein-coupled receptors (GPCRs) play important roles in many biological processes in which pharmaceutical intervention may be useful. High level expression and native purification of GPCRs are important steps in the biochemical and structural characterization of these molecules. Here, we describe enhanced mammalian cell expression and purification of a codon-optimized variant of the chemokine receptor CCR5, a GPCR that plays a central role in the entry of the human immunodeficiency virus-1 (HIV-1) into immune cells. CCR5 could be solubilized in its native state as determined by its ability to be precipitated by 2D7, a conformation-dependent anti-CCR5 antibody, and by the HIV-1 gp120 envelope glycoprotein. The 2D7 antibody recognized immature and mature forms of CCR5 equally, whereas gp120 preferentially recognized the mature form, a result that underscores a role for posttranslational modification of CCR5 in its HIV-1 coreceptor function. The methods described herein contribute to the analysis of CCR5 and are likely to be applicable to many other GPCRs.
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PMID:Enhanced expression, native purification, and characterization of CCR5, a principal HIV-1 coreceptor. 1049 46

The probability of HIV transmission depends on the infectiousness of the infected partner, the susceptibility of the healthy partner, and the biological characteristics of HIV strains. A substantial role is attributable to the individual HIV susceptibility, which is affected by immunological and genetic factors. Among genetic factors, the chemokine receptor CCR5 has been thoroughly studied. CCR5 is a co-receptor for fusion and entry of macrophage-tropic variants of HIV-1, which are involved in sexual transmission. Consistent evidence shows that the absence of cell-surface expression of the HIV co-receptor CCR5, due to a homozygous 32 base pair deletion, renders individuals highly resistant to infection by macrophage-tropic HIV strains. Therefore, knowledge of this and of other genetic and immunologic factors that affect HIV-1 transmission is essential in understanding HIV-1 entry into cells, developing strategies for combating HIV-1 transmission and spread, and implementing new models for HIV-1 therapies and, hopefully, vaccines.
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PMID:Do chemokines play a role in HIV-1 heterosexual transmission? Susceptibility to HIV infection. 1050 32


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