Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CC-chemokine receptor 5 (CCR5) is the principal coreceptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). We have generated a set of anti-CCR5 monoclonal antibodies and characterized them in terms of epitope recognition, competition with chemokine binding, receptor activation and trafficking, and coreceptor activity. MC-4, MC-5, and MC-7 mapped to the amino-terminal domain, MC-1 to the second extracellular loop, and MC-6 to a conformational epitope covering multiple extracellular domains. MC-1 and MC-6 inhibited regulated on activation normal T cell expressed and secreted (RANTES), macrophage inflammatory polypeptide-1beta, and Env binding, whereas MC-5 inhibited macrophage inflammatory polypeptide-1beta and Env but not RANTES binding. MC-6 induced signaling in different functional assays, suggesting that this monoclonal antibody stabilizes an active conformation of CCR5. Flow cytometry and real-time confocal microscopy showed that MC-1 promoted strong CCR5 endocytosis. MC-1 but not its monovalent isoforms induced an increase in the transfer of energy between CCR5 molecules. Also, its monovalent isoforms bound efficiently, but did not internalize the receptor. In contrast, MC-4 did not prevent RANTES binding or subsequent signaling, but inhibited its ability to promote CCR5 internalization. These results suggest the existence of multiple active conformations of CCR5 and indicate that CCR5 oligomers are involved in an internalization process that is distinct from that induced by the receptor's agonists.
 ...
PMID:Multiple active states and oligomerization of CCR5 revealed by functional properties of monoclonal antibodies. 1185 25

Macrophages, microglia, and other mononuclear phagocytes serve as cellular reservoirs for viral persistence in patients with acquired immunodeficiency syndrome. To understand host mechanisms that affect human immunodeficiency virus type 1 (HIV-1) pathogenesis by modulating expression of coreceptors, cytokine regulation of CC chemokine receptor 5 (CCR5) and CD4 expression on monocytes, monocyte-derived macrophages (MDMs), and microglia was investigated. Interleukin (IL)-4 and IL-10 enhanced the entry and replication of HIV-1 in microglia through up-regulation of CD4 and CCR5 expression, respectively. IL-4 stimulated HIV-1 replication in MDMs but down-regulated CD4 and CCR5 expression and inhibited virus entry, whereas IL-10 had the opposite effects. Thus, mechanisms independent of CCR5 and CD4 expression levels are involved in pathways that regulate HIV-1 replication in MDMs. CCR5 up-regulation by IL-10 was associated with increased migration of microglia in response to macrophage inflammatory protein-1beta. These findings suggest that increased production of T helper type 2 cytokines in the later stages of disease can enhance virus entry and replication in mononuclear phagocytes and facilitate chemotactic migration.
 ...
PMID:Regulation of CC chemokine receptor 5 and CD4 expression and human immunodeficiency virus type 1 replication in human macrophages and microglia by T helper type 2 cytokines. 1192 Mar 12

Lipopolysaccharide (LPS) can inhibit human immunodeficiency virus (HIV) infection in monocytes in vitro. To test the hypothesis that an LPS effect on CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5), known coreceptors for HIV, contributes to this effect, 8 healthy men were intravenously injected with Escherichia coli LPS (4 ng/kg), and monocyte CXCR4 and CCR5 expression was monitored by fluorescence-activated cell sorter analysis. LPS induced a decrease in the fraction of peripheral blood monocytes expressing CXCR4 and CCR5, reaching a nadir after 2 h (both P<.001 vs. baseline). In whole blood in vitro, not only LPS but also lipoarabinomannan (a cell wall component of Mycobacterium tuberculosis) and lipoteichoic acid (a cell wall component of Staphylococcus aureus) down-regulated the expression of CXCR4 and CCR5 on monocytes (all P<.05). Exposure of monocytes to (myco)bacterial agents may render them relatively resistant to infection with HIV by an effect on HIV coreceptors.
 ...
PMID:Expression of human immunodeficiency virus coreceptors CXC chemokine receptor 4 and CC chemokine receptor 5 on monocytes is down-regulated during human endotoxemia. 1192 Mar 24

The factors governing interindividual variability in disease progression among children vertically infected with human immunodeficiency virus type 1 (HIV-1) remain unclear. Because it has recently been shown in infected adults that the density of CC chemokine receptor 5 (CCR5) molecules at the surface of nonactivated (human leukocyte antigen [HLA]-DR(-)) CD4+ T cells correlates with disease progression, the same correlation was sought in children. HLA-DR(-)CD4+ T cell surface CCR5 density was constant over time and correlated with the bioclinical stage and with the CD4 cell slope observed before antiretroviral treatment. In addition, CCR5 density was negatively correlated with the intensity of the decrease in viremia during antiretroviral therapy and was positively correlated with CD4 cell slope since birth. These results are compatible with the hypothesis that CCR5 density is a key factor governing disease progression in pediatric HIV-1 infection and, thereby, an indicator of prognosis. Moreover, they suggest that therapies aimed at reducing CCR5 accessibility should slow down HIV disease evolution in children.
 ...
PMID:Response to treatment and disease progression linked to CD4+ T cell surface CC chemokine receptor 5 density in human immunodeficiency virus type 1 vertical infection. 1193 Mar 15

CC chemokine receptor 5 (CCR5) is a coreceptor for cellular entry of monocyte-tropic (R5) strains of human immunodeficiency virus (HIV) type 1, which has been implicated as the predominant phenotype of HIV in early infection. The CCR5 agonists macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normally T cell-expressed and -secreted) have been shown to block replication of R5 virus in vitro and have gained attention as potential antiviral factors. However, a few reports have suggested that other chemokines may also block R5 HIV-1, including monocyte chemoattractant protein (MCP)-2 (CC chemokine ligand 8). We demonstrate that MCP-2 specifically inhibits replication of R5 HIV-1 and that this activity is additive to that of RANTES. Furthermore, MCP-2 induces a robust, pertussis toxin-sensitive calcium flux in primary lymphocytes, and cross-desensitization studies indicate that MCP-2 acts via CCR5. These data confirm that MCP-2 is a ligand for CCR5 on CD4(+) lymphocytes and can specifically block R5 HIV-1.
 ...
PMID:Monocyte chemoattractant protein-2 (CC chemokine ligand 8) inhibits replication of human immunodeficiency virus type 1 via CC chemokine receptor 5. 1193 Mar 29

Rhesus monkeys (Macaca mulatta) chronically administered opioids were more susceptible to simian immunodeficiency virus (SIV) strain mac239 (SIVmac239) infection than those without prior exposure to opioids. Increased plasma viremia in morphine-dependent monkeys allowed SIV to be detected in the animals' peripheral blood mononuclear cells (PBMC) without cocultivation with a tissue culture cell line. In contrast, virus titers from the PBMC of morphine-naive SIVmac239-infected animals were undetectable in the absence of cocultivation. PBMC isolated from noninfected animals and treated with morphine sulfate in vitro produced an increase in the expression of beta-chemokine receptor 5 (CCR5). Because both SIVmac239 and human immunodeficiency virus (HIV) require CCR5 for cell entry, the unique role of morphine in promoting SIV infection may provide a mechanism to account for the high incidence of HIV disease among drug-using populations.
 ...
PMID:Morphine promotes simian acquired immunodeficiency syndrome virus replication in monkey peripheral mononuclear cells: induction of CC chemokine receptor 5 expression for virus entry. 1208 34

Most of the research about viral interactions with human chromosomes was done during the sixties and early seventies and very few was performed after the human immunodeficiency virus (HIV) appearance as an epidemic in the eighties. The objective of this work was to estimate if particular chromosomal changes follow the infection of homosexual males by HIV and to determine if the lifestyle, habits, sexual practices, of our sample of male homosexuals predisposes them to chromosomal abnormalities at a higher rate than the background level of cytogenetic damage the general population has. This was a double blinded case-control study, 17 individuals positive for HIV antibodies (HIV+) detected by enzyme-linked immunosorbent assay (ELISA) and confirmed by western blot (WB) were the cases, and 17 individuals negative for HIV antibodies (HIV-) the controls. These men were a very homogeneous population in terms of age, social status, lifestyles, drug abuse, sexual practices and education. Blood was collected between September 1988 and October 1989. Fresh whole blood was cultured in duplicate for 72 hr. Cell harvest followed conventional methods. Once all cell cultures were gathered, the tubes were picked up at random and air dried chromosome preparations were trypsin-giemsa banded (GTG) after overnight incubation at 60 C degrees. The percentage of gaps and breaks these men had was not different from the reported for the general population, nor were there significant difference among both groups (O.R. = 1.8) in items of amount of chromosomal fragility. The distinction among them was at the level of the specific chromosomal sites where the gaps and breaks located, being sites at 2p21 and at 3p21 four times more frequent among HIV+. These probably represent viral modification sites on chromosomes which are known to look like non-staining gaps which are caused by the virus or viral products. This presumption is supported by an earlier report of repeated breaks at 3p21.1, in fact this was the most common lesion site in this study of chromosomal aberrations of male homosexuals and the authors even considered the probability of "a new type of chromosome marker". Furthermore, years later the CKR5 structural gene was mapped to human chromosome 3p21. This gene codes for the chemokine receptor 5 (CKR5) protein which serves as a secondary receptor on CD4+ T lymphocytes for certain strains of HIV-1. It is possible that this gene was being transcribed in HIV+ men and the consequent "staggering" of DNA contributed to the production of gaps and breaks at 3p21.
 ...
PMID:Chromosomal defects in 34 male homosexuals, half of them with HIV antibodies. 1229 63

Human CC chemokine receptor 5 (CCR5), a member of the superfamily of G protein-coupled receptors, regulates the activation and directed migration of leukocytes and serves as the main coreceptor for the entry of R5 tropic strains of human immunodeficiency viruses. We have previously shown that RANTES/CCL5 binding to CCR5 induces GPCR kinase (GRK)- and protein kinase C (PKC)-mediated phosphorylation of four distinct C-terminal serine residues. To study these phosphorylation events in vivo, we have generated monoclonal antibodies, which specifically react only with either phosphorylated or nonphosphorylated CCR5. These phosphosite-specific antibodies reveal that following ligand stimulation of the receptor serine 337 is exclusively phosphorylated by a PKC-mediated mechanism, while GRKs phosphorylate serine 349. GRK-mediated receptor phosphorylation proceeds in a regular time-dependent manner (t(12) approximately 2 min) with an apparent EC(50) of 5 nm. In contrast, PKC phosphorylates serine 337 at 50-fold lower concentrations and in a very rapid, albeit transient manner. Protein phosphatases that are active at neutral pH and are inhibited by okadaic acid rapidly dephosphorylate phosphoserine 337, but less efficiently phosphoserine 349, in intact cells and in an in vitro assay. Immunofluorescence microscopy demonstrates that phosphorylated receptors accumulate in a perinuclear compartment, which resembles recycling endosomes. This study is the first to analyze in detail the spatial and temporal dynamics of GRK- versus PKC-mediated phosphorylation of a G protein-coupled receptor and its subsequent dephosphorylation on the level of individual phosphorylation sites.
 ...
PMID:Analysis of ligand-stimulated CC chemokine receptor 5 (CCR5) phosphorylation in intact cells using phosphosite-specific antibodies. 1240 70

Although a number of chemokine receptors display coreceptor activities in vitro, chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) remain the major coreceptors used by the human immunodeficiency virus type 1 (HIV-1). In this study, we used an envelope-mediated fusion assay to demonstrate low CCR4 coreceptor activity with some primary HIV-1 and simian immunodeficiency virus-1 (mac316) isolates in vitro. The coreceptor activity was sensitive to CCR4-specific antibodies and to the CCR4-specific chemokine ligand macrophage-derived chemokine (MDC)/chemokine ligand 22 (CCL22). Treatment of peripheral blood mononuclear cells (PBMCs; which express high levels of CCR4) with CCL22 caused down-modulation of endogenous CCR4 but had no significant effect on HIV-1 entry, suggesting that CCR4 may not be used as an entry coreceptor. Despite expression of other minor coreceptors on PBMCs, CCR5 and CXCR4 are preferentially used by HIV-1 isolates, as shown by chemokine-inhibition data. To determine the factors involved in this selective use, we analyzed CCR4 coreceptor activity and compared it with CCR5 use in PBMCs. We used a quantitative fluorescence-activated cell-sorting assay to estimate the numbers of CCR4 and CCR5 antibody-binding sites (ABS) on PBMCs. Although CCR4 was found on a higher percentage of CD4(+) cells, CCR5 ABS was twofold greater than CCR4 ABS on CD4(+) cells. Confocal microscopy revealed strong cell-surface CD4/CCR5 but weak CD4/CCR4 colocalization in PBMCs. Binding studies demonstrated that soluble gp120 had greater affinity to CCR5 than CCR4. The results suggested that coreceptor density, colocalization with CD4, and affinity of the viral gp120 to the coreceptor may determine preferential coreceptor use by HIV-1.
 ...
PMID:Multiple determinants are involved in HIV coreceptor use as demonstrated by CCR4/CCL22 interaction in peripheral blood mononuclear cells (PBMCs). 1242 30

C-C chemokine receptor 5 (CCR5) is the primary coreceptor for human immunodeficiency virus type 1 (HIV-1) infection. Native chemokines that bind to CCR5 inhibit HIV-1 infection, albeit weakly, but chemically modified chemokines inhibit infection more efficiently. We have investigated the inhibitory mechanism of three N-terminally modified RANTES variants (AOP-, NNY-, and PSC-RANTES) with the MT-2 human T-cell line stably expressing either native or mutated CCR5. The RANTES analogues showed the same rank order (PSC > NNY > AOP) in their capacity to induce prolonged CCR5 internalization, inhibit surface reexpression, and prevent HIV-1 infection on MT-2 cells expressing wild-type CCR5 or CCR5 with four C-terminal serine phosphorylation sites mutated to alanine. None of the RANTES analogues caused internalization of a C-terminal cytoplasmic domain deletion mutant of CCR5, and each derivative had equal potency in inhibiting HIV-1 infection of MT-2 cells expressing this mutant. We conclude that the C-terminal cytoplasmic residues of CCR5 are necessary for receptor sequestration by RANTES analogues but that the process and the relative activity of each derivative are not dependent upon phosphorylation of the C-terminal serine residues. Two mechanisms of antiviral activity are demonstrated: receptor blockade and receptor sequestration. Potency correlates with the ability to induce CCR5 sequestration but not with receptor binding, suggesting that sequestration may make the greater contribution to antiviral activity.
 ...
PMID:Two mechanisms for human immunodeficiency virus type 1 inhibition by N-terminal modifications of RANTES. 1254 51


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