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

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effect of antiretroviral therapy on vascular activation in 41 human immunodeficiency (HIV)--infected patients receiving a regimen that included either at least 1 protease inhibitor (PI; n = 21) or a nonnucleoside reverse-transcriptase inhibitor (NNRTI; n = 20). A control group of 21 healthy subjects was included for comparison. Levels of endothelial markers (soluble vascular cell adhesion molecule [sVCAM]--1, soluble intercellular adhesion molecule--1, and von Willebrand factor) were higher in HIV-infected persons before treatment than in control subjects and decreased significantly after 5--13 months of treatment. Levels of sVCAM-1 and von Willebrand factor correlated significantly with initial virus load. d-dimer concentrations also decreased significantly after initiation of treatment. PI- and NNRTI-containing regimens had similar effects. Therapy did not reduce levels of the soluble platelet (sP) activation markers sP-selectin and CD40 ligand. The inhibition of markers of vascular activation may counterbalance sequelae of therapy-induced dyslipidemia and potentially prevent development of atherosclerosis in HIV-infected patients.
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PMID:Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with human immunodeficiency virus type 1. 1186 97

Dendritic cells (DCs) play a critical role in the initiation of the immunological response against Leishmania parasites. However, the receptors involved in amastigote-dendritic cell interaction are unknown, especially in absence of opsonizing antibodies. We have studied the interaction of Leishmania pifanoi axenic amastigotes with the C-type lectin DC-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN, CD209), a receptor for ICAM-2, ICAM-3, human immunodeficiency virus gp120, and Ebola virus. L. pifanoi amastigotes interact with immature human dendritic cells and CD209-transfected K562 cells in a time- and dose-dependent manner. Leishmania amastigote binding to human dendritic cells and DC-SIGN-transfected cells is inhibited by a function-blocking DC-SIGN-specific monoclonal antibody. More importantly, this monoclonal antibody dramatically reduces internalization of Leishmania amastigotes by immature human DCs. These results constitute the first description of a nonviral pathogen ligand for DC-SIGN and provide evidence for a relevant role of DC-SIGN in Leishmania amastigote uptake by dendritic cells. Our finding has important implications for Leishmania host-cell interaction and the immunoregulation of cutaneous leishmaniasis.
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PMID:Dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN, CD209), a C-type surface lectin in human DCs, is a receptor for Leishmania amastigotes. 1212 1

The C-type lectin human dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3-grabbing non-integrin (DC-SIGN) plays important roles in pattern recognition by dendritic cells in the immune system. In addition to binding human immunodeficiency virus (HIV), this type II membrane protein binds with high affinity to the adhesion molecules ICAM-3 and -2 to promote important dendritic cell interactions with naive T cells and endothelial cells, respectively. DC-SIGNR, a human DC-SIGN homologue expressed on sinusoidal endothelial cells in liver and lymph node, also binds and transmits HIV virus. We describe the cloning and characterization of a family of murine complementary DNAs (cDNAs) called SIGNR1, expressed in skin and spleen, that encode C-type lectins highly related to human DC-SIGN and DC-SIGNR. We also report the genomic structure of the SIGNR1 gene and compare it to that of human DC-SIGN and DC-SIGNR. The different transcripts (alpha, beta, gamma, delta) are generated by differences in 5' untranslated sequences, alternative splicing and/or the use of different polyadenylation sites. The predicted open reading frames encoded by the cDNAs are most closely related to human DC-SIGN and DC-SIGNR in the cytoplasmic domain, the transmembrane region and the carbohydrate recognition domain. Moreover, the alternatively spliced transcripts encode proteins that lack the transmembrane region or have modified carbohydrate recognition domains. Northern hybridization experiments with several different SIGNR1 cDNA probes reveal transcripts of 1.3 and 2.1 kb that are expressed in a tissue-restricted fashion in murine skin, spleen and lung. In situ hybridization and immunocytochemistry experiments demonstrate that, like human DC-SIGN, the murine messenger RNAs are expressed in subsets of dendritic cells in the spleen and skin.
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PMID:Molecular characterization of the murine SIGNR1 gene encoding a C-type lectin homologous to human DC-SIGN and DC-SIGNR. 1213 41

Mycobacterium avium is a facultative intracellular pathogen cleared rapidly via intact host defense mechanisms. In the absence of adequate T cell function, as occurs in HIV-1-induced immunodeficiency, M. avium becomes an opportunistic infection with uncontrolled replication and reinfection of macrophage hosts. How M. avium infects, survives, and replicates in macrophages without signaling an effective microbicidal counterattack is unresolved. To address whether M. avium signals the expression of molecules, which influence mycobacterial survival or clearance, human monocyte-derived macrophage cultures were exposed to M. avium. Within minutes, M. avium, or its cell wall lipoarabinomannan, binds to the adherent macrophages and induces a spectrum of gene expression. In this innate response, the most abundant genes detected within 2 h by cDNA expression array involved proinflammatory chemokines, cytokines including TNF-alpha and IL-1, and adhesion molecules. Associated with this rapid initial up-regulation of recruitment and amplification molecules was enhanced expression of transcription factors and signaling molecules. By 24 h, this proinflammatory response subsided, and after 4 days, when some bacteria were being degraded, others escaped destruction to replicate within intracellular vacuoles. Under these conditions, inducible NO synthase was not up-regulated and increased transferrin receptors may facilitate iron-dependent mycobacterial growth. Sustained adhesion molecule and chemokine expression along with the formation of multinucleated giant cells appeared consistent with in vivo events. Thus, in the absence of T lymphocyte mediators, macrophages are insufficiently microbicidal and provide a nonhostile environment in which mycobacteria not only survive and replicate, but continue to promote recruitment of new macrophages to perpetuate the infection.
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PMID:Mycobacterium avium infection and modulation of human macrophage gene expression. 1244 35

Reaction patterns of the 7th Human Leukocyte Differentiation Antigen Workshop blind panel adhesion molecules were studied on CD3/CD4, CD3/CD8, CD3/TCR gamma delta double positive T cells from peripheral blood of patients with chronic graft versus host disease (n = 8) and healthy controls (n = 4). Reactivity of 14 adhesion antibodies was tested by three-colour immunophenotyping. The mean proportion of CD3+ T cells (69 +/- 19%). CD3/CD8++ (31 +/- 13%) and CD3/TCR gamma delta++ (4 +/- 2%) T sub-populations of patients were comparable with the healthy controls. However, the mean percentage of CD3/CD4++ T cell subset in patients (14 +/- 12%) proved to be significantly decreased in comparison with the normal control value (34 +/- 16%) presumably due to secondary immunodeficiency. The workshop antibodies proved to be reactive with three T cell subsets expressing the examined antigens. Based on the results of the adhesion molecule workshop new CD categories have been introduced: CD156b as a transmembrane protein, CD167a as an epithelial tyrosin kinase receptor, CD168 as a receptor for hyaluronan mediated motility (RHAMM) and CD171 as a co-stimulatory adhesion molecule. There were significant differences in the expression of the CD167a and CD156b antigens on the CD3/CD4++ subset between the samples of patients compared with the controls characterizing the CD4+ T lymphocyte subpopulation in chronic graft versus host disease.
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PMID:Reactivity of new adhesion molecules on lymphocytes from patients with chronic graft versus host disease. 1279 1

Some dendritic cells (DC) express a cell-surface lectin called 'dendritic cell-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin' (DC-SIGN). DC-SIGN has been shown to mediate a type of infection called 'trans' infection, where DC bind human immunodeficiency virus (HIV) and efficiently transfer the virus to T cells. We investigated the possibility that mannose-binding lectin (MBL), a soluble lectin that functions as a recognition molecule in innate immunity and that binds to HIV, could block trans infection mediated by DC-SIGN. Binding studies with glycoprotein (gp)120/gp41-positive and -negative virus preparations suggested that DC-SIGN and MBL bind primarily to glycans on gp120/gp41, as opposed to glycans on host-cell-derived proteins, indicating a close overlap in the binding site of the two lectins and supporting the notion that MBL could prevent binding of HIV to DC-SIGN. Preincubation of X4, R5 or dual-tropic HIV strains with MBL prevented DC-SIGN-mediated trans infection of T cells. The mechanism of MBL blocking trans infection of T cells was at least partly caused by blocking of virus binding to DC-SIGN positive cells. This study shows that MBL prevents DC-SIGN-mediated trans infection of T cells in vitro and suggests that in infected persons, MBL may inhibit DC-SIGN-mediated uptake and spread of HIV.
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PMID:Inhibition of DC-SIGN-mediated trans infection of T cells by mannose-binding lectin. 1294 Nov 44

Previous works have indicated that incorporation of surface glycoprotein into retroviruses such as the human immunodeficiency virus type 1 (HIV-1) is not a highly specific process because several cellular glycoproteins can be inserted within the mature viral particle. The mechanism(s) that govern the acquisition of such host constituents have remained so far elusive. In this study, we have investigated the role played by the viral envelope (Env) of HIV-1 in the acquisition of host intercellular adhesion molecule type I (ICAM-1). ICAM-1 proteins were still present on viruses carrying much lower levels of gp120/gp41 due to a mutation in the matrix (MA) domain or on Env-deficient viruses when produced in immortalized and primary human cell lines. Interestingly, infectivity of an HIV-1 MA mutant that carry a suboptimal amount of Env proteins was restored to a certain degree by the presence of ICAM-1 when infection was performed in cells expressing an activated form of its natural counter-ligand, LFA-1.
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PMID:Envelope glycoproteins are not required for insertion of host ICAM-1 into human immunodeficiency virus type 1 and ICAM-1-bearing viruses are still infectious despite a suboptimal level of trimeric envelope proteins. 1518 63

Coinfections with opportunistic and pathogenic bacteria induce human immunodeficiency virus (HIV) replication through microbial antigen activation of NF-kappaB. Here, we assessed whether HIV type 1 protease inhibitors (PI) block microbial antigen activation of NF-kappaB. Human microvessel endothelial cells were transiently transfected with either endothelial cell-leukocyte adhesion molecule NF-kappaB luciferase or interleukin 6 (IL-6) promoter luciferase constructs by using FuGENE 6, and they were treated with PI (nelfinavir, ritonavir, or saquinavir) prior to stimulation with the Toll-like receptor 4 (TLR4) and TLR2 ligands, with lipopolysaccharide (LPS), soluble Mycobacterium tuberculosis factor, or Staphylococcus epidermidis phenol-soluble modulin, respectively, or with tumor necrosis factor alpha (TNF-alpha). Luciferase activity was measured by using a Promega luciferase kit. TNF-alpha release from the supernatant was measured by enzyme-linked immunosorbent assay. Cell death was assessed by lactate dehydrogenase assay. We observed that PI pretreatment blocked the TLR2- and TLR4- as well as the TNF-alpha-mediated NF-kappaB activation, in a dose-dependent manner. PI pretreatment also blocked the LPS-induced IL-6 promoter transactivation and TNF-alpha secretion. These data suggest that PI block HIV replication not only by inhibiting the HIV protease but also by blocking the TLR- and TNF-alpha-mediated NF-kappaB activation and proinflammatory cytokine production. These findings may help explain the immunomodulatory effects of PI, and they suggest an advantage for PI-containing drug regimens in the treatment of HIV-infected patients who are coinfected with opportunistic and pathogenic bacteria.
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PMID:Human immunodeficiency virus type 1 protease inhibitors block toll-like receptor 2 (TLR2)- and TLR4-Induced NF-kappaB activation. 1538 51

We have examined the molecular basis for the selective incorporation of the adhesion molecule ICAM-1 within human immunodeficiency virus type 1 (HIV-1). The process of ICAM-1 incorporation was investigated by using different ICAM-1 constructs in combination with virus capture and immunoprecipitation studies, Western blot and confocal microscopy analyses, and infectivity assays. Experiments conducted with viruses bearing a truncated version of ICAM-1 revealed that the cytoplasmic domain of ICAM-1 governs insertion of this adhesion molecule into HIV-1. Further experiments suggested that there is an association between ICAM-1 and the virus-encoded Pr55(Gag) polyprotein. This study represents the first demonstration that structural Gag polyproteins play a key role in the uptake of a host-derived cell surface by the virus entity. Taken together, our results indicate that interactions between viral and cellular proteins are responsible for the selective uptake of host ICAM-1 by HIV-1. This observation describes a new strategy by which HIV-1 can modulate its replicative cycle, considering that insertion of ICAM-1 within nascent virions has been shown to increase virus infectivity.
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PMID:Interaction between the cytoplasmic domain of ICAM-1 and Pr55Gag leads to acquisition of host ICAM-1 by human immunodeficiency virus type 1. 1547 32

Central nervous system (CNS) dysfunction is commonly observed in children with human immunodeficiency virus type 1 (HIV-1) infection, but the mechanism(s) whereby HIV-1 causes encephalopathy remains incompletely understood. Human brain microvascular endothelial cells (HBMECs), which constitute the blood-brain barrier, are likely to contribute to HIV-1 encephalopathy, but it is unclear whether HIV-1 receptors (CD4, chemokine receptors) are present on HBMECs. In the present study, the presence of CD4 in six different children was demonstrated. Moreover, the presence of CD4 in situ on brain sections was shown. Distribution of CD4 expression was heterogeneous among microvessels; staining for CD4 was strong in some vessels and absent in other adjacent vessels. CD4 and chemokine coreceptors were found to be functional as intercellular adhesion molecule (ICAM)-1 expression increased upon incubation of HBMECs with activating anti-CD4 and anti-chemokine receptor antibodies. The presence of CD4 and chemokine receptors in human brain endothelium of children may have implications for the pathogenesis of HIV-1 encephalopathy and explain the higher incidence of CNS involvement in HIV-1-infected children as compared to adults.
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PMID:CD4 and chemokine receptors on human brain microvascular endothelial cells, implications for human immunodeficiency virus type 1 pathogenesis. 1577 Jul 70


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