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

The role of CD4 during the human immunodeficiency virus type 1 (HIV-1) life cycle in T cells is not restricted to binding functions. HIV-1 binding to CD4 also triggers signals that lead to nuclear translocation of NF-kappaB and are important to the productive infection process. In addition to its cytoplasmic tail, in the ectodomain, the immunoglobulin (Ig) CDR3-like region of CD4 domain 1 seemed to play a role in this cascade of signals. We demonstrate in this work that the structural integrity of the CDR3-like loop is required for signal transduction. Substitutions of negatively charged residues by positively charged residues within the CDR3-like loop either inhibited NF-kappaB translocation after HIV-1 and gp120-anti-gp120 immune complexes binding to E91K,E92K mutants or induced its constitutive activation for E87K,D88K mutants. Moreover, A2.01-3B cells expressing the E91K,E92K mutant exhibited a lower HIV-1Lai replication. These cells, however, expressed p56(lck), demonstrated NF-kappaB translocation upon PMA stimulation, bound HIV-1Lai envelope glycoprotein with high affinity, and contained HIV-1 DNA 24 h after exposure to virus. E91K, E92K, and E87K,D88K mutant CD4 molecules were unable to bind a CD4 synthetic aromatically modified exocyclic, CDR3.AME-(82-89), that mimics the CDR3-like loop structure and binds to native cell surface CD4. This result together with molecular modeling studies indicates that the CDR3.AME-(82-89) analog binds to the CDR3-like loop of CD4 and strongly suggests that this region represents a site for CD4 dimerization. The negative charges on the CDR3-like loop thus appear critical for CD4-mediated signal transduction most likely related to CD4 dimer formation.
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PMID:Transduction of activation signal that follows HIV-1 binding to CD4 and CD4 dimerization involves the immunoglobulin CDR3-like region in domain 1 of CD4. 923 45

The temporal appearance and levels of human immunodeficiency virus type 1 (HIV-1) tat, rev, nef, env and gag mRNA species were examined using a synchronized, one-step, cell-to-cell HIV-1 infection model involving HUT-78 cells and HIV- 1 persistently infected H3B cells. Individual mRNAs were quantified by RT-PCR using RNA standards transcribed in vitro from cDNA clones. Consistent with an infection that produces high yields of virus, significant levels of env and gag mRNAs were detected in the cytoplasm of infected cells late in the infection cycle. However, at no time after infection did levels of tat, rev and nef mRNA, which encode the regulatory proteins of HIV-1, exceed their levels present in the persistently infected virus donor H3B cells. The absence of early phase induction of these mRNAs is in contrast to what is observed in cell-free HIV-1 infections or in PMA-stimulated HIV-1 chronically infected cell lines. Our results suggest that tat and rev mRNAs are already present in the cytoplasm of the persistently infected virus donor cells at levels sufficient for initiation and establishment of a highly productive infection in HIV-1 fusion-mediated infected cells. Thus, lack of sufficient Tat and Rev proteins is not likely to be the limiting factor for virus production in H3B cells, nor is increased production of these proteins likely to be the cause of the increased virus production seen following cell-to-cell transmission.
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PMID:Kinetics of viral RNA synthesis following cell-to-cell transmission of human immunodeficiency virus type 1. 926 85

Unstimulated lymphocytes from FIV-infected cats undergo spontaneous apoptosis in vitro as indicated by internucleosomal DNA fragmentation and hypodiploid DNA content of nuclei. Unlike what is reported in HIV-infected individuals, we observed that cell death of cat lymphocytes was inhibited by activation. Spontaneous apoptosis was reduced by the addition of cat serum and after activation by phorbol ester (PMA), superantigens (SEB, SEA), and to a lesser extent by mitogens such as concanavalin A and pokeweed mitogen. In contrast, apoptosis of lymphocytes from FIV-infected, but not from control cats was increased in the presence of calcium ionophore (ionomycin). Analysis of the phenotype of cells undergoing apoptosis revealed that cell death is not restricted to a cell subpopulation but involved all lymphocyte subsets. These data suggest that the mature lymphocytes of FIV-infected cats appear programmed to die by apoptosis unless rescued by specific agents, such as protein kinase C activators or mitogens.
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PMID:Spontaneous programmed cell death (PCD) process of lymphocytes of FIV-infected cats: cellular targets and modulation. 933 78

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.
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PMID:Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. 934 82

The chemokine receptor CXCR4 (also designated fusin and LESTR) is a cofactor for fusion and entry of T cell-tropic strains of HIV-1. CXCR4 is expressed in various cell types; however, the mechanisms involved in the regulation of its expression remain unknown. To delineate these mechanisms, approximately 1.2 kb of DNA from the immediate 5' upstream region of CXCR4 gene was cloned, sequenced, and characterized. Transient expression assays using CXCR4 promoter/luciferase gene reporter constructs revealed that stimulation with PMA plus ionomycin up-regulates the CXCR4 promoter activity in the A3.01 CD4+ T cell line and PBL and that a DNA fragment from -93 to +59 relative to the transcription start site contributes markedly to the basal and induced activity. This fragment contains a consensus TATA box, two potential GC boxes, and a potential nuclear respiratory factor (NRF)-1 binding site, which were confirmed by gel mobility shift assays and footprinting analysis. Mutagenesis studies revealed that a NRF-1 site is especially important for the basal and induced activity of the CXCR4 promoter. Transient expression assays further revealed that stimulation of PBL with either IL-2 or Abs to CD3 and CD28 enhances the CXCR4 promoter activity. Inducibility of the CXCR4 promoter activity by T cell stimulation suggests that overexpression of CXCR4 may be one of the mechanisms whereby immune activation and/or perturbation of the cytokine network up-regulate HIV expression and replication and thus contribute to the progression of HIV disease.
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PMID:Cloning and analysis of the promoter region of CXCR4, a coreceptor for HIV-1 entry. 937 28

To further clarify the complex transcriptional regulation of the human GM-CSF gene, which was extensively investigated in activated T cells, we have studied the role of an upstream NF-kappaB like site in the 5637 non-lymphoid cell line, which derives from a bladder carcinoma and constitutively produces GM-CSF. This sequence, named the A element, has an active role on GM-CSF transcription and is responsive to the tumor promoter PMA in transient transfection experiments. We describe here a heterodimeric binding complex of NF-kappaB subunits (c-Rel and p65) which is identical to the one obtained using the HIV-LTR-kappaB site as recognition sequence and different from the one (c-Rel and p50) observed with nuclear extracts from Mo T-lymphoid HTLV-II infected cells.
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PMID:c-Rel and p65 subunits bind to an upstream NF-kappaB site in human granulocyte macrophage-colony stimulating factor promoter involved in phorbol ester response in 5637 cells. 941 29

CD8+ T-lymphocytes from HIV+ individuals contain short telomeres, a sign of cell senescence. To test our hypothesis that the cell type is functionally defective in the biochemical indices related to cell proliferation, we investigated the profiles of intracellularly generated H2O2 levels with or without PMA as well as immunoreactive catalase levels using flow cytometric method. We observed that, in HIV+ but not in HIV- individuals, the constitutively generated H2O2 level was significantly lower in CD8+ T-cells compared with CD4+ T-cells. Importantly, activated effector CD8+CD28- cells showed remarkably low H2O2 levels compared with CD8+CD28+ cells, and the latter in HIV+ individuals also showed low levels. A similar defect of CD8+ cells of HIV+ individuals was also seen with H2O2 levels stimulated with PMA in the presence of a catalase inhibitor. Furthermore, the immunoreactive catalase content was lower in CD8+ cells compared with CD4+ cells only in HIV+ individuals. These results suggest that CD8+ T-lymphocytes are functionally defective with the constitutively generated and PMA-elicited levels of H2O2 and the corresponding scavenger. Diminished immunocompetence of HIV+ individuals may be caused, in part, by the functional defect of CD8+ T-cells.
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PMID:Suppression of intracellular hydrogen peroxide generation and catalase levels in CD8+ T-lymphocytes from HIV+ individuals. 943 11

Several studies have suggested that regulation of expression of the costimulatory molecule CD28 on the T-cell surface may play an important role in AIDS pathogenesis. In a study of T-cells from HIV+ donors, we find that activation with anti-CD3 plus anti-CD28 results in a mitogenic response which was approximately 86% suppressed for both CD4+ and CD8+ T-cells when compared to normal control cells. With PMA costimulation (instead of anti-CD28), the anti-CD3 response was suppressed much less, by 64 and 61%, respectively. With Con A as opposed to CD3 stimulation, the degree of suppression was less with either coactivator but still more severe with CD28 than with PMA coactivation. It has been reported that the CD28 subset of CD8+ T-cells is diminished in HIV+ individuals and could account for these results. It is possible as well that the CD28 costimulatory pathway in the CD4+ T-cells particularly is altered due to intervention by the HIV. While our data do not differentiate between these two possibilities, it show that the immune status is compromised in the HIV+ individual not only in terms of number of CD4+ T-cells, but in their activation response as well.
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PMID:The proliferative response of HIV+ T-cells (CD4+ and CD8+) are severely suppressed via CD28 coactivation. 944 31

Although the molecular mechanisms by which the HIV-1 triggers either T cell activation, anergy, or apoptosis remain poorly understood, it is well established that the interaction of HIV-1 envelope glycoproteins with cell surface CD4 delivers signals to the target cell, resulting in activation of transcription factors such as NF-kappa B and AP-1. In this study, we report the first evidence indicating that kinases MEK-1 (MAP kinase/Erk kinase) and ERK-1 (extracellular signal-regulated kinase) act as intermediates in the cascade of events that regulate NF-kappa B and AP-1 activation upon HIV-1 binding to cell surface CD4. We found that CEM cells transfected with dominant negative forms of MEK-1 or ERK-1 do not display NF-kappa B activation after HIV-1 binding to CD4. In contrast, NF-kappa B activation was observed in these cells after PMA stimulation. Although the different cell lines studied expressed similar amounts of CD4 and p56(lck), HIV-1 replication and HIV-1-induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK-1 or ERK-1 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK-1 or wild-type ERK-1. In light of recently published data, we propose that a positive signal initiated following oligomerization of CD4 by the virus is likely to involve a recruitment of active forms of p56(lck), Raf-1, MEK-1, and ERK-1, before AP-1 and NF-kappa B activation.
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PMID:Involvement of extracellular signal-regulated kinase module in HIV-mediated CD4 signals controlling activation of nuclear factor-kappa B and AP-1 transcription factors. 946 49

The chemokine receptor CCR5 is a cofactor for cellular entry of macrophage-tropic strains of HIV-1. Expression of CCR5 is restricted to T cells, macrophages, and certain cell lines; however, the mechanisms controlling its expression remain largely unknown. To delineate these mechanisms, approximately 1.0 kb of DNA from the immediate 5' upstream region of CCR5 was cloned and characterized. CCR5 promoter activity was up-regulated by PMA, and a region spanning -417 to +61 relative to the transcription start site was sufficient for the basal and induced activity. DNase I footprinting assays demonstrated several protected areas within this region, and gel shift assays determined binding sites for transcriptional factors Oct-1, Oct-2, T cell factor 1alpha, and GATA1. CCR5 promoter activity was also induced by IL-2 or anti-CD3 Ab, while stimulation with anti-CD28 Ab markedly reduced CD3-mediated up-regulation of the CCR5 promoter. Flow cytometry confirmed the findings at the level of cell surface expression. Further delineation of the regulation of the CCR5 promoter will be important for a more comprehensive understanding of the pathogenesis of HIV disease.
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PMID:Cloning and analysis of the promoter region of CCR5, a coreceptor for HIV-1 entry. 954 84


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