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

The effect of a single bolus injection (0.4 g/kg) of intravenous immunoglobulin (IVIG) on the tumor necrosis factor (TNF) system in human immunodeficiency virus type 1 (HIV-1)-infected patients was investigated. At 140 h after infusion, there was a significant decrease in levels of TNF-alpha and a significant increase in levels of soluble TNF receptors (sTNFR) in both plasma and lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMC). A rapid (within 1 h) decline in expression of membrane-bound TNF-alpha and p55-TNFR on PBMC persisted throughout the study. In contrast, there was an increased expression of membrane-bound p75-TNFR after 140 h. IVIG administration also resulted in significantly increased numbers of circulating CD4 lymphocytes, correlated with down-regulation of TNF-alpha activity in PBMC supernatants. Thus, down-regulation of the abnormally increased TNF-alpha activity may be achieved by IVIG administration. Studies evaluating the possible therapeutic role of long-term TNF-alpha suppression by IVIG may be warranted in HIV-1-infected patients.
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PMID:Effects of intravenous immunoglobulin in vivo on abnormally increased tumor necrosis factor-alpha activity in human immunodeficiency virus type 1 infection. 933 49

As cytokines and 1,25-dihydroxyvitamin D [1,25-(OH)2D] appear to have an important role in bone homeostasis, we examined the possibility that human immunodeficiency virus (HIV)-infected patients, characterized by enhanced levels of proinflammatory cytokines and 1,25-(OH)2D deficiency, have disturbed bone metabolism by analyzing serum markers of bone formation (osteocalcin) and bone resorption (C-telopeptide) in 73 HIV-infected patients. HIV-infected patients with advanced clinical and immunological disease and high viral load were characterized by increased C-telopeptide and particularly by markedly depressed osteocalcin levels. HIV-infected patients had enhanced activation of the TNF system. Serum concentrations of p55 and p75-TNF receptors were negatively correlated with osteocalcin, and p75-TNF receptor was positively correlated with C-telopeptide. HIV-infected patients with advanced disease also had decreased serum concentrations of 1,25-(OH)2D, but this parameter was not correlated with osteocalcin or C-telopeptide. During 24 months with highly active antiretroviral therapy there was a marked rise in serum osteolcalcin levels together with a profound fall in viral load and TNF components and a marked rise in CD4+ T cell counts. Also, there was a shift from no correlation to a significant correlation between osteocalcin and C-telopeptide levels during such therapy. The present study suggests disturbed bone formation and resorption during HIV infection. Our findings indicating synchronization of bone remodeling during highly active antiretroviral therapy may represent a previously unrecognized beneficial effect of such therapy and expand our knowledge of the interactions between cytokines and bone in the bone-remodeling process.
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PMID:Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. 992 75

The chronic immune activation state in HIV disease leads to increased activity of the rate-limiting tryptophan-kynurenine pathway enzyme indoleamine 2,3-dioxygenase (2,3-IDO), thereby increasing the formation of neurotoxic tryptophan metabolites such as kynurenine and quinolinic acid. We investigated whether highly active antiretroviral therapy (HAART) (median duration, 100 days; range, 50-188 days) lowers serum levels of these metabolites in HIV-infected individuals and if so, whether this was paralleled by changes in a surrogate marker for immune activation, i.e., soluble tumor necrosis factor receptor p75 (sTNFR p75) concentrations. Baseline quinolinic acid (848 nM, 95% CI 567-1130 vs. 303 nM, 95% CI 267.1-339.5) and kynurenine (4.1 microM, 95% CI 3.3-4.9 vs. 2.7 microM, 95% CI 2.4-2.9) concentrations as well as the mean kynurenine-to-tryptophan ratio (108.2, 95% CI 76.1-140.4 vs. 51.4, 95% CI 47.6-55.3) in 17 HIV-1-infected outpatients (7 with AIDS) were significantly higher than those in 55 healthy age-matched controls (p < 0.01), respectively. Serum quinolinic acid concentrations in 14 of 17 patients decreased (mean, -44.4%) during HAART in comparison with baseline (471.2 nM, 95% CI 288-654.3; p = 0. 022). Thirteen of these 14 patients also had decreases in sTNFR p75 concentrations. Overall, the mean sTNFR p75 concentration decreased by 36.3% (13.5 ng/ml, 95% CI 9.3-17.8 vs. 8.6 ng/ml, 95% CI 5.9-11. 4; p = 0.01, n = 17). Reduction in viral load through HAART and subsequent mitigation of the pathological immune activation state in HIV disease may have reduced 2,3-IDO over activation. This eventually led to a decrease in quinolinic acid formation. The parallel reduction of the immune activation marker sTNFR p75 supports this hypothesis.
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PMID:Parallel decrease in neurotoxin quinolinic acid and soluble tumor necrosis factor receptor p75 in serum during highly active antiretroviral therapy of HIV type 1 disease. 1095 19

The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key regulatory protein in the HIV-1 replication cycle. Tat interacts with cellular transcriptional factors and cytokines, such as tumor necrosis factor (TNF-alpha), and alters the expression of a variety of genes in HIV-1-infected and noninfected cells. To further elucidate the mechanisms by which HIV-1 Tat amplifies the activity of TNF-alpha, we transfected the HIV-1 tat gene into an epithelial (HeLa) cell line. We observed that Tat-expressing cells had increased NF-kappa B-dependent trans-activational activity due to enhanced NF-kappa B--DNA binding in response to TNF-alpha treatment. Tumor necrosis factor receptor (TNFR) p55 was the prominent receptor, as neutralizing antibodies to TNFR p55, but not to TNFR p75, blocked TNF-alpha-mediated NF-kappa B activation. Furthermore, tat-transfected cells were more sensitive to TNF-alpha-induced cytotoxicity and only the neutralizing antibodies to TNFR p55 completely protected the cells. To determine whether TNFR p55 was involved in amplification of cellular response to TNF-alpha by HIV-1 Tat, we investigated the effect of TNF-alpha on TNFR p55 expression in the tat-transfected cells. TNF-alpha treatment resulted in a reduction in both TNFR p55 mRNA and protein levels in the control cells but not in the tat-transfected cells as determined with Northern blot and Western blot analyses, respectively. Our results indicate that HIV-1 Tat may inhibit TNF-alpha-induced repression of TNFR p55 and thereby amplify TNF-alpha activity in these stably transfected cells.
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PMID:HIV type 1 Tat inhibits tumor necrosis factor alpha-induced repression of tumor necrosis factor receptor p55 and amplifies tumor necrosis factor alpha activity in stably tat-transfected HeLa Cells. 1152 82

IL-16 is a multi-functional cytokine that uses CD4 as a receptor to signal diverse biological activities by target cells including T-lymphocytes, monocytes and eosinophils. IL-16 has been shown to repress HIV-1 infection in lymphocytes and monocytic cells and it is active against both laboratory and naturally acquired virus isolates. In lymphocytes, the repressive effect of IL-16 occurs at the level of virus transcription, while it appears to inhibit viral entry in monocytic cells. Clinical studies comparing serum IL-16 levels with the state of HIV-1 disease suggest that this cytokine is a functionally significant endogenous antiviral factor. The antiviral activity of IL-16 may be of therapeutic benefit in HIV/AIDS but its greatest potential is for immune reconstitution. Stimulation of CD4+ T-cells with IL-16 primes cells to respond to IL-2, by upregulating the expression of IL-2 receptor p75 (CD25). Co-treatment of peripheral blood mononuclear cells (PBMC) with IL-16 plus IL-2 (or IL-15) in vitro selectively expands the population of CD4+ T-cells. Clinical trials of recombinant IL-2 have already shown promise in HIV/AIDS. In combination with IL-16, the beneficial effects of IL-2 may be augmented and specifically targeted to CD4+ T-cells. Thus, IL-16 shows considerable promise as an agent for the biological therapy of HIV/AIDS.
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PMID:Prospects for IL-16 in the treatment of AIDS. 1172 16

The effect of etanercept, a soluble p75 tumor necrosis factor (TNF) receptor:Fc fusion protein (Enbrel; Immunex, Seattle, WA) on plasma cytokines was evaluated in 11 HIV-infected subjects receiving highly active antiretroviral therapy (HAART) for 28 weeks with or without subcutaneous or intravenous recombinant human interleukin 2 (rhIL-2). Plasma IL-6 and C-reactive protein (CRP) levels increased after rhIL-2 treatment. Etanercept pretreatment attenuated these increases. Median plasma IL-6 levels were 20.29 pg/ml 4 days after rhIL-2 and 7.87 pg/ml 4 days after etanercept and rhIL-2 (p = 0.22); median CRP levels were 78.73 and 46.16 microg/ml, respectively (p = 0.03). An effect on TNF bioactivity could not be assessed as all measurements were below limits of detection. No significant changes were seen in temperature or plasma levels of IL-4, IL-10, IL-12, interferon gamma, or HIV-1 RNA levels. All subjects had undetectable or low-level HIV-1 RNA levels before etanercept dosing. One subject died; however, her death was thought to be unrelated to etanercept. Pretreatment with etanercept may blunt activation of IL-6 and CRP expression induced by rhIL-2. The safety and utility of etanercept in HIV-infected persons should be explored further.
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PMID:Effect of etanercept (Enbrel) on interleukin 6, tumor necrosis factor alpha, and markers of immune activation in HIV-infected subjects receiving interleukin 2. 1207 62

We studied human immunodeficiency virus, type 1 (HIV-1) integrase (IN) complexes derived from nuclei of human cells stably expressing the viral protein from a synthetic gene. We show that in the nuclear extracts IN exists as part of a large distinct complex with an apparent Stokes radius of 61 A, which dissociates upon dilution yielding a core molecule of 41 A. We isolated the IN complexes from cells expressing FLAG-tagged IN and demonstrated that the 41 A core is a tetramer of IN, whereas 61 A molecules are composed of IN tetramers associated with a cellular protein with an apparent molecular mass of 76 kDa. This novel integrase interacting protein was found to be identical to lens epithelium-derived growth factor (LEDGF/p75), a protein implicated in regulation of gene expression and cellular stress response. HIV-1 IN and LEDGF co-localized in the nuclei of human cells stably expressing IN. Furthermore, recombinant LEDGF robustly enhanced strand transfer activity of HIV-1 IN in vitro. Our findings indicate that the minimal IN molecule in human cells is a homotetramer, suggesting that at least an octamer of IN is required to accomplish coordinated integration of both retroviral long terminal repeats and that LEDGF is a cellular factor involved in this process.
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PMID:HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. 1240 1

We have reported that human immunodeficiency virus type 1 (HIV-1) integrase (IN) forms a specific nuclear complex with human lens epithelium-derived growth factor/transcription co-activator p75 (LEDGF/p75) protein. We now studied the IN-LEDGF/p75 interaction and nuclear import of IN in living cells using fusions of IN and LEDGF/p75 with enhanced green fluorescent protein and far-red fluorescent protein HcRed1. We show that both the N-terminal zinc binding domain and the central core domains of IN are involved in the interaction with LEDGF/p75. Both domains are essential for nuclear localization of IN as well as for the association of IN with condensed chromosomes during mitosis. However, upon overexpression of LEDGF/p75, the core domain fragment of IN was recruited to the nuclei and mitotic chromosomes with a distribution pattern characteristic of the full-length protein, indicating that it harbors the main determinant for interaction with LEDGF/p75. Although the C-terminal domain of IN was dispensable for nuclear/chromosomal localization, a fusion of the C-terminal IN fragment with enhanced green fluorescent protein was found exclusively in the nucleus, with a diffuse nuclear/nucleolar distribution, suggesting that the C-terminal domain may also play a role in the nuclear import of IN. In contrast to LEDGF/p75, its alternative splice variant, p52, did not interact with HIV-1 IN in vitro and in living cells. Finally, RNA interference-mediated knock-down of endogenous LEDGF/p75 expression abolished nuclear/chromosomal localization of IN. We conclude, therefore, that the interaction with LEDGF/p75 accounts for the karyophilic properties and chromosomal targeting of HIV-1 IN.
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PMID:LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. 1279 94

Human lens epithelium-derived growth factor (LEDGF)/p75 protein forms a specific nuclear complex with human immunodeficiency virus type 1 (HIV-1) integrase and is essential for nuclear localization and chromosomal association of the viral protein. We now studied nuclear import of LEDGF/p75 in live and semipermeabilized cells. We show that nuclear import of LEDGF/p75 is GTP-, Ran-, importin-alpha/beta-, and energy-dependent and that the protein competes with the canonical SV40 large T antigen nuclear localization signal (NLS) for nuclear import receptors. We identified the NLS of LEDGF/p75 through deletion analysis and site-directed mutagenesis. The LEDGF/p75 NLS, 148GRKRKAEKQ156, belongs to the canonical SV40-like family. Fusion of this short peptide to the amino terminus of Escherichia coli beta-galactosidase rendered the fusion protein nuclear, confirming that the LEDGF/p75 NLS is transferable. Moreover, a single amino acid change in the NLS was sufficient to exclude the mutant LEDGF/p75 protein from the nucleus and abolish nuclear import of HIV-1 integrase.
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PMID:Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. 1516 64

Human immunodeficiency virus type 1 (HIV-1), feline immunodeficiency virus (FIV), and Moloney murine leukemia virus (MoMLV) integrases were stably expressed to determine their intracellular trafficking. Each lentiviral integrase localized to cell nuclei in close association with chromatin while the murine oncoretroviral integrase was cytoplasmic. Fusions of pyruvate kinase to the lentiviral integrases did not reveal transferable nuclear localization signals. The intracellular trafficking of each was determined instead by the transcriptional coactivator LEDGF/p75, which was required for nuclear localization. Stable small interfering RNA expression eliminated detectable LEDGF/p75 expression and caused dramatic, stable redistribution of each lentiviral integrase from nucleus to cytoplasm while the distribution of MoMLV integrase was unaffected. In addition, endogenous LEDGF/p75 coimmunoprecipitated specifically with each lentiviral integrase. In vitro integration assays with preintegration complexes (PICs) showed that endogenous LEDGF/p75 is a component of functional HIV-1 and FIV PICs. However, HIV-1 and FIV infection and replication in LEDGF/p75-deficient cells was equivalent to that in control cells, whether cells were dividing or growth arrested. Two-long terminal repeat circle accumulation in nondividing cell nuclei was also equivalent to that of LEDGF/p75 wild-type cells. Virions produced in LEDGF/p75-deficient cells had normal infectivity. We conclude that LEDGF/p75 fully accounts for cellular trafficking of diverse lentiviral, but not oncoretroviral, integrases and is the main lentiviral integrase-to-chromatin tethering factor. While lentiviral PIC nuclear import is unaffected by LEDGF/p75 knockdown, this protein is a component of functional lentiviral PICs. A role in HIV-1 integration site distribution merits investigation.
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PMID:LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes. 1530 44


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