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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship of serum human immunodeficiency virus-1 (HIV-1) RNA levels to HIV-1 RNA levels in other compartments, such as the lungs, is not well characterized. The purpose of this study was to determine the viral burden of HIV-1 in the lungs by comparing HIV-1 RNA in cell-free bronchoalveolar lavage fluid (BALF) with that in serum. Specimens were examined from 77 HIV-seropositive adults (CD4(+) cell counts: 0 to 700 cells/mm(3); 48% receiving prescribed antiretroviral agents), comprising 43 asymptomatic individuals who were compared with 34 persons with active lung disease caused by Pneumocystis carinii (n = 26), bacteria (n = 3), Mycobacterium avium complex (n = 2), Nocardia sp. (n = 1), Aspergillus sp. (n = 1), or pulmonary Kaposi's sarcoma (n = 1). For serum HIV-1 RNA, the proportion of subjects with detectable levels and the mean values were similar for asymptomatic individuals and persons with active lung disease (85% versus 86%, respectively) (6.64 x 10(4) versus 1. 81 x 10(5) HIV-1 RNA copies/ml; p = 0.13). In contrast, HIV-1 RNA in BALF was more often detected (16% versus 62%; p = 0.001), and mean values were higher (1.04 x 10(5) versus 3.31 x 10(6) HIV-1 RNA copies/ml; p = 0.032), in subjects with active lung disease than in asymptomatic subjects, independent of early or advanced clinical stages of HIV-related disease. For both study groups, HIV-1 RNA levels in BALF exceeded those in serum in 56% of cases by up to 66-fold, and did not correlate with local levels of tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, or interleukin-16. HIV-1 proviral DNA in cells from BALF was detected in up to 86% of subjects, more frequently in persons with advanced HIV disease (p = 0.0496), and often involved > 10% of BALF cells, but did not correlate with HIV-1 RNA detected in BALF. These data provide evidence for active HIV-1 replication in the lungs. HIV-1 replication is compartmentalized relative to serum, may be restricted, is independent of HIV-1 proviral DNA and clinical stage of HIV, and may be influenced by pulmonary disease such as P. carinii pneumonia or by other local or lung-specific factors. The lungs represent a large reservoir for HIV-1, and may present a source of persistent HIV-1 replication even during periods of apparent clinical latency of HIV-1 infection.
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PMID:Enhanced in vivo human immunodeficiency virus-1 replication in the lungs of human immunodeficiency virus-infected persons with Pneumocystis carinii pneumonia. 1058 27

The role of human immunodeficiency virus type 1 (HIV-1) infection on the ability of human monocytes/macrophages to phagocytose Mycobacterium avium complex (MAC) in vivo and in vitro and the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on this function were investigated. By use of a flow cytometric assay to quantify phagocytosis, HIV-1 infection was found to impair the ability of monocyte-derived macrophages to phagocytose MAC in vitro, whereas GM-CSF significantly improved this defect. Phagocytosis was not altered by exposure to a mutant form of GM-CSF (E21R) binding only to the alpha chain of the GM-CSF receptor, suggesting that signaling by GM-CSF that leads to augmentation of phagocytosis is via the beta chain of the receptor. In a patient with AIDS and disseminated multidrug-resistant MAC infection, GM-CSF treatment improved phagocytosis of MAC by peripheral blood monocytes and reduced bacteremia. These results imply that GM-CSF therapy may be useful in restoring antimycobacterial function by human monocytes/macrophages.
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PMID:Granulocyte-macrophage colony-stimulating factor augments phagocytosis of Mycobacterium avium complex by human immunodeficiency virus type 1-infected monocytes/macrophages in vitro and in vivo. 1060 95

Several studies documenting the association of bacteremia and severity of neutropenia in HIV-infected patients, as well as studies using the colony stimulating factors filgrastim or sargramostim to prevent and treat neutropenia in this patient population, are summarized. Three studies are described in which low absolute neutrophil count was associated with increased incidence of bacterial infections in patients with HIV infection. Two hematopoietic growth factors called colony stimulating factors (filgrastim and sargramostim) are available in the United States, but neither is approved by FDA for the treatment or prevention of neutropenia in HIV-infected patients. Studies have shown both filgrastim and sargramostim to be effective in treating neutropenia in HIV-infected patients without increasing the viral load. In one study, filgrastim use on a daily or intermittent basis was associated with reduction in severe neutropenia or death; in addition, filgrastim-treated patients had fewer bacterial infections, fewer hospital days (both total number of days and days associated only with bacterial infections), and a reduced need for i.v. antimicrobials compared with HIV-infected controls. In another study, neutropenia caused by zidovudine was successfully treated with sargramostim. Both filgrastim and sargramostim show promise in treating and preventing neutropenia in HIV-infected patients. More research is needed to determine the patient population who can best benefit from therapy with these agents and to determine the relative advantages and disadvantages of filgrastim and sargramostim.
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PMID:Treatment of HIV-related neutropenia. 1061 82

Over the past decade, the involvement of tyrosine kinases in signal transduction pathways evoked by cytokines has been intensively investigated. Only relatively recently have the roles of serine/threonine kinases in cytokine-induced signal transduction and anti-apoptotic pathways been examined. Cytokine receptors without intrinsic kinase activity such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and the interferons were thought to transmit their regulatory signals primarily by the receptor-associated Jak family of tyrosine kinases. This family of tyrosine kinases activates STAT transcription factors, which subsequently transduced their signals into the nucleus to modulate gene expression. Cytokine receptors with intrinsic tyrosine kinase activity such as c-Kit were initially thought to transduce their signals independently of serine/threonine kinase cascades. Recently, both of these types of receptor signaling pathways have been shown to interact with serine/threonine kinase pathways as maximal activation of these tyrosine kinase regulated cascades involve serine/threonine phosphorylation modulated by, for example MAP kinases. A common intermediate pathway initiating from cytokine receptors is the Ras/Raf/MEK/ERK (MAPK) cascade, which can result in the phosphorylation and activation of additional downstream kinases and transcription factors such as p90Rsk, CREB, Elk and Egr-1. Serine/threonine phosphorylation is also involved in the regulation of the apoptosis-controlling Bcl-2 protein, as certain phosphorylation events induced by cytokines such as IL-3 are anti-apoptotic, whereas other phosphorylation events triggered by chemotherapeutic drugs such as Paclitaxel are associated with cell death. Serine/threonine phosphorylation is implicated in the etiology of certain human cancers as constitutive serine phosphorylation of STATs 1 and 3 is observed in chronic lymphocytic leukemia and can be inhibited by the chemotherapeutic drug fludarabine. Serine/threonine phosphorylation also plays a role in the etiology of immunodeficiencies. Activated STAT5 proteins are detected in reduced levels in lymphocytes recovered from HIV-infected individuals and immunocompromised mice. Serine/threonine phosphorylation may be an important target of certain chemotherapeutic drugs which recognize the activated proteins. This meeting report and mini-review will discuss the interactions of serine/threonine kinases with signal transduction and apoptotic molecules and how some of these pathways can be controlled by chemotherapeutic drugs. Leukemia (2000) 14, 9-21.
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PMID:Serine/threonine phosphorylation in cytokine signal transduction. 1063 71

Neutropenia frequently complicates infection due to human immunodeficiency virus (HIV). The etiology of neutropenia in this setting includes bone marrow infection or infiltration, myelosuppressive therapies, the presence of antibodies to HIV, and accelerated apoptosis. Protection against microbial invaders by neutrophils is further compromised by impaired chemotaxis and phagocytosis, production of toxic oxygen species, and expression of cellular adhesion molecules. Neutropenia is a significant risk factor for bacterial infection in HIV-infected patients. Endogenous cytokines, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor, regulate neutrophil count and function. Treatment with recombinant human methionyl G-CSF (filgrastim) has lessened neutropenia in patients with HIV infection. Clinical trials have shown that the incidence of bacterial infections and the number of consequent days of hospitalization for HIV-infected patients receiving filgrastim therapy are lower. Filgrastim treatment also allows administration of larger doses of myelosuppressive agents.
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PMID:Neutropenia, neutrophil dysfunction, and bacterial infection in patients with human immunodeficiency virus disease: the role of granulocyte colony-stimulating factor. 1067 24

A non-cognate mechanism of protection against human immunodeficiency virus-1 (HIV-1) infection involves up-regulation of beta-chemokines, which bind and may down-modulate the CCR5 co-receptors, thereby preventing transmission of M-tropic HIV-1. The objective of this investigation was to evaluate this mechanism in vivo in non-human primates. Rhesus macaques were immunized by a modified targeted lymph nodes (TLN) route with recombinant simian immunodeficiency virus (SIV) glycoprotein 120 (gp120) and p27 in alum, and adsorbed recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) with either interleukin (IL)-2 or IL-4. Immunization induced significant increases in the concentrations of CD8 cell-derived suppressor factor (CD8-SF), regulated on activation normal T cells expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, and down-modulation of the proportion of cells expressing CCR5 (r = 0.737, P<0.05). The macaques were then challenged with SIVmac 220 by the rectal mucosal route. The plasma SIVmac RNA showed a significant inverse correlation with the CD8-SF or the concentration of the three beta-chemokines (r = 0.831 and 0.824, P<0.01), but a positive correlation between the proportion of CCR5+ cells and SIVmac RNA (r = 0.613, P = 0.05). These results demonstrate for the first time in vivo that immunization up-regulates beta-chemokines, which may down-modulate CCR5 co-receptors, and both functions are significantly correlated with the viral load. Hence, the non-cognate beta-chemokine-CCR5 mechanism should be considered as complementary to specific immunity in vaccination against HIV.
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PMID:Up-regulation of beta-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus transmission in non-human primates. 1079 5

The depletion of immune T cells by human immunodeficiency virus type-1 (HIV-1) infection is a major mechanism involved in the pathogenesis of AIDS. Here, we examined a possible effector function of blood monocyte-derived dendritic cells (DCs) to induce apoptosis in bystander CD4+ and CD8+ T cells. The DCs were generated by culturing monocytes in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. The DCs exposed to HIV-1 particles were co-cultured with healthy donor-derived blood T cells at a ratio of 1:20. Analyses by percent cell mortality, staining with propidium iodide and reactivity with Annexin V revealed the induction of apoptosis in both CD4+ and CD8+ target T cells. Further, this apoptosis occurred without stimulation with mitogens when the cell cycle of target T cells shifted from G0 to G1, probably due to the mitogenic effect of the DCs. Thus, induction of apoptosis in both CD4+ and CD8+ T cells occurred via interaction with DCs adsorbed with HIV-1 particles.
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PMID:Exposure of normal monocyte-derived dendritic cells to human immunodeficiency virus type-1 particles leads to the induction of apoptosis in co-cultured CD4+ as well as CD8+ T cells. 1080 98

In view of the role of gammadelta(+) T cells in mucosal protection against infection, the proportion of gamma delta T cells was examined in cells eluted from lymphoid and mucosal tissues of macaques immunized with simian immunodeficiency virus (SIV) gp120 and p27 in alum and challenged with live SIV by the rectal mucosal route. This revealed a significant increase in gammadelta T cells eluted from the rectal mucosa (p < 0.01) and the related iliac lymph nodes (p < 0.0001) in protected as compared with infected macaques. Preferential homing of PKH-26-labeled gammadelta(+) T cells from the primed iliac lymph nodes to the rectal and cervico-vaginal mucosa was demonstrated after targeted iliac lymph node as compared with i. m. immunization. Investigations of the mechanism of protection revealed that gammadelta(+) T cells can generate antiviral factors, RANTES, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta which can prevent SIV infection by binding to the CCR5 coreceptors. Up-regulation of gammadelta(+) T cells was demonstrated by immunization of macaques with heat shock protein (HSP)70 linked to peptides and with granulocyte-macrophage colony-stimulating factor (GM-CSF). This was confirmed by in vitro studies showing that GM-CSF can up-regulate gammadelta(+) T cells from macaques immunized with HSP-linked peptides but not those from naive animals. We suggest that a novel strategy of immunization with HSP70 linked to antigen may generate both cognate immunity to the antigen and innate immunity by virtue of up-regulation of gammadelta(+) T cells. These cells generate antiviral factors and the three beta-chemokines that prevent binding and transmission of SIV or M-tropic HIV by the CCR5 coreceptor.
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PMID:The role of gammadelta T cells in generating antiviral factors and beta-chemokines in protection against mucosal simian immunodeficiency virus infection. 1094 Sep 16

This study addresses the role of interleukin (IL)-8, a CXC-chemokine, the level of which is reported to be raised in the peripheral circulation of human immunodeficiency virus-1 (HIV-1)-infected individuals, during the induction of HIV-1 expression from latency and during cytokine-mediated HIV-1 up-regulation. IL-8 at the higher concentrations tested (> or = 100 ng/ml) was unable to induce HIV-1 expression in the chronically infected promonocytic U1 cell line, as measured by p24 antigen enzyme-linked immunosorbent assay (ELISA), whereas at lower concentrations of 1 and 10 ng/ml, constitutive HIV-1 expression was only marginally reduced. HIV-1 replication in acutely infected U937 cells was also significantly reduced by IL-8. The potent up-regulation of HIV-1 expression in U1 cells by tumour necrosis factor-alpha (TNF-alpha) remained unaffected by the addition of IL-8. HIV-1 induction by IL-1beta, IL-6 and TNF-beta, cytokines grouped here as intermediate HIV-1 inducers, was suppressed by IL-8 at concentrations of 1 and 10 ng/ml. However, IL-8 at 100 ng/ml did not significantly alter the effect of IL-1beta, synergized with IL-6 in enhancing, and marginally suppressed TNF-beta-induced HIV-1 expression. IL-8 suppressed granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhanced interferon-gamma (IFN-gamma)-induced HIV-1 expression in a dose-dependent manner. Pretreatment of U1 cells with IL-8 did not alter the IL-8-mediated effects on cytokine-induced HIV-1 expression, suggesting that this chemokine exerts its effect at the time of HIV-1 induction or at a postinduction stage. Furthermore, IL-8 was itself induced by cytokines that up-regulate HIV-1 expression in U1 cells and the levels produced correlated directly with the levels of p24 antigen produced, suggesting common pathways for cytokine induction of both HIV-1 and IL-8. These results show that IL-8, typically a non-inducer, can differentially modulate HIV-1 expression in U1 cells and that this is dependent on the inducing cytokine and on the concentration of IL-8.
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PMID:Interleukin-8 fails to induce human immunodeficiency virus-1 expression in chronically infected promonocytic U1 cells but differentially modulates induction by proinflammatory cytokines. 1101 65

Preliminary preclinical and clinical data suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) may decrease viral replication. Therefore, 105 individuals with AIDS who were receiving nucleoside analogue therapy were enrolled in a placebo-controlled, double-blind study and were randomized to receive either 125 microgram/m(2) of yeast-derived, GM-CSF (sargramostim) or placebo subcutaneously twice weekly for 6 months. Subjects were evaluated for toxicity and disease progression. A significant decrease in mean virus load (VL) was observed for the GM-CSF treatment group at 6 months (-0.07 log(10) vs. -0.60 log(10); P=.02). More subjects achieved human immunodeficiency virus (HIV)-RNA levels <500 copies/mL at >/=2 evaluations (2% on placebo vs. 11% on GM-CSF; P=.04). Genotypic analysis of 46 subjects demonstrated a lower frequency of zidovudine-resistant mutations among those receiving GM-CSF (80% vs. 50%; P=.04). No difference was observed in the incidence of opportunistic infections (OIs) through 6 months or survival, despite a higher risk for OI among GM-CSF recipients. GM-CSF reduced VL and limited the evolution of zidovudine-resistant genotypes, potentially providing adjunctive therapy in HIV disease.
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PMID:A randomized, placebo-controlled trial of granulocyte-macrophage colony-stimulating factor and nucleoside analogue therapy in AIDS. 1102 77


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