Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

Granulocytopenia is a complication of human immunodeficiency virus disease, as well as a toxic manifestation of zidovudine therapy. To evaluate pharmacokinetic and pharmacodynamic relationships, 11 AIDS-AIDS-related complex patients who had developed zidovudine-associated granulocytopenia (mean absolute neutrophil count, 1,077/mm3) were examined after addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to zidovudine. GM-CSF was administered as a daily (1.0 or 0.3 micrograms/kg) or every-other-day (0.3 micrograms/kg) subcutaneous dose over a 28-day period. Zidovudine was continued at the same daily dosage as was previously being administered. Of 11 patients, 7 (1.0 micrograms/kg, n = 5; 0.3 micrograms/kg, n = 2) had a pharmacologic response to GM-CSF with an increase to a mean absolute neutrophil count of 3,189 cells per mm3 at 4 weeks (P < 0.05). The peak concentration of GM-CSF in plasma ranged from 11.5 to 84.4 pg/ml, and the time to peak ranged from 1 to 3 h. No correlation between GM-CSF disposition and hematologic response was noted. A decreased plasma zidovudine-glucuronide/zidovudine ratio was noted after 1 week of GM-CSF, and an increase in the area under the plasma concentration-versus-time curve for zidovudine was found in three patients after 4 weeks. Low doses of GM-CSF can raise the granulocyte count in patients with zidovudine-induced neutropenia. The use of GM-CSF and zidovudine may represent a viable treatment option for persons with human immunodeficiency virus infection who develop neutropenia while receiving zidovudine but do not tolerate alternative nucleoside analogs. Further studies are needed to assess the complex interaction between these two agents.
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PMID:Pharmacokinetics and pharmacodynamics of granulocyte-macrophage colony-stimulating factor and zidovudine in patients with AIDS and severe AIDS-related complex. 846 Sep 20

In blood, the CD4+ T cells of patients with human immunodeficiency virus type 1 (HIV-1) harbor HIV-1; however, whether the CD4+ blood monocytes carry the virus is controversial. Tissue macrophages are known to be infected. To determine in blood monocytes from HIV-1-seropositive patients contain HIV-1, we separated monocytes and T-cell subsets by using monoclonal antibodies bound to magnetic beads and by monocyte adherence to glass. Monocytes were cultured with macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3. After 14 days in culture, cells were analyzed for the presence of HIV-1 antigen and multinucleated giant cells (MGCs). Freshly isolated cell subsets were analyzed for HIV-1 proviral DNA by PCR with modified env (SK68i and SK69i2) and gag (SK145i and SK150) primers. We found that (i) monocytes cultured without depletion of CD4+ T cells (11 of 11 patients) were HIV-1 antigen positive and showed dramatically increased spontaneous formation of MGCs (ii) monocytes cultured after depletion of CD4+ T cells (three experiments) were HIV-1 antigen negative and showed markedly decreased MGC formation, and (iii) in specimens from 14 patients subsequently analyzed by PCR, purified CD4+ T cells were positive for HIV-1 proviral DNA in all patients. In 11 of 14 patients (79%), the monocyte fractions were HIV-1 proviral DNA negative, while in the remaining 3 patients, the monocytes were positive for HIV-1 proviral DNA. In conclusion, the major reservoir for HIV-1 infection in human peripheral blood is the CD4+ T cell (14 of 14 cases).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Blood monocytes from most human immunodeficiency virus type 1-infected patients do not carry proviral DNA. 855 97

Recombinant human tumor necrosis factor (TNF) binding protein-1 (r-h TBP-1) and recombinant human soluble dimeric TNF receptor (rhu TNFR:Fc) were used to determine the relative contributions of TNF to phorbol myristate acetate (PMA) and cytokine-induced human immunodeficiency virus type 1 (HIV-1) replication in chronically infected cell lines. Treatment of HIV-1-infected promonocytic U1 cells with r-h-TBP-1 or rhu TNFR:Fc reduced PMA-induced HIV-1 p24 antigen production in a concentration-dependent manner, with a maximal inhibition of approximately 90%. Maximal inhibition of p24 antigen production in T-lymphocytic ACH-2 cells was 47% with r-hTBP-1 and 42% with rhu TNFR:Fc. r-hTBP-1 and rhu TNFR:Fc also decreased p24 antigen synthesized by U1 cells in response to other stimuli, including phytohemagglutinin (PHA)-induced supernatant, granulocyte-macrophage colony-stimulating factor, interleukin-6, and TNF. Addition of r-hTBP-1 to U1 cells during the last 4 h of a 24 h incubation with PMA still inhibited p24 antigen production by 15%. U1 cells stimulated with 10(-7) M PMA released approximately 1 ng/ml endogenous TBP-1 with an initial peak observed at 1 h and a second peak at 24 h after PMA stimulation. r-hTBP-1 also partially reversed inhibition of U1 cellular proliferation caused by PMA. Both r-hTBP-1 and rhu TNFR:Fc blocked PMA induction of nuclear factor (NK)- kappa B DNA-binding activity in U1 cells in association with decreases in HIV-1 replication. We conclude that soluble TNF receptors can inhibit stimuli-induced HIV-1 expression and NK- kappa B DNA-binding activity in chronically infected U1 cells.
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PMID:Soluble tumor necrosis factor receptors inhibit phorbol myristate acetate and cytokine-induced HIV-1 expression chronically infected U1 cells. 860 87

A proportion of HIV-infected individuals experience episodes of localized or systemic bacterial infections caused by Gram-negative bacteria. Many of the clinical side effects of these infections are associated with the production of proinflammatory cytokines, which are induced primarily by LPS, a constituent of the bacterial cell wall of Gram-negative bacteria. The present study examines the mechanisms involved in LPS-mediated induction of HIV expression in U1 cells, a promonocytic cell line chronically infected with HIV. Stimulation of U1 cells by LPS alone induced minimal levels of HIV expression, which was significantly enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF). Costimulation of U1 cells with LPS plus GM-CSF resulted in the accumulation of steady-state levels of HIV RNA; however, only a weak induction of HIV long terminal repeat-driven transcription, which was not associated with the activation of the cellular transcription factor nuclear factor-kappa B, was noted. Costimulation of cells with LPS plus GM-CSF induced the production of proinflammatory cytokines, IL-8, IL-1 beta and IL-6, but not TNF-alpha. IL-1 receptor antagonist (ra) inhibited LPS enhancement of HIV expression in GM-CSF-stimulated cells, suggesting that endogenous IL-1 was involved in LPS-mediated viral production. In this regard, anti-inflammatory cytokines inhibited LPS plus GM-CSF-stimulated HIV expression, and this effect closely correlated with inhibition of IL-1 beta release and, in particular, with up-regulation of endogenous IL-1ra production. Thus, the balance between an endogenously produced viral inducer (IL-1 beta ) and an inhibitor (IL-1ra) may represent an important pathway leading to modulation of HIV expression from monocytic cells.
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PMID:Modulation of endogenous IL-1 beta and IL-1 receptor antagonist results in opposing effects on HIV expression in chronically infected monocytic cells. 861 79

Disparate findings have been reported as to whether human immunodeficiency virus (HIV) affects cytokine production by macrophages (MA). We investigated production of different cytokines and of macrophage inflammatory protein (MIP)-1alpha by HIV-1Ba-L- or HIV-1Ada-infected blood-derived MA. Relative to controls, only MIP-1alpha levels increased twofold to > 10-fold in supernatants 2 to 3 weeks postinfection (PI), at the time of maximum virus production; levels of the other chemokines (RANTES, interleukin (IL)-8) and cytokines (IL-1alpha, IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1) investigated were not affected. MIP-1alpha mRNA signal assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) was, however, only occasionally greater in cells from infected cultures relative to controls. MIP-1alpha levels in supernatants remained in the same range as in control cultures when more than 10 mmol/L Zidovudine was added 24 hours PI, which indicates involvement of virus replication in the effect. Anti-MIP-1alpha antibody labeling identified a 10% to 25% subset of MA, strongly expressing HLA-DR and CD4, and also stained by anti-IL-6 and anti-TNF-alpha antibodies. Two weeks PI, dual staining showed that the majority of the 5% to 20% cells that were p24+ belonged to the MIP-1alpha+ population, which may define a MA subset capable to better sustain HIV replication. MIP-1alpha induced by HIV replication in MA might play a role in the pathophysiology of HIV infection; in impaired hematopoiesis; or as a CD4+ and CD8+ lymphocyte chemoattractant, by recruiting either or both HIV-susceptible and cytotoxic T lymphocytes to virus replication sites.
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PMID:Macrophage inflammatory protein-1alpha is induced by human immunodeficiency virus infection of monocyte-derived macrophages. 863 52

The dendritic cell (DC) lineage of white blood cells specializes in capturing antigens and stimulating T-dependent immunity. Because of their efficacy in inducing T cell responses in vivo without other adjuvants, DCs can be considered "nature's adjuvant." DCs are the least abundant of leukocytes, but methods for generating large numbers of DCs are being developed. Ex vivo, DCs develop from CD34+ progenitors cultured in the presence of a combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha). This kind of work is stimulating interest in charging DCs with clinically relevant antigens and inducing active immunity in patients. Targeting antigens to DCs may become feasible also because of the identification of distinct antigen receptors such as DEC-205, a DECalectin with 10 contiguous, C-type lectin domains. DEC-205 can mediate adsorptive uptake and presentation via DCs. AIDS is another disease for which DCs should be considered in designing new therapies, since DCs can play a major role in promoting HIV-1 replication. Many HIV-1 isolates induce syncytia between DCs and CD4+ memory T cells. These syncytia in turn are the site for a productive infection with HIV-1, possibly because requisite transcription factors like NF-kappaB and Sp1 are separately provided by DCs and T cells, respectively. Further attention to the DC lineage should provide new avenues for manipulating the immune system in several clinical contexts.
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PMID:Dendritic cells and immune-based therapies. 869 42

In order to assess the efficacy and safety of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in the treatment of HIV-associated leukopenia, 35 subjects suffering from severe leukopenia/neutropenia (24 with a previous diagnosis of AIDS, 11 with AIDS-related complex), received rHuGM-CSF at 0.5-3 micrograms/Kg/day subcutaneously for a mean period of 9.7 +/- 12.5 weeks (range 2-43 weeks). Five patients have been treated continuously for more than 6 months. rHuGM-CSF administration led to a significant (at least two-fold; P < .001) increase in total leukocyte, neutrophil and monocyte count by the second week of treatment, subsequently maintained through the entire course of therapy. No considerable effects on other hematological, immunological and virological parameters have been detected. Patients treated with rHuGM-CSF did not suffer from novel opportunistic diseases, while bacterial infections occurred in only 3 cases (pneumonia in 2, otitis/mastoiditis in 1). Long-term treatment with rHuGM-CSF allowed continuation or resumption of potentially myelotoxic drugs in 22 patients out of 35. A self-limited flu-like syndrome represented the most common adverse event (observed in 15 patients), while no other significant clinical or laboratory abnormalities were found. In conclusion, long-term rHuGM-CSF therapy showed a good efficacy and safety profile in the treatment of HIV-related leukopenia, also increasing tolerability to potentially myelosuppressive drugs, and leading to a significant reduction in morbidity due to secondary infections.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in leukopenic patients with advanced HIV disease. 880 19

Activation of human blood neutrophils and monocytes for enhanced release of toxic oxygen radicals may take place after priming with several cytokines including hematopoietic growth factors. The potential impact of human immunodeficiency virus (HIV) on this response and the relative potency of various cytokines remains unclear. Blood neutrophils and monocytes were isolated from 25 HIV outpatients with variable immunodeficiency. Oxidative burst response upon stimulation with N-formyl-methionyl-leucyl-phenylalanine was assessed in neutrophils after priming with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-g), and in monocytes after priming with GM-CSF and IFN-g. Monocyte oxidative burst responses were not changed in patients or controls. In contrast, following priming with IFN-g, GM-CSF or medium (but not G-CSF) the neutrophils in HIV patients with CD4 counts > 200 x 10(9)/L exhibited a significantly higher chemiluminescence response than was seen in healthy age-matched controls, whereas the response in patients with lower CD4 counts was not different from controls. At comparable concentrations, GM-CSF induced a significantly higher priming than G-CSF and IFN-g. A significant positive correlation between CD4 counts and priming activity of GM-CSF and IFN-g on neutrophils was observed. We conclude that neutrophils in HIV infection have a normal or enhanced response to the oxidative metabolism priming activity of hematopoietic growth factors in vitro, whereas priming effect on monocytes was not seen.
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PMID:Priming of neutrophil and monocyte activation in human immunodeficiency virus infection. Comparison of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and interferon-gamma. 897 88

Human contact with the nontuberculous mycobacteria (NTM) is quite common, yet serious infections with these organisms were relatively infrequent until the advent of AIDS. Mycobacteria present an important window on the interaction of the innate (neutrophils, macrophages, NK cells) and acquired (T cells and B cells) immune systems. In their attempt to infect macrophages, the mycobacteria use their complex glycopeptidolipid cell wall to down-regulate macrophage responses. Once inside, mycobacteria are subject to the panoply of primary macrophage responses (e.g., vacuolar acidification, lytic enzymes). The infected macrophage produces cytokine signals (e.g., chemokines, interleukin [IL]-12] that recruit and stimulate lymphocytes from the innate (NK cell) and acquired (T and B cells) arms of the immune response to help kill the invading mycobacteria. Lymphocyte products that are central to the activation of macrophages to increased mycobacterial killing include tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF). The precise mechanisms by which these cytokines work remains unknown. Rare patients who have refractory disseminated NTM infection without HIV infection probably have underlying immune defects in critical pathways for control of mycobacteria. We have recently characterized one such family and found abnormal IL-12 regulation. Interferon-gamma, the cytokine primarily elicited by IL-12, has been used successfully with antimycobacterials for treatment of these patients. The window on the interaction of the innate and acquired immune systems that mycobacteria afford is being opened. Understanding the cell-cell interactions and cytokines involved in NTM infections will lead to new therapeutic approaches.
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PMID:Host defense against nontuberculous mycobacterial infections. 897 76

In order to characterize the biological properties of human immunodeficiency virus type 1 (HIV-1) variants from different tissues (peripheral blood mononuclear cells [PBMC], lymph node, spleen, brain, and lung) of one patient, we have chosen long-range PCR to amplify virtually full-length HIV proviruses and to construct replication-competent viruses by adding a patient-specific 5' long terminal repeat. To avoid selection during propagation in CD4+ target cells, we transfected 293 cells and used the supernatants from these cells as challenge viruses for tropism studies after titration on human PBMC. Despite differences in the V3 loop of the major variants found in brain and lung compared to lymphoid tissues all recombinant HIV clones obtained showed identical cell tropism and replicative kinetics. After infection of human PBMC these viruses replicated with similar kinetics, with a slow/low-titer, non-syncytium-inducing phenotype. In contrast to the prediction of macrophage tropism, drawn from the V3 loop sequence, none of these viruses infected monocyte-derived macrophages. The challenge of blood dendritic cells by these recombinant viruses in the presence of tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and interleukin-4 resulted in a productive infection only after adding stimulated CD4+ T lymphocytes. Therefore, the biological properties of the HIV-1 variants derived from nonlymphoid tissue of this patient did not differ from those of HIV-1 variants from lymphoid tissue with respect to tropism for primary cells such as PBMC, macrophages, and blood dendritic cells.
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PMID:Biological characterization of human immunodeficiency virus type 1 clones derived from different organs of an AIDS patient by long-range PCR. 918 81


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