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)

The study of monocyte/macrophage functions after human immunodeficiency virus type 1 (HIV-1) infection may help in understanding the pathogenesis of AIDS. The production of four cytokines, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor (GM-CSF), by peripheral blood monocytes/macrophages was evaluated after in vitro infection with HIV-1. HIV-1 infection of these monocytes/macrophages did not result in release of any of these cytokines. Similarly, treatment of uninfected cells with purified recombinant HIV-1 envelope protein did not result in cytokine production. After stimulation with endotoxin or endotoxin plus interferon-gamma, HIV-1-infected monocytes/macrophages produced amounts of TNF alpha, IL-6, GM-CSF, and IL-1 beta comparable to that of uninfected cells. HIV-1 infection does not appear to induce or alter cytokine production by mononuclear phagocytes, which retain the capacity to produce these cytokines after endotoxin stimulation.
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PMID:Production of cytokines by peripheral blood monocytes/macrophages infected with human immunodeficiency virus type 1 (HIV-1). 218 29

The immunoregulatory cytokine interleukin 6 (IL-6) directly upregulates production of human immunodeficiency virus (HIV) in acutely as well as in chronically infected cells of monocytic lineage. In addition, IL-6 synergizes with tumor necrosis factor alpha (TNF-alpha) in the induction of latent HIV expression. Unlike TNF-alpha, upregulation of viral expression induced by IL-6 alone does not occur at the transcriptional level and it is not associated with accumulation of HIV RNA. However, when IL-6 and TNF-alpha synergistically stimulate HIV production, accumulation of HIV RNA and increased transcription are observed, indicating that IL-6 affects HIV expression at multiple (transcriptional and post-transcriptional) levels.
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PMID:Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor alpha by transcriptional and post-transcriptional mechanisms. 219 94

The skin-specific immune surveillance system protects against invading microorganisms and transformed cells expressing tumor-specific neoantigens. This system includes antigen-presenting Langerhans cells, dermal and epidermal T lymphocytes, cytokine-producing keratinocytes, and draining peripheral lymph nodes. In patients infected with human immunodeficiency virus-1 (HIV-1), this surveillance system appears to be compromised, as evidenced by a reduction in the epidermal Langerhans cell population. Because human epidermal Langerhans cell express surface-bound CD4 antigens, HLA-DR antigens, and Fc-IgG receptors, all of which are involved in HIV-1 binding to, or entry into, the target cell, the reduction in Langerhans cells in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) may be a direct consequence of HIV-1 infection and subsequent injury to Langerhans cells. Detailed ultrastructural studies have confirmed moderate to severe morphologic damage in some Langerhans cells of such patients and the presence of HIV-1-like particles on Langerhans cell surface membranes and in the extracellular spaces. The biologic consequences of Langerhans cell infection by HIV-1 could be either impaired antigen presentation function of viable Langerhans cells or possible transmission of the retrovirus to the T-cell compartment in skin or lymph nodes, with subsequent depletion of CD4+ T cells via widespread syncytia formation between HIV-1-infected and noninfected cells. The facts that herpes simplex virus, specific cytokines, and ultraviolet B radiation can activate signals for HIV-1 expression and that epidermal cells can elaborate large amounts of cytokines, particularly with enhanced ultraviolet B exposure, may have important clinical implications for HIV-1-infected patients.
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PMID:Langerhans cells in HIV-1 infection. 219 48

The chronically infected promonocytic clone U1 expresses low-to-undetectable constitutive levels of human immunodeficiency virus (HIV). Virus replication in these cells can be increased up to 25-fold by phorbol esters (phorbol-12-myristate-13-acetate), recombinant cytokines such as tumor necrosis factor-alpha, and cytokine-enriched mononuclear cell supernatants. We have tested specific activators of protein kinases (PK) and PK inhibitors (isoquinolinesulfonamide derivatives), as well as calcium-mobilizing agents, for their effect on constitutive and induced virus expression in U1 cells. Virus expression was measured by reverse transcriptase, Western blot, and nuclear run-on analysis. Activation of PKC by 1-oleyl,2-acetylglycerol, a synthetic analog of the natural ligand 1,2-diacylglycerol, and bryostatin 1 (a recently described specific PKC activator) resulted in a two- to eightfold increase in virus production. In contrast, activators of cyclic-nucleotide-dependent PKs were not effective in inducing virus expression. PK inhibitors were tested for their effect on HIV upregulation by cytokines and other inducing agents. The isoquinolinesulfonamide derivative H7, a potent inhibitor of PKC activation, effectively blocked (70 to 90%) HIV induction by cytokines and phorbol-12-myristate-13-acetate. The derivative HA1004, which is more selective for cyclic-nucleotide-dependent kinases, did not suppress viral induction. In addition, increases in intracellular calcium levels dramatically enhanced HIV production induced by both specific PKC activators and cytokines. These results indicate that activation of PKC is a common pathway involved in the upregulation of HIV expression in chronically infected cells stimulated by cytokines and other inducing agents.
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PMID:Direct and cytokine-mediated activation of protein kinase C induces human immunodeficiency virus expression in chronically infected promonocytic cells. 220 Aug 85

Monocyte/macrophages (M/M) are an important target cell for human immunodeficiency virus (HIV) infection in the body. The study of HIV infection in these cells, however, is rather complicated because they represent a variable population, and because HIV entry and replication in M/M may be markedly influenced by a number of factors. These must be considered in therapeutic approaches to HIV infection. In the present set of experiments, we studied the interaction between certain agents which increase the infection of monocyte/macrophages (M/M) by HIV and two groups of anti-HIV agents: dideoxynucleosides and specific inhibitors of gp120-CD4 binding. We found that the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which markedly enhances HIV replication in M/M, does not affect the activity of recombinant soluble CD4 (sCD4) or OKT4A, two agents which block gp120-CD4 binding. However, it had varying effects on different dideoxynucleosides: GM-CSF increased the net anti-HIV activity of 3'-azido2',3'-dideoxythymidine (AZT), while at the same time it reduced the activity of 2',3'-dideoxycytidine (ddC) and 2',3'-dideoxyinosine (ddI). These effects probably represent an interplay between varying effects of GM-CSF on drug entry and phosphorylation. In additional experiments, we showed that very low concentrations of anti-HIV antibodies could enhance HIV infection of the U937 monocytoid cell line. Interestingly, while this effect has been hypothesized to occur through a CD4-independent mechanism, we found that the anti-HIV activities of both sCD4 and OKT4A were unchanged under conditions of enhancement.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ability of anti-HIV agents to inhibit HIV replication in monocyte/macrophages or U937 monocytoid cells under conditions of enhancement by GM-CSF or anti-HIV antibody. 222 41

Interleukin-6 (IL-6/B cell stimulatory factor 2) has been found to drive activated human B-lymphocytes through the final stages of differentiation to become immunoglobulin-producing cells. Most patients with common variable immunodeficiency (CVI) have B-lymphocytes that fail to differentiate into high-rate immunoglobulin-secreting cells in vivo and in vitro. In view of (1) the known effects of IL-6 to promote B-lymphocyte terminal differentiation and (2) the defect in differentiation in B-lymphocytes of patients with CVI, we believed that it was important to analyze the role of this cytokine in patients with CVI. Using an IL-6-dependent murine hybridoma cell line in a bioassay, serum IL-6 levels were determined in 17 patients with CVI and in eight normal control subjects. Thirteen of the 17 patients with CVI exhibited serum IL-6 levels that were twofold to 18-fold higher than the range (mean, +2 SD) of normal control subjects. Spontaneous IL-6 production by peripheral blood mononuclear cells (PBMC) of patients with CVI was significantly higher than that from normal control subjects, whereas lipopolysaccharide maximally stimulated IL-6 production by PBMCs of patients with CVI or PBMCs of normal control subjects was equivalent. A substance inhibitory of IL-6 bioactivity was found in equivalent amounts in sera of both patients and normal control subjects. Sera from patients with CVI with high IL-6 bioactivity were found to have saturated this IL-6 inhibitory substance, thus resulting in large amounts of free IL-6 in the sera. These studies suggest that the failure of B cells from patients with CVI to terminally differentiate into high-rate immunoglobulin-secreting cells cannot be attributed to a decrease in the serum levels of IL-6 and that the increased circulating IL-6 levels in patients with CVI result from hyperproduction rather than decreased use of IL-6. The persistently elevated levels of IL-6 observed in some patients with CVI may secondarily result in the induction of the neoplastic and autoimmune phenomena associated with this disease.
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PMID:Elevated serum interleukin-6 associated with a failure in B cell differentiation in common variable immunodeficiency. 222 13

A promonocytic cell model was used to investigate cytokine gene transcription in U937 and U9-IIIB cells chronically infected with human immunodeficiency virus type 1 (HIV-1). The production of interferon (alpha-1 interferon [IFN-alpha 1], IFN-alpha 2, and IFN-beta), interleukin (interleukin 1 alpha [IL-1 alpha], IL-1 beta, and IL-6), and tumor necrosis factor alpha (TNF-alpha) mRNA was characterized by quantitative polymerase chain reaction mRNA phenotyping in U937 and U9-IIIB cells following coinfection with Sendai paramyxovirus or stimulation with lipopolysaccharide (LPS). Chronic HIV-1 infection of U9-IIIB cells resulted in a low constitutive level of transcription of TNF and IL-1 genes but not IFN genes; however, when the cells were coinfected with Sendai virus, 10- to 20-fold higher levels of IFN-beta, IL-1 beta, IL-6, and TNF-alpha mRNA were observed in U9-IIIB cells than in similarly induced U937 cells. The enhanced levels of cytokine RNA in virus-infected U9-IIIB cells were also accompanied by higher levels of IFN antiviral activity and TNF secretion than in U937 cells. Transcript levels for IFN-alpha 1 and IFN-alpha 2 were equivalently induced in virus-infected U937 and U9-IIIB cells, indicating that a generalized derepression of cytokine gene expression did not occur as a consequence of HIV-1 infection. When LPS was used as an inducer, a distinct pattern of cytokine gene expression was detected in U9-IIIB cells. TNF-alpha and IL-1 beta but not IFN-alpha or IFN-beta transcripts were induced by LPS. These results suggest that HIV-1 infection of promonocytic cells may prime or sensitize cells such that subsequent antigenic challenge leads to coordinate enhancement of cytokine gene expression.
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PMID:Coordinate enhancement of cytokine gene expression in human immunodeficiency virus type 1-infected promonocytic cells. 224 88

Interleukin-6 (IL-6), a multifunctional cytokine produced in monocytes, fibroblasts, and other cell types, is induced by a variety of stimuli, including bacteria, viruses, and other cytokines. When normal monocyte cultures were exposed to a monocytotropic strain of human immunodeficiency virus (HIV), HTLV-IIIBa-L, significant levels of IL-6 bioactivity were detected in the culture supernatants after 12 to 43 days of incubation, at a time when there was associated evidence of HIV production. Similarly, when normal monocyte cultures were cocultured with peripheral blood mononuclear cells from HIV-infected individuals, HIV replication in these cultures was associated with production of IL-6. In further studies, we determined that mean serum levels of IL-6 bioactivity were abnormally elevated in HIV-seropositive individuals with stage 1/2 infection (25.2 x/divided by 1.8 U/mL) and stage 3/4 infection (46.1 x/divided by 1.7 U/mL) when compared with normals (1.6 x/divided by 1.2 U/mL). In contrast mean serum IL-6 levels were not different from normal in stage 5/6 infection (2.7 x/divided by 1.6 U/mL). A selected group of 12 HIV-seropositive individuals (stages 1, 2, and 3) who harbored HIV capable of replicating in T cells but not in monocyte cultures had a mean serum IL-6 level of 5.3 U/mL (x/divided by 1.5), a value significantly lower (P less than .004) than that measured in control HIV-seropositive individuals infected with monocytropic HIV (39 x/divided by 1.9 U/mL). In addition, serum IL-6 levels in HIV-seropositive individuals (stages 1 through 6) correlated directly with serum immunoglobulin G (IgG) levels (R = .74, P less than .001). Monocytes but not T cells are capable of a high level IL-6 production in vitro, and monocyte-derived IL-6 stimulates Ig production in activated B cells. Thus, HIV-seropositive individuals who often are infected with monocytotropic HIV and often display abnormally elevated serum IgG levels may exhibit these abnormalities as a consequence of abnormally elevated IL-6 levels induced by HIV.
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PMID:Induction of interleukin-6 during human immunodeficiency virus infection. 225 4

Relationships between nutrition and infection are generally complex, bidirectional, and not perfectly worked out. Healthy people can adapt to simple decreases in intake or increases in expenditure. However, the imposition of infection with associated cytokines may impair such adaptations, resulting in wasting of lean tissue. In human immunodeficiency virus (HIV) infection, nutritional abnormalities are common. Lean body mass depletion is associated temporally with death in a subset of acquired immune deficiency syndrome (AIDS) patients. Weakness, fatigue, and anorexia are important symptomatic complaints affecting quality of life. Pathophysiologic mechanisms remain speculative, although there is reason to suspect four theoretic factors: decreased intake, malabsorption, hypermetabolism, and altered metabolism. More than one disturbance may be necessary for clinical wasting to develop; ie, a primary abnormality plus a failure of homeostatic adaptation. Excess cytokine production also may be involved, but this is uncertain. Therapeutics remain empiric in the absence of known mechanisms. Current options are restricted to diet adjustments or supplements, treatment of underlying diseases (where possible), and rarely, parenteral alimentation. Promising investigational possibilities include an appetite stimulant (megestrol acetate) and therapies to oppose cytokine production or actions, but definitive beneficial effects on nutritional status, subjective performance, disease activity, or survival have not yet been demonstrated. Advances in clinical therapeutics await an improved understanding of pathophysiologic mechanisms and carefully designed clinical trials testing proposed interventions.
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PMID:Current approach to the treatment of human immunodeficiency virus-associated weight loss: pathophysiologic considerations and emerging management strategies. 225 24

The activation of nuclear factor kappa B (NF-kappa B) has been implicated in the regulation of transcription of a variety of genes and has been shown to be essential for the expression of genes controlled by the long terminal repeat of human immunodeficiency virus (HIV LTR). We show here that intracellular thiol levels play a key role in regulating this process. That is, stimulation with tumor necrosis factor alpha and/or phorbol 12-myristate 13-acetate activates NF-kappa B and markedly decreases intracellular thiols; N-acetyl-L-cysteine, an efficient thiol source, prevents this thiol decrease and blocks the activation of NF-kappa B; and the lack of activated NF-kappa B prevents the activation of the HIV LTR and the transcription of genes under its control. These findings reveal a previously unrecognized genetic regulatory mechanism in which cytokine-induced shifts in intracellular thiol levels are crucial in the control of NF-kappa B activity and thereby influence the spectrum of genes expressed by cytokine-stimulated cells.
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PMID:Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. 226 44


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