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)

Human immunodeficiency virus (HIV) infection of brain macrophages and astroglial proliferation are central features of HIV-induced central nervous system (CNS) disorders. These observations suggest that glial cellular interactions participate in disease. In an experimental system to examine this process, we found that cocultures of HIV-infected monocytes and astroglia release high levels of cytokines and arachidonate metabolites leading to neuronotoxicity. HIV-1ADA-infected monocytes cocultured with human glia (astrocytoma, neuroglia, and primary human astrocytes) synthesized tumor necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta) as assayed by coupled reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and biological activity. The cytokine induction was selective, cell specific, and associated with induction of arachidonic acid metabolites. TNF-beta, IL-1 alpha, IL-6, interferon alpha (IFN-alpha), and IFN-gamma were not produced. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factor were detected in large amounts after high-performance liquid chromatography separation and correlated with cytokine activity. Specific inhibitors of the arachidonic cascade markedly diminished the cytokine response suggesting regulatory relationships between these factors. Cocultures of HIV-infected monocytes and neuroblastoma or endothelial cells, or HIV-infected monocyte fluids, sucrose gradient-concentrated viral particles, and paraformaldehyde-fixed or freeze-thawed HIV-infected monocytes placed onto astroglia failed to induce cytokines and neuronotoxins. This demonstrated that viable monocyte-astroglia interactions were required for the cell reactions. The addition of actinomycin D or cycloheximide to the HIV-infected monocytes before coculture reduced, > 2.5-fold, the levels of TNF-alpha. These results, taken together, suggest that the neuronotoxicity associated with HIV central nervous system disorders is mediated, in part, through cytokines and arachidonic acid metabolites, produced during cell-to-cell interactions between HIV-infected brain macrophages and astrocytes.
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PMID:Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease. 146 Apr 27

The capacity of human monocytes/macrophages (M/M) infected with a human immunodeficiency virus-1 (HIV-1) isolate to produce several immunomodulating cytokines including interleukin-1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), IL-6, IL-8, and macrophage chemoattractant and activating factor (MCAF) was examined. Although HIV infection itself induced significant increases in the level of mRNAs for IL-1 beta, TNF-alpha, IL-6, and IL-8, the levels of lipopolysaccharide (LPS)-induced mRNAs for IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, IL-8, and MCAF were decreased over those of uninfected LPS-stimulated cells. In addition, HIV-infected M/M produced lower amounts of IL-8 protein, as measured by radioimmunoassay over an 18-day culture period. These results suggest that HIV infection generally suppresses the LPS-inducible cytokine production in human M/M. The impact of the role of these cytokines in the immunity and pathogenesis of HIV-1 infection is discussed.
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PMID:Decrease in cytokine production by HIV-infected macrophages in response to LPS-mediated activation. 172 30

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

Human hepatocellular carcinoma (HCC) cell lines, HEP-G2, J5, and SK-HEP-1, which differ in their differentiation status, were compared for their trans-activating activities after treatment with cytokines or 12-O-tetradecanoylphorbol-13-acetate (TPA). These cells were transfected with a long terminal repeat (LTR) which was derived from human immunodeficiency virus type 1 (HIV-1) and ligated to chloramphenicol acetyl transferase (CAT) gene. After treatment with interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), interferon-gamma (IFN-gamma), or TPA, they exhibited various degrees of enhancement of transactivation. The well differentiated HEP-G2 cells exhibited the highest degree of enhancement with these agents, while the poorly differentiated SK-HEP-1 cells showed no enhancement with cytokines and slight enhancement with TPA. The J5 cells, which were intermediate in their status of differentiation, showed a moderate degree of enhancement with cytokines and TPA. These results suggest that HCC cells at different stages of differentiation may produce different levels of cellular transacting factors activated by each of these agents. To map the cytokine response elements (CREs) in the HIV-1-LTR, HEP-G2 cells were transfected with nested series of 5' deletion mutants of HIV-1-LTR and treated with each of these cytokines. It was found that not only the degrees but also the patterns of enhancement varied depending upon the presence of positive or negative regulatory sequences in HIV-1-LTR, and that the NF-kappa B sequence played an important role, either by itself or in conjunction with the 5'-proximal response elements (REs) to interact with cellular trans-activating factors elicited by the cascade of transduction responses to cytokines. Despite the presence of promoters including kappa B and IFN-gamma RE as well as IL-6RE sequence in HIV-1-LTR-transfected cells, the poorly differentiated SK-HEP-1 cells showed no enhancement of transactivation by these cytokines, suggesting the lack of receptors or activity of some signal transduction factors which are present in well differentiated HEP-G2 and moderately differentiated J5 cells.
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PMID:Cytokine regulation of HIV-1 LTR transactivation in human hepatocellular carcinoma cell lines. 762 43

Interleukin (IL)-1 is constitutively produced by monocytes of human immunodeficiency virus (HIV)-seropositive persons. The changes in the production of IL-1 by monocytes of 24 HIV-infected patients were investigated during the course of 8 months of antiretroviral therapy. At month 8, the amounts of biologically active IL-1 and IL-1 alpha and -beta proteins produced by freshly obtained monocytes and by monocytes cultured for 24 h in the absence of lipopolysaccharide (LPS) decreased significantly compared with pretreatment values or decreased below the limits of detection in the assays. Antiretroviral therapy also resulted in enhanced secretion of IL-1 receptor antagonist (IL-1Ra) by LPS-stimulated patients' monocytes. The reduction in the constitutive production of IL-1 and the increased ability of stimulated cells to produce IL-1Ra associated with antiretroviral therapy may also be of importance in reducing a major pathway of amplification of viral replication in infected monocytes and lymphocytes.
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PMID:Antiretroviral therapy suppresses the constitutive production of interleukin-1 associated with human immunodeficiency virus infection. 762 2

Serum immunoreactive interleukin (IL-)1 alpha, IL-4, IL-6 and tumor necrosis factor (TNF) alpha were measured in 42 patients with primary hypogammaglobulinemia (25 common variable immunodeficiency (CVI), 10 congenital hypogammaglobulinemia (CH), 7 X-linked agammaglobulinemia (XLA), and in 21 healthy controls. The cytokine levels were correlated to other immunological parameters including serum levels of neopterin and soluble CD8 (sCD8) antigen. IL-6 was detectable in 48% and IL-4 in 36% of the CVI patients, but in none of the controls. Seventy-five percent of the CVI patients with elevated IL-4 levels had detectable IL-6. In contrast, no patients in the XLA group and only three CH patients had detectable IL-4 or IL-6 levels. TNF alpha and IL-1 alpha were detected in only a few serum samples with no significant differences between patients and controls. In the CVI group elevated IL-6 levels were significantly associated to reduced numbers of CD4+ and CD19+ lymphocytes, elevated levels of neopterin and sCD8 antigen, and occurrence of splenomegaly and bronchiectasis. The raised IL-6 levels were confirmed in longitudinal testing, probably reflecting a characteristic immunological dysregulation in these patients. Cytokine alterations may play a role in the pathogenesis of the immunodeficiency and for the clinical manifestations in CVI patients. Alternatively, elevated cytokine levels may be only a marker of chronic immune activation, particularly in monocytes, possibly delineating a distinct subgroup of patients within the heterogeneous CVI group.
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PMID:Elevated serum levels of interleukin-4 and interleukin-6 in patients with common variable immunodeficiency (CVI) are associated with chronic immune activation and low numbers of CD4+ lymphocytes. 790 14

One of the difficulties in understanding the complex pathology of human immunodeficiency virus (HIV) infection is to explain the progressive depletion of the CD4 helper T cell population and consequently the destruction of the immune system. Although cytopathic effects of HIV are observed in vitro, they cannot in vivo account for CD4 T cell depletion because relatively few cells are productively infected. Thus immunological mechanisms must be envisaged. We have found that peripheral blood lymphocytes (PBLs) from asymptomatic HIV-infected individuals are primed for a suicide process known as apoptosis or programmed cell death (PCD). DNA fragmentation characteristic of apoptosis was enhanced by stimulation of lymphocytes with ionomycin, a known inducer of apoptosis in suitably primed cells. Identification of the T cell subpopulations programmed for apoptosis indicated that both CD4+ and CD8+ cells died when cultured without stimulation or when polyclonally stimulated with ionomycin. Activation-induced cell death was also observed after stimulation with self-MHC class II-dependent superantigens, namely bacterial toxins from Staphylococcus (SEB), Streptococcus (ETA), and Myocoplasma (MAM) and under these conditions the CD4+ T cells were preferentially affected. To explore whether new macromolecular synthesis were required for apoptosis, various known inhibitors of apoptosis such as cycloheximide, cyclosporin A, Zn2+, or EGTA were tested. Activation-induced apoptosis was found sensitive to these inhibitors, indicating an active mechanism, but apoptosis observed in nonstimulated cultures was not, suggesting that these cells already contained the complete machinery for death. Prevention of apoptosis could be obtained in the presence of a mixture of cytokines and the minimal signal necessary for this prevention was IL-1 alpha and IL-2. Finally, a correlation between PCD and AIDS-pathogenesis was suggested by the comparison of lymphocytes from lentivirus-infected primates suceptible (SIV-infected macaques) and resistant (HIV-infected chimpanzees) to AIDS. Altogether our results suggest that, during HIV or SIV infection, PCD may contribute in vivo to the deletion of reactive T cells after antigenic stimulation.
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PMID:Programmed cell death in AIDS-related HIV and SIV infections. 810 39

The mechanisms by which human immunodeficiency virus (HIV) infection provokes progressive neurodegeneration and dementia in acquired immunodeficiency syndrome (AIDS) remain obscure. In HIV-infected (HIV+) individuals, we found that the brain cells preferentially infected by HIV, viz. the microglia, were abundant, activated, and intensely immunopositive for interleukin-1 alpha (IL-1 alpha), an immune response-generated cytokine that increases the synthesis and processing of beta-amyloid precursor proteins (beta-APP) and promotes proliferation and activation of astroglia. We also found an increase in the number of activated astroglia expressing elevated levels of S100 beta, a cytokine that increases intraneuronal calcium levels and promotes excessive growth of neuronal processes (neurites). These glial changes were accompanied by increased expression of beta-APP immunoreaction product in neurons and overgrown (dystrophic) neurites. In addition, some neurons contained monoclonal antibody Tau-2 immunopositive, neurofibrillary tangle-like structures. Our findings provide evidence that glial activation with increased expression of IL-1 alpha and S100 beta may be important in the neuropathogenesis of AIDS dementia. We propose that HIV infection promotes excessive microglial IL-1 alpha expression with consequent astrogliosis and increased expression of S100 beta. Overexpression of these two cytokines may then be involved in AIDS neuropathogenesis by inducing gliosis, growth of dystrophic neurites, and calcium-mediated neuronal cell loss in AIDS.
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PMID:Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimer's disease. 817 6

The majority of human immunodeficiency virus (HIV)-seropositive patients develop bone marrow abnormalities associated with hematopoietic malfunction during the progression of disease. One important manifestation of HIV-associated hematopoietic dysfunction is that after myelosuppression, bone marrow recovery, a process known to be mediated in part by the production of stromal cell-derived hematopoietic growth factors, is impaired. We sought to test the hypothesis that bone marrow stromal cells are infected by HIV-1 in vivo and that production of certain stromal cell-derived hematopoietic growth factors is deficient as a consequence. In this report, we demonstrate that bone marrow microvascular endothelial cells (MVEC), a key element of the stroma, are the predominant cells infected by HIV (5% to 20%) in bone marrow stromal cultures obtained from 11 consecutive HIV-seropositive patients. Although HIV-infected stromal cultures enriched for MVEC constitutively express normal levels of interleukin (IL)-4, IL-6, granulocyte (G)-colony-stimulating factor (CSF), granulocyte-macrophage (GM)-CSF, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and Steel factor, IL-1 alpha-induced release of IL-6 and G-CSF is significantly reduced in these cultures. These observations suggest that HIV infection of bone marrow MVEC reduces the capacity of hematopoietic stroma to respond to regulatory signals that normally augment blood cell production during periods of increased demand.
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PMID:Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors. 878 52

Infection with the human immunodeficiency virus HIV-1 is associated with the expansion of a CD14lowCD16high monocyte subset in peripheral blood. This subset, which represents a minor subpopulation of monocytes in healthy individuals, increases during HIV infection and, in patients with AIDS, may represent up to 40% of the total circulating monocyte cell population. The CD14lowCD16high circulating monocytes co-express MAX.1, p150,95 and HLA-DR which are typical of tissue macrophage markers. These cells also express higher levels of intracellular interleukin (IL)-1 alpha and tumor necrosis factor (TNF)-alpha than the CD14highCD16low monocyte population from the same patients. The CD14lowCD16high cells also express low levels of CD35, CD11a and CD4 in common with normal monocytes. When cultured in vitro, monocytes from HIV-seropositive individuals differentiated within a few hours into an elongated fibroblastoid shape characteristic of migratory cells. Our results suggest that the expansion of the CD14lowCD16high monocyte subset, which produce high amount sof TNF-alpha and IL-1 alpha, may participate in the immune dysfunction observed during HIV infection.
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PMID:CD14lowCD16high: a cytokine-producing monocyte subset which expands during human immunodeficiency virus infection. 856 32


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