Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of the human immunodeficiency virus (HIV-1) Nef protein in T cell activation pathways was investigated using a Jurkat CD4+ cell line stably transfected with a Nef expression vector. Secretion of IL-2 and TNF-alpha, surface expression of IL-2R, and DNA-binding activity of NF-kappa B and AP-1 (Fos/Jun) complex in response to phorbol myristate acetate, TNF-alpha, or immobilized antibodies to CD3 were monitored. These parameters were not modified by Nef expression in Jurkat cells, whereas stimulation with the same stimuli resulted in partial inhibition of LTR activation in Nef+ Jurkat cells. This inhibition was not mediated through Nef phosphorylation on Thr-15 or GTP-binding activity because mutations in critical sites did not alter this inhibition. Analysis of truncated LTRs confirmed that inhibition of LTR activation was not mediated through NF-kappa B-binding activity but through the region containing the negative responding elements (NREs). These results suggest that Nef downmodulates LTR activation without significantly inhibiting the capacity of T cells to respond to immunological activations.
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PMID:Role of HIV-1 Nef expression in activation pathways in CD4+ T cells. 791 14

Human immunodeficiency virus infection leads to a deregulated production of a number of cytokines. Some of them (IL-1, IL-6, TNF-alpha, interferon-gamma) are produced in increased amounts in vivo, whereas the production of IL-2 is decreased. This latter abnormality plays a pivotal role in the establishment of the immunodeficiency. Some cytokines (IL-1, IL-6, TNF-alpha) stimulate the in vitro replication of HIV, whereas others (mainly the interferons) inhibit it. The effect of cytokines in vivo in the spreading of HIV remains, however, largely unknown. Cytokines may also be involved in the development of many clinical manifestations associated with HIV infection. IL-1, IL-6 and TNF-alpha may play a role in tissue damages associated with opportunistic infections, in HIV-related encephalopathy and in cachexia. Cytokines, mainly IL-6, IL-10 and IL-13, may stimulate the growth of malignant cells during Kaposi sarcoma or lymphomas. Better knowledge of the role of cytokines during HIV infection should allow new therapeutic approaches based on the use of either recombinant cytokines or specific antagonists, with the aim of limiting both HIV spreading and the clinical manifestations of this infection.
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PMID:Cytokines in HIV infection. 792 84

Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. 799 15

U1 cells, a subclone of U937 cells chronically infected with human immunodeficiency virus type 1 (HIV-1), produced HIV-1 only in the presence of inducers such as 12-O-tetradecanoxylphorbol 13-acetate (TPA) or tumor necrosis factor (TNF)-alpha. The expression of HIV-antigen on U1 cells induced by TPA or TNF-alpha was found to be prevented by sodium 5,6-benzylidene-L-ascorbate (SBA) in a concentration-dependent manner. Treatment of U1 cells with SBA in the presence of inducers resulted in cell death with cell shrinkage, chromatin condensation and DNA fragmentation into nucleosomal oligomers, characteristics of apoptosis. In contrast, SBA had scarcely any apoptotic effect on U1 cells in the absence of inducers. SBA did not also induce apoptosis in parental U937 cells in the presence or absence of inducers. These results suggest that HIV-replicating U1 cells selectively undergo apoptosis on treatment with SBA.
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PMID:Sodium benzylideneascorbate induces apoptosis in HIV-replicating U1 cells. 807 75

Soluble tumor necrosis factor (TNF) receptors were recently detected in the circulation of patients with early HIV-induced disease, at significantly higher levels than in control subjects. They were proposed as markers of disease progression and of the degree of immunodeficiency. We report that adsorption of heat-inactivated HIV-1 LAI to isolated human monocytes triggers the release of both TNF-alpha and its natural specific inhibitor, the soluble TNF receptor (sTNF-R)75, but not that of sTNF-R55. Only limited inhibition of sTNF-R release was obtained in the presence of a fully neutralizing anti-TNF-alpha monoclonal antibody, suggesting that stimulation by TNF-alpha was only partially responsible for sTNF-R release. HIV-1 LAI induced a higher sTNF-R/TNF ratio than lipopolysaccharide, a well-known monocyte activator. Monocytes thus represent a cellular source of sTNF-R that can be detected in the circulation of HIV-infected patients from seroconversion onwards. The release of sTNF-R could be of great significance in the control of HIV infection via the cytokine network and especially TNF-alpha.
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PMID:Induction of soluble tumor necrosis factor receptor (sTNF-R75) release by HIV adsorption on cultured human monocytes. 808 26

Human CD4+ T cell clones infected in vitro with the human immunodeficiency virus (HIV), unlike their noninfected counterparts, induced both proliferation and immunoglobulin (Ig) production by both autologous and allogeneic B cells through an antigen (Ag)-nonspecific, MHC-unrestricted, contact-dependent mechanism. This was done apparently without expressing the CD40 ligand. Interestingly, HIV-infected T cell clones, unlike their noninfected counterparts, constitutively expressed mRNA for, and released in the supernatants measurable amounts of, TNF-alpha and a proportion of T blasts from the HIV-infected unstimulated T cell clones showed membrane TNF-alpha expression. Furthermore, both B cell proliferation and Ig production induced by HIV-infected unstimulated T cell clones, but not those evoked by their noninfected anti-CD3-stimulated counterparts, were strongly and consistently inhibited by either anti-TNF-alpha or anti-TNF-alpha receptor antibodies. Finally, when T blasts from HIV-infected unstimulated T cell clones were fractionated by cell sorting into membrane TNF-alpha-negative and membrane TNF-alpha-positive cells, only the latter retained the capacity to polyclonally activate B cells. Human CD4+ T cell clones infected in vitro with herpesvirus saimiri (HVS) also showed constitutive membrane TNF-alpha expression, as well as the ability to induce Ag-nonspecific, MHC-unrestricted, contact-dependent, polyclonal B cell activation. These data suggest that human CD4+ T cell clones, when infected by certain viruses, can provide abnormal B cell help that appears to be related to the expression of membrane TNF-alpha by virus-infected T cells.
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PMID:Abnormal B cell helper activity by virus-infected human CD4+ T cells. 812 98

The participation of cell ceramide in tumor necrosis factor (TNF)-alpha-stimulated NF-kappa B activation in Jurkat T cells and HL-60 cells was studied. TNF-alpha readily stimulated NF-kappa B activity in both cell lines as assayed by electrophoretic mobility shift assay and the use of a human immunodeficiency virus-chloramphenicol acetyltransferase reporter construct. However, TNF-alpha stimulation did not increase cell ceramide levels in either cell line. The exogenous addition of a short chain ceramide, N-acetylsphingosine, to Jurkat cells had no effect on NF-kappa B activity. When Jurkat T cells were exposed to the glucosylceramide synthase inhibitor, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, endogenous ceramide levels increased 4-fold. The increase in ceramide, however, did not result in NF-kappa B activation nor did it potentiate TNF-alpha or phorbol ester-stimulated activity. We conclude that TNF-alpha-induced NF-kappa B activation occurs in Jurkat and HL-60 cell lines that do not demonstrate an increase in TNF-alpha-induced ceramide. Increasing ceramide levels by the addition of short chain ceramides or the use of a glucosylceramide synthase inhibitor can be dissociated from activation of NF-kappa B by TNF-alpha.
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PMID:Dissociation of endogenous cellular ceramide from NF-kappa B activation. 813 72

Opiates alter a variety of functional activities of the somatic immune system; within the central nervous system, however, their effects on immune responses are unknown. In the present study, we investigated the effect of morphine on the release of tumor necrosis factor (TNF)-alpha from murine neonatal microglia. Microglial cell cultures did not release TNF-alpha when incubated with morphine alone; however, an enhanced (P < .01) release of TNF-alpha was observed when cultures were first primed with morphine for 24 h and then stimulated with lipopolysaccharide. A bell-shaped dose-response curve was observed for the priming effect of morphine; maximal enhancement of TNF-alpha release (310 +/- 15% of control) was detected at a concentration of 10(-10) M morphine. Pretreatment of microglia for 30 min with opioid receptor antagonists (i.e. naloxone and beta-funaltrexamine) completely blocked the priming effect of morphine. In addition, morphine treatment amplified (P < .01) the priming effect of lipopolysaccharide on phorbol myristate acetate-triggered superoxide anion production by microglial cell cultures, and this effect was abrogated (P < .01) by anti-TNF-alpha antibody. Furthermore, culture supernatants derived from microglial cell cultures that had been treated with morphine before stimulation with lipopolysaccharide had an increased capacity to upregulate human immunodeficiency virus-1 expression in the latently infected promonocytic clone U1. This effect was also blocked by anti-TNF-alpha antibody. These findings suggest that morphine primes microglia for enhanced production of TNF-alpha which could alter several functional activities of these cells within the brain.
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PMID:Priming effect of morphine on the production of tumor necrosis factor-alpha by microglia: implications in respiratory burst activity and human immunodeficiency virus-1 expression. 816 25

SIVsmmPBJ 1.9 is an extremely virulent clone of the simian immunodeficiency virus SIVsmmPBj 14 that causes an acute lethal disease in pigtail macaques, with death occurring 6 to 8 days after infection. The disease is characterized by bloody mucoid diarrhea, lymphoid hyperplasia, and giant cell pneumonia. We have developed an in vitro model for the production of multinucleated giant cells (MGCs) in which peripheral blood monocytes rapidly fuse to form MGCs when cultured in lymphocyte-conditioned medium and antibody against class II MHC. We have tested the effect of SIVsmmPBj on monocytes in our MGC model system. Peripheral blood mononuclear cells (PBMCs) from normal healthy human subjects, when cultured in the presence of anti-class II MHC monoclonal antibody and SIVsmmPBj 1.9, but not either alone, resulted in the formation of MGCs within 4 days. Experiments using Transwell chambers indicated that such MGCs are formed by fusion of monocytes, not by virus-induced fusion of lymphocytes. SIVsmmPBj 1.9 is unique in inducing MGC formation in that other SIV and HIV isolates do not induce MGCs. Whereas SIVsmmPBj 1.9 grown in PBMCs was a potent inducer of MGCs in the presence of anti-class II MHC antibody, SIVsmmPBj 1.9 grown in CEMx174 failed to do so. Antibodies against IFN-gamma and TNF-alpha significantly inhibited SIVsmmPBj/anti-class II-induced formation of MGCs. These results indicate that cytokines released in response to SIVsmmPBj 1.9, in conjunction with antibodies to class II MHC, caused fusion of monocytes.
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PMID:Simian immunodeficiency virus SIVsmmPBj 1.9 induces multinucleated giant cell formation in human peripheral blood monocytes. 817 65

From the sera of patients with advanced cancer, a novel factor called SDF (serum-derived factor) was partially purified. SDF was shown to stimulate transcription from the long terminal repeat (LTR) of human immunodeficiency virus type 1 (HIV-1) by transient CAT assay. It did not stimulate gene expression of various control promoters including Rous sarcoma virus, human c-fos, c-myc, c-H-ras and chicken beta-actin genes. The SDF preparation did not contain any detectable TNF-alpha or TNF-beta, and differed in its physicochemical properties from TNFs. We concluded that SDF might be a novel factor associated with the clinical features of advanced cancer. It is speculated that SDF might have some role in disease progression of AIDS as well as in the development of the cachectic conditions in AIDS associated with malignancies.
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PMID:Identification in the sera from patients with advanced cancer of a factor which stimulates gene expression from human immunodeficiency virus type 1. 823 10


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