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)

Hypericin is a naturally occurring photosensitizer that displays potent antiviral activity in the presence of light. The absence of light in many regions of the body may preclude the use of hypericin and other photosensitizers as therapeutic compounds for the treatment of viral infections in vivo. The chemiluminescent oxidation of luciferin by the luciferase from the North American firefly Photinus pyralis was found to generate sufficiently intense and long-lived emission to induce antiviral activity of hypericin. Light-induced virucidal activity of hypericin was demonstrated against equine infectious anemia virus, a lentivirus structurally, genetically, and antigenically related to the human immunodeficiency virus. The implications for exploiting chemiluminescence as a "molecular flashlight" for effecting photodynamic therapy against virus-infected cells and tumor cells are discussed.
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PMID:Chemiluminescent activation of the antiviral activity of hypericin: a molecular flashlight. 799 18

The binding of Rev to the Rev-response element (RRE) of the human immunodeficiency virus (HIV) is essential for RNA transport and expression of structural proteins such as gp160 encoded by env. To determine if env expression could be disrupted by complementary oligodeoxynucleotides (ODNs), band-shift studies were used to identify RRE sites that are essential for the formation of Rev-RRE complexes [Chin, D. J. (1992) J. Virol. 66, 600-607] or the stability of preformed complexes. In this report, we describe complete disruption of preformed Rev-RRE complexes by a subset of 15 ODNs complementary to stem-loop V. The most potent ODN complementary to bases CUGGGGCAUCAAGC disrupted 50% of preformed complexes at 1.2 microM, a 400-fold molar excess over the RNA. Expression of env in COS7 cells was blocked by nuclear microinjection of ODNs with C-5 propyne-modified pyrimidines and phosphorothioate linkages. Inhibition was highly dependent upon RNA target position, internucleotide chemistry, ODN sequence, and concentration. Unmodified phosphodiester or phosphorothioate ODNs were inactive. For the most potent ODN, 50% of the injected cells' env expression (I50) was blocked with 0.1 microM. A translational block is unlikely since these ODNs blocked expression of a luciferase vector in which the RRE was placed downstream of the termination codon. Consistent with their in vitro effects upon Rev-RRE complexes, stem-loop V ODNs were 9-fold more active than stem-loop II ODNs in blocking env expression while having a reduced (I50 = 0.27 microM) but equivalent potency against luciferase-RRE. These results suggest that disruption of Rev-RRE complexes may assist in blocking env expression.
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PMID:Inhibition of human immunodeficiency virus type-1 env expression by C-5 propyne oligonucleotides specific for Rev-response element stem-loop V. 803 74

The human immunodeficiency virus 1 (HIV-1) tat gene encodes a protein of critical importance for viral transcription. In addition, Tat has been shown capable of entering cells, stimulating cell proliferation, and altering host cell gene expression. We examined the effect of Tat on the expression of the transforming growth factor alpha (TGF-alpha) gene in MDA468 human breast carcinoma cells. We showed that these cells were capable of supporting the activation of the HIV-1 long terminal repeat by Tat. Then, in cotransfection assays, in which the TGF-alpha promoter was linked to a luciferase reporter gene and the tat gene was expressed under the control of the SV40 early promoter, we showed that tat gene expression increased TGF-alpha-luciferase reporter function but only in cells stimulated with epidermal growth factor (EGF). The effects of tat and EGF were dose dependent. To confirm these cotransfection data, Tat was expressed in Escherichia coli as a fusion protein with glutathione-S-transferase (GST) and purified on glutathione-agarose. GST-Tat was introduced into the MDA468 cells either in the presence of chloroquine or by scrape loading. The biological activity of GST-Tat was tested on cells that had been stablely transfected with the HIV-1 long terminal repeat linked to luciferase as a reporter. GST-Tat was then introduced into the cells, and the level of TGF-alpha mRNA was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human immunodeficiency virus 1 Tat stimulates transcription of the transforming growth factor alpha gene in an epidermal growth factor-dependent manner. 812 96

NF-kappa B is inducible transcription factor present in many cell types in a latent cytoplasmic form. So far, only immune cells including mature B cells, thymocytes, and adherent macrophages have been reported to contain constitutively active forms of NF-kappa B in the nucleus. A recent study showed that the human immunodeficiency virus type 1 (HIV-1) promoter is highly active in several brain regions of transgenic mice (J. R. Corboy, J. M. Buzy, M. C. Zink, and J. E. Clements, Science 258:1804-1807, 1992). Since the activity of this viral enhancer is governed mainly by two binding sites for NF-kappa B, we were prompted to investigate the state of NF-kappa B activity in neurons. Primary neuronal cultures derived from rat hippocampus and cerebral cortex showed a high constitutive expression of an HIV-1 long terminal repeat-driven luciferase reporter gene, which was primarily dependent on intact NF-kappa B binding sites and was abolished upon coexpression of the NF-kappa B-specific inhibitor I kappa B-alpha. Indirect immunofluorescence and confocal laser microscopy showed that the activity of NF-kappa B correlated with the presence of the NF-kappa B subunits p50 and RelA (p65) in nuclei of cultured neurons. NF-kappa B was also constitutively active in neurons in vivo. As investigated by electrophoretic mobility shift assays, constitutive NF-kappa B DNA-binding activity was highly enriched in fractions containing neuronal nuclei prepared from rat cerebral cortex. Nuclear NF-kappa B-specific immunostaining was also seen in cryosections from mouse cerebral cortex and hippocampus. Only a subset of neurons was stained. Activated NF-kappa B in the brain is likely to participate in normal brain function and to reflect a distinct state of neuronal activity or differentiation. Furthermore, it may explain the high level of activity of the HIV-1 enhancer in neurons, an observation potentially relevant for the etiology of the AIDS dementia complex caused by HIV infection of the central nervous system.
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PMID:Constitutive NF-kappa B activity in neurons. 819 37

The RAW264 murine macrophage cell line was used as a model to examine the role of the tat and nef gene products in the transcription regulation of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) in macrophages. Contrary to claims that the activity of the HIV-1 LTR responds poorly in rodent cells to trans activation by the viral tat gene product, cotransfection of RAW264 cells with a tat expression plasmid in transient transfection assays caused a > 20-fold increase in reporter gene expression that was inhibited by mutations in the TAR region. RAW264 cells stably transfected with the tat plasmid displayed similarly elevated HIV-1 LTR-driven reporter gene activity. By contrast to previous reports indicating a negative role for nef in HIV transcription, cotransfection of RAW264 cells with a nef expression plasmid trans activated the HIV-1 LTR driving either a chloramphenicol acetyltransferase or a luciferase reporter gene. The action of nef was specific to the LTR, as expression of nef had no effect on the activity of the simian virus 40, c-fms, urokinase plasminogen activator, or type 5 acid phosphatase promoter. trans-activating activity was also manifested by a frameshift mutant expressing only the first 35 amino acids of the protein. The effects of nef were multiplicative with those of tat gene product and occurred even in the presence of bacterial lipopolysaccharide, which itself activated LTR-directed transcription. Examination of the effects of selected mutations in the LTR revealed that neither the kappa B sites in the direct repeat enhancer nor the TAR region was required as a cis-acting element in nef action. The action of nef was not species restricted; it was able to trans activate in the human monocyte-like cell line Mono Mac 6. The presence of a nef expression cassette in a neomycin phosphotransferase gene expression plasmid greatly reduced the number of G418-resistant colonies generated in stable transfection of RAW264 cells, and many of the colonies that were formed exhibited very slow growth. The frameshift mutant was also active in reducing colony generation. Given the absence of any effect of the frameshift mutation on nef function, its actions on macrophage growth and HIV transcription are discussed in terms of the role of the N-terminal 30 amino acids and of stable secondary structures in the mRNA.
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PMID:Effects of the tat and nef gene products of human immunodeficiency virus type 1 (HIV-1) on transcription controlled by the HIV-1 long terminal repeat and on cell growth in macrophages. 823 Apr 18

Topical dinitrochlorobenzene (DNCB) is often used for evaluating contact skin hypersensitivity in immunocompromised patients. We have determined, in this study, that topical application of DNCB alone, even without induction of contact skin hypersensitivity, was sufficient to observe activation of the human immunodeficiency virus promoter (long terminal repeat) in the skin of an HIV-1 long terminal repeat-luciferase transgenic mouse model. Such treatment might be contra-indicative in patients infected with the human immunodeficiency virus, because in earlier studies DNCB-exposed skin dendritic cells might migrate into draining lymph nodes which play an important role in AIDS pathogenesis.
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PMID:Activation of the human immunodeficiency virus type 1 long terminal repeat by skin-sensitizing chemicals in transgenic mice. 829 83

Ribosomal frameshifting is an essential requirement for replication of many viruses and retrovirus-like elements. It is regarded as a potential target for antiretroviral therapy. It has been shown that the frameshifting event takes place in the -1 direction within a sequence, the slippery sequence, which is usually followed by structured RNA. To distinguish between the basic sequence requirements and the modulating elements in intact cells, we have established a sensitive assay system for quantitative determination of ribosomal frameshifting in mammalian cell culture. In this assay system, the gag and pol genes of human immunodeficiency virus type 1 are replaced by the genes for the functional enzymes beta-galactosidase and luciferase, respectively. The sensitivity of the test system allows us to demonstrate for the first time that the slippery sequence, a heptanucleotide, is sufficient to mediate a basal level of ribosomal frameshifting independent of its position within a gene. The stem-loop sequence serves only as a positive modulator. These data indicate that frameshifting could also occur during translation of cellular genes in which a slippery sequence is present within the reading frame. The resulting putative transframe proteins might have a functional importance for cellular processes.
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PMID:A heptanucleotide sequence mediates ribosomal frameshifting in mammalian cells. 835 Apr 13

We have tested whether breakdown of phosphatidylcholine (PC) initiated by exogenous addition of a PC-specific phospholipase C (PC-PLC) from Bacillus cereus or by endogenous overexpression of PC-PLC induces functional activation of NF-kappa B and increases human immunodeficiency virus (HIV) enhancer activity. PC-PLC-activated hydrolysis of PC was found to induce bona fide p50/p65 NF-kappa B binding activity in three different cell lines of human or murine origin. No significant changes in the turnover of other cellular phospholipids were detected in PC-PLC-treated cells. Induction of NF-kappa B by PC-PLC did not depend on de novo synthesis of proteins or autocrine secretion of either tumor necrosis factor or interleukin 1. In human monocytic and lymphoblastoid T-cell lines, induction of NF-kappa B by PC-PLC resulted in clear induction of luciferase expression vectors placed under the control of synthetic kappa B enhancers or wild type, but not kappa B-mutated, HIV long terminal repeat constructs. HIV replication was increased by PC-PLC in chronically infected monocytes and T lymphocytes. NF-kappa B activation promoted by addition of exogenous PC-PLC correlated with an intense production of diacylglycerol. However, addition of a phosphatidylinositol-specific PLC from B. cereus also induced diacylglycerol but did not activate kappa B enhancer-directed vectors. PC-PLC-induced NF-kappa B activation could not be blocked by a specific inhibitor of phorbol ester-inducible protein kinases C. These results indicate that a cellular transduction pathway, dependent on specific PC breakdown, is functional in T lymphocytes and monocytes and may be used by various transmembrane receptors to activate HIV transcription through NF-kappa B-dependent induction of the HIV enhancer.
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PMID:Phosphatidylcholine hydrolysis activates NF-kappa B and increases human immunodeficiency virus replication in human monocytes and T lymphocytes. 841 62

This study explores human immunodeficiency virus 1 (HIV-1)-regulated diphtheria toxin A (DT-A) gene expression as a means of eradicating HIV-infected cells. Previously, we constructed luciferase and DT-A plasmids, containing cis-acting Tat and Rev responsive elements, which showed low basal expression and required both Tat and Rev for maximal expression. Cell lines which had stably integrated the DT-A constructs were resistant to HIV production. To reduce toxicity due to basal expression, this study investigates the effect of mutations in the HIV enhancer on expression of luciferase and DT-A plasmids. Some mutations were found to substantially reduce basal expression while still allowing for trans-activation. Such mutations, in combination with attenuated versions of DT-A, may make regulated toxin gene expression feasible as a therapy for AIDS.
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PMID:Effects of enhancer mutations on the expression of human immunodeficiency virus 1-regulated luciferase and diphtheria toxin A chain genes in transfected cells. 844 66

A new bioluminescent detection system combined with a sandwich DNA hybridisation reaction in microwells has been developed for the detection of human immunodeficiency virus type 1 (HIV-1) provirus DNA amplified by the polymerase chain reaction (PCR). First, a fragment of the HIV-1 gag gene was amplified. The amplified DNA fragments were denatured and hybridised to a capture probe immobilised in microwells and to a biotinylated detection probe. A streptavidin-pyruvate kinase conjugate could then react on the biotinylated probe and the kinase activity detected by means of the luciferin-luciferase system, with production of a bioluminescent signal. This sandwich assay followed by a bioluminescent reaction detected as little as 7 amol of target DNA. The bioluminescent assay detected 5 HIV copies generated after one round of PCR, even if no band was seen on an agarose gel. The assay was applied to the detection of HIV-proviral DNA in peripheral blood mononuclear cells after one round of PCR and allowed to clearly identify a positive sample as compared to nested PCR.
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PMID:DNA probe hybridisation in microwells using a new bioluminescent system for the detection of PCR-amplified HIV-1 proviral DNA. 853 57


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