Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus type 1 (HIV-1)-infected mononuclear phagocytes (MP; brain macrophages and microglia) secrete a number of toxic factors that affect the pathogenesis of HIV-1-associated dementia (HAD). The identification and relative role of each MP toxin for neuronal dysfunction during HAD are not well understood. Interleukin-8 (IL-8), a CXC chemokine involved in leukocyte activation and chemotaxis, is constitutively produced by MP, and elevated levels of IL-8 mRNA were detected in the brains of patients with HIV-1 encephalitis (HIVE) by both ribonuclease protection assays and real-time PCR. To determine the role that IL-8 might play in the neuronal dysfunction in HAD, we studied its effect on synaptic transmission and plasticity in the CA1 region of hippocampus, the seat of learning and memory. Bath application of IL-8 (50 ng/ml) to rat hippocampal slices had no effect on basal synaptic transmission. However, IL-8 was shown to inhibit long-term potentiation (LTP) in a concentration-dependent manner. In control and IL-8-treated slices, the LTP magnitudes were 167.8% +/- 11.9% (mean +/- SE; n = 17) and 122.2% +/- 16.2% of basal levels (n = 13), respectively. These differences were statistically significant (P < 0.05). Preincubation of hippocampal slices with a monoclonal CXCR2 antibody (2 microg/ml) but not control IgG (2 microg/ml) blocked IL-8-induced inhibition of LTP. The expression of CXCR2 receptors in the CA1 region was shown by Western blot assays. The induction of IL-8 in HAD, its inhibition of LTP, and the expression of its receptor, CXCR2, in the hippocampus all suggest that it plays a role in the cognitive dysfunction associated with HAD.
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PMID:Inhibition of long-term potentiation by interleukin-8: implications for human immunodeficiency virus-1-associated dementia. 1254 17

The HIV-1 Rev protein plays a pivotal role in viral replication, and therefore, inhibition of its function should block the progression of the virus-induced immune deficiency syndrome (AIDS). Here, RNA molecules have been shown to inhibit import of the HIV-1 Rev protein into nuclei of permeabilized cells. Nuclear uptake of biotinylated recombinant His-tagged Rev-GFP was assessed in nuclear extracts from digitonin-permeabilized cells by binding to either importin beta-receptors or nickel molecules immobilized on a microtiter plate. Using this method together with fluorescence microscopy, we determined that nuclear import of Rev is inhibited by the addition of a reticulocyte lysate which routinely is used as a source of nuclear import receptors. This inhibition was released by treatment with the RNase enzyme. Also t-RNA molecules and the oligoribonucleotide RRE IIB, namely, the second stem structure of the Rev responsive element (RRE) of the viral RNA, inhibit Rev nuclear import. Similar results were obtained when BSA molecules with covalently attached Rev-arginine rich motif (ARM) peptides were used as a nuclear transport substrate, indicating that the nuclear import inhibition of the Rev protein is due to the presence of the ARM domain. Binding experiments revealed that the RNA molecules inhibit the interaction between the ARM region and importin beta, implying that the RNA prevents the formation of the import complex. The implication of our results for the regulation of the nuclear import of Rev as well as for the use of RNA molecules as antiviral drugs is discussed.
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PMID:Inhibition of nuclear import mediated by the Rev-arginine rich motif by RNA molecules. 1261 57

Astrocytes may be infected with the human immunodeficiency virus type 1 (HIV-1) or exposed to the HIV protein gp120, yet their role in the pathogenesis of HIV dementia is largely unknown. To characterize the effects of HIV on astrocytic transcription, microarray analysis and ribonuclease protection assays (RPA) were performed. Infection of astrocytes by HIV or treatment with gp120 had differential and profound effects on gene transcription. Of the 1153 oligonucleotides on the immune-based array, the expression of 108 genes (53 up; 55 down) and 82 genes (32 up; 50 down) were significantly modulated by gp120 and HIV infection respectively. Of the 1153 oligonucleotides on the neuro-based array, 58 genes (25 up; 33 down) and 47 genes (17 up; 30 down) were significantly modulated by gp120 and HIV infection respectively. Chemokine and cytokine induction occurred predominantly by HIV infection, whereas gp120 had no significant effect. These results were confirmed by RPA. The authors conclude that profound alterations of astrocytic function occur in response to HIV infection or interaction with viral proteins, suggesting that astrocytes may play an important role in the pathogenesis of HIV dementia.
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PMID:Differential transcriptional regulation by human immunodeficiency virus type 1 and gp120 in human astrocytes. 1277 19

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of HIV disease. Exposure of human macrophages to HHV-6A or HHV-6B profoundly impaired their ability to produce interleukin 12 (IL-12) upon stimulation with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor-alpha (TNF-alpha); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1 beta (MIP-1 beta) was not negatively affected. To exclude the involvement of IL-12-suppressive cytokines, such as IL-10 and TNF-alpha, the viral stocks were fractionated by ultra-centrifugation. The bulk of the suppressive activity was recovered within the virion-rich pelleted fraction that was virtually devoid of such cytokines. IL-12 suppression was independent of viral replication, and the effect was not abrogated upon ultraviolet-light inactivation of the viral inoculum. The mechanism of HHV-6-mediated IL-12 suppression was investigated by RNase protection assays, which demonstrated unaltered levels of IL-12 p35 mRNA and only a modest reduction in p40 mRNA, which was insufficient to account for the near-complete loss of both extracellular and intracellular IL-12 protein. Moreover, both the IFN-gamma and the LPS signaling pathways were intact in HHV-6-treated cells. These data suggest that HHV-6 can dramatically affect the generation of effective cellular immune responses, providing a novel potential mechanism of HHV-6-mediated immunosuppression.
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PMID:Selective suppression of IL-12 production by human herpesvirus 6. 1282

Deletion mutation of the RNA 5' leader sequence of simian immunodeficiency virus (SIV) was used to localize the virus packaging signal. Deletion of sequences upstream of the major splice donor (SD) site produced a phenotype most consistent with a packaging defect when analysed by both RNase protection assay and RT-PCR. Sequences downstream of the SD were deleted and produced varying effects but did not affect packaging: a large downstream deletion had little effect on function, whereas a nested deletion produced a profound replication defect characterized by reduced protein production. Secondary structure analysis provided a potential explanation for this. The major packaging signal of SIV appears to be upstream of the SD in a region similar to that of human immunodeficiency virus type 2 (HIV-2) but unlike that of HIV-1; however, the packaging signal of all three viruses are at a similar distance from their respective cap sites. This conserved positioning suggests that it is more important in the virus life cycle than the position of the signal relative to the SD.
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PMID:The packaging signal of simian immunodeficiency virus is upstream of the major splice donor at a distance from the RNA cap site similar to that of human immunodeficiency virus types 1 and 2. 1291 63

Principally expressed on the surface of T lymphocytes, the chemokine and HIV receptor CXCR4 has been shown to serve key roles in both chemotaxis and HIV-1-entry into T cells. Understanding the regulation of CXCR4 expression is therefore of paramount importance to further elucidating its endogenous role and contributions to HIV-1 pathogenesis. Using an RNase protection assay (RPA), we have demonstrated that mitogenic stimulation of purified human peripheral blood T lymphocytes (PBL) decreased CXCR4 mRNA relative to unstimulated controls in a calcineurin-dependent manner; an expression pattern mimicked by the chemokine receptor CCR7. A change in transcriptional activity, not in mRNA stability, was required for control of CXCR4 and CCR7 expression. Changes in CXCR4 mRNA expression translated into a stimulation- and calcineurin-dependent decrease in cell surface CXCR4 expression. We have previously demonstrated that CXCR4 mRNA and protein is regulated by cAMP; here we show that calcium and calcineurin signaling pathways modify cAMP-driven changes. Moreover, we provide data supporting a role for the transcription factor YY1 in calcineurin-dependent regulation of CXCR4 expression.
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PMID:Regulation of CXCR4 expression in human T lymphocytes by calcium and calcineurin. 1456 73

HIV-1 Tat has been proposed as a key agent in many AIDS-related disorders, including HIV-1-associated neurological diseases. We have recently shown that Tat expression induces a significant increase in T lymphocytes in the brains of Tat transgenic mice. The CNS infiltration of T lymphocytes has been noted in AIDS patients. In the present study using this unique genetic system we attempted to understand the underlying mechanisms of Tat expression-induced infiltration of T lymphocytes by examining chemokine expression. RNase protection assay revealed that in addition to CCL2 (monocyte chemoattractant protein-1), CCL3 (macrophage inflammatory protein-1alpha (MIP-1alpha)), CCL4 (MIP-1beta), CCL5 (RANTES), CXCL2 (MIP-2), and CXCL10 (inducing protein-10), XCL1 (lymphotactin/single C motif-1alpha/activation-induced, T cell-derived and chemokine-related cytokine) was identified to be up-regulated by Tat expression. XCL1 is a C chemokine and plays a specific and important role in tissue-specific recruitment of T lymphocytes. Thus, we further determined the relationship between Tat and XCL1 expression. Tat-induced XCL1 expression was further confirmed by XCL1-specific RT-PCR and ELISA. Combined in situ hybridization and immunohistochemical staining identified astrocytes, monocytes, and macrophages/microglia as XCL1-producing cells in vivo. Using human astrocytes, U87.MG cells, as an in vitro model, activation of XCL1 expression was positively correlated with Tat expression. Moreover, the XCL1 promoter-driven reporter gene assay showed that Tat-induced XCL1 expression occurred at the transcriptional level. Taken together, these results demonstrate that Tat directly trans-activated XCL1 expression and suggest potential roles of Tat-induced XCL1 expression in the CNS infiltration of T lymphocytes during HIV-1 infection and subsequent HIV-1-induced neurological diseases.
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PMID:Induction of C chemokine XCL1 (lymphotactin/single C motif-1 alpha/activation-induced, T cell-derived and chemokine-related cytokine) expression by HIV-1 Tat protein. 1473 74

We screened two independent RNA libraries consisting of molecules of 50 nucleotides of random sequence, one of which had additional viral psi-sequences to isolate RNA aptamers that bound to the mature form of the nucleocapsid (NC) protein of Human Immunodeficiency Virus Type-1 (HIV-1). Surface Plasmon Resonance measurements and gel shift assays showed that the RNA aptamers bound with high affinity and specificity. We employed RNase footprinting to characterize the RNA structures and to map their protein binding sites. Most of the selected RNA aptamers contained a plausible pseudoknot in addition to the characteristic stem-loop structure. Moreover, the pseudoknots were part of the NC binding sites. We propose that higher order structures such as pseudoknots may constitute binding motifs for nucleic acid binding proteins, especially for NC protein, which is a nucleic acid chaperone.
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PMID:RNA aptamers that bind the nucleocapsid protein contain pseudoknots. 1474 35

This report describes a procedure to generate enzymatically active, isolated HIV RNase H domain. In contrast to previously described preparations, the RNA cleavage activity of the untagged RNase H domain was surprisingly similar to that of the full-length HIV-RT protein. Signature cleavages at 18 and 9 nucleotides downstream of a recessed RNA 5'-end were retained with the isolated RNase H domain. Activity was strongly decreased by deletion of 3 amino acids from the C-terminus, consistent with an important structural or functional role of the C-terminal alpha-helix. A prototype N-hydroxyimide (2-hydroxy-4H-isoquinoline-1,3-dione) was found to inhibit the activity of the isolated HIV RNase H domain as well as the RNase H activity of full-length HIV reverse transcriptase. In contrast, the compound did not significantly inhibit the structurally closely related Escherichia coli RNase HI. Specific binding of N-hydroxyimide compounds to the isolated RNase H domain was observed by protein fluorescence quenching.
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PMID:Activity of the isolated HIV RNase H domain and specific inhibition by N-hydroxyimides. 1506 60

APOBEC3G, a member of an RNA/DNA cytidine deaminase superfamily, has been identified as a cellular inhibitor of HIV-1 infectivity, possibly through the dC to dU deamination of the first minus strand cDNA synthesized during reverse transcription. Virions incorporate APOBEC3G during viral assembly in non-permissive cells, and this incorporation is inhibited by the viral protein Vif. The mechanism of APOBEC3G incorporation into HIV-1 is examined in this report. In the absence of Vif, cytoplasmic APOBEC3G becomes membrane-bound in cells expressing HIV-1 Gag, and its incorporation into Gag viral-like particles (VLPs) is proportional to the amount of APOBEC3G expressed in the cell. The expression of Vif, or mutant Gag unable to bind to membrane, prevents the APOBEC3G association with membrane. HIV-1 Gag alone among viral proteins is sufficient for packaging of APOBEC3G into Gag VLPs, and this incorporation requires the presence of Gag nucleocapsid. The presence of amino acids 104-156 in APOBEC3G, located in the linker region between two zinc coordination motifs, is also required for its incorporation into Gag VLPs. Evidence against an RNA bridge facilitating the Gag/APOBEC3G interaction includes data indicating that 1) the incorporation of APOBEC3G occurs independently of viral genomic RNA, 2) a Gag/APOBEC3G complex is immunoprecipitated from cell lysate after RNase treatment, and 3) the zinc coordination motif, rather than the regions flanking this motif, have been implicated in RNA binding in another family member, APOBEC1.
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PMID:The interaction between HIV-1 Gag and APOBEC3G. 1515 5


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