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)

To explore the mechanism by which morphine promotes the incidence of HIV infection, we evaluated the regulatory role of morphine on the interferon-gamma (IFN-gamma) promoter in activated T cells from wild type and mu-opioid receptor knockout mice. Our results show that morphine inhibited anti-CD3/CD28-stimulated IFN-gamma promoter activity in a dose-dependent manner. Chronic morphine treatment of T cells increased intracellular cAMP. To evaluate the role of cAMP in morphine's modulatory function, the effects of dibutyryl cyclic AMP and forskolin were investigated. Both dibutyryl cyclic AMP and forskolin treatment inhibited IFN-gamma promoter activity. Treatment with pertussis toxin, but not with a protein kinase A inhibitor, antagonized morphine's inhibitory effects. Morphine inhibited phosphorylation of ERK1/2 and p38 MAPK; in addition, morphine treatment in the presence of either ERK1/2 or p38 MAPK inhibitor (PD98059 or SB203580) resulted in an additive inhibition of IFN-gamma promoter activity. The transcription factor activator protein-1, NF-kappaB, and nuclear factor of activated T cells (NFAT) were negatively regulated by morphine. Overexpression of NF-kappaB p65 rescued the inhibitory effect of morphine on IFN-gamma promoter activity. However, only when NFATc1 was co-overexpressed with c-fos was the inhibitory effect of morphine on IFN-gamma promoter counteracted. The inhibitory effects of morphine were not observed in T cells obtained from mu-opioid receptor knockout mice, suggesting that morphine modulation of IFN-gamma promoter activity is mediated through the mu-opioid receptor. In summary, our data indicate that morphine modulation of IFN-gamma promoter activity is mediated through two distinct cAMP-dependent pathways, the NF-kappaB signaling pathway and the ERK1/2, p38 MAPK, AP-1/NFAT pathway.
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PMID:Morphine negatively regulates interferon-gamma promoter activity in activated murine T cells through two distinct cyclic AMP-dependent pathways. 1284 91

Current attempts at active immunization of patients to their adenocarcinomas have heretofore met with a curiously little success. The carrier antigens, viral vector proteins, and other co-administered antigens typically elicit strong cell-mediated or humoral responses while the relevant cancer antigen elicits undetectable or feeble responses and often minimal if any retardation of malignant tissue growth is seen. There are exceptions but clearly more effective cancer antigen immunization strategies are needed. Adenylate cyclase, AC, catalyses the conversion of ATP to cyclic adenosine monophosphate (cAMP). Increased cAMP down regulates tumor necrosis factor-alpha, TNF, and decreased cAMP reliably up-regulates synthesis and release of TNF. TNF enhances dendritic cell (DC) maturation processes started by other stimuli. TNF promotes antigen responding CD4+ and CD8+ lymphocytes' proliferation, and suppresses suppressor T cells during primary immunization. Tenofovir is an oral antiviral drug currently used in anti-HIV treatments. It is an acyclic nucleoside analogue of adenosine monophosphate that also happens to increase TNF. The mechanism has not been established but antagonism of cAMP's inhibition of TNF is the likely path. Prostaglandin E (PGE) is a stimulatory allosteric modifier of AC and thus suppresses TNF via the resultant increase of cAMP. Since cyclooxygenase, COX, is the rate-controlling enzyme in PGE production, COX inhibitors, otherwise known as non-steroidal anti-inflammatory drugs (NSAID), increase TNF synthesis and release by depriving AC of PGE. Indomethacin, diclofenac and ketorolac are COX inhibitors that have been on the market for many years that would be well suited for use to increase TNF levels. This paper reviews the data on TNF up-regulation by tenofovir and COX inhibitors and the consequent augmented antigen driven lymphocyte proliferation secondary to increased TNF and suggests exploration of tenofovir and COX inhibitors like indomethacin, diclofenac or ketorolac in augmentation of current cancer immunotherapy attempts. Profound COX inhibition can lead to a compensatory leukotriene increase and leukotrienes have been identified as growth and survival factors in various gastrointestinal cancers. Therefore, zileuton, an orally active 5-lipooxygenase inhibitor that prevents leukotriene synthesis, should be added whenever profound COX inhibition is undertaken in cancer immunotherapies.
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PMID:Tenofovir, COX inhibitors and zileuton during cancer immunotherapies: up-regulated TNF-alpha increases antigen driven lymphocyte proliferation. 1294 2

Previous NMR relaxation studies of the isolated RNase H domain of HIV-1 reverse transcriptase at low pH have revealed that it is substantially more dynamic and less ordered than the relatively stable and catalytically active E. coli RNase HI. Using more recently developed techniques, we have investigated the dynamic behavior of the RNase H domain of HIV-1 reverse transcriptase at a more physiological pH (6.8), under a variety of solution conditions: no Mg(2+), 80 mM Mg(2+), and 80 mM Mg(2+) plus AMP ligand. In addition, we have repeated the previous measurements on a sample containing 100 mM sodium acetate, pH 5.4. Under all conditions studied, the order parameters from NMR relaxation analysis are uniformly high (>0.8) for most of the domain with the exception of the C-terminal region. Subtle differences can be found among the conditions studied, although the statistical significance of the differences is marginal. Residues 71-114 show a slight increase in order parameter with the addition of 5'-AMP. Conformational exchange, measured with CPMG relaxation dispersion experiments in the presence of Mg and AMP, were detected for some NH sites, predominantly located in the N-terminal region of the protein near strands beta2 and beta3 and helix alpha(A) (residues 28-69). In contrast with earlier studies indicating pathologically extreme dynamic behavior that apparently correlated with inactivity of the isolated domain, the relaxation analysis under the conditions of the present study yielded parameters that are more similar to those of the active E. coli RNase HI. A comparison of the order parameters obtained from a model-free analysis of the relaxation data with the B-factors in the crystal structures of the RNase H domain, both for the isolated domain and for the full HIV-1 reverse transcriptase structure, suggests that the dynamic behavior is similar in all cases.
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PMID:Backbone dynamics of the RNase H domain of HIV-1 reverse transcriptase. 1526 Apr 76

HIV-1 reverse transcriptase can remove chain terminators from blocked DNA ends through a nucleotide-dependent mechanism. We show that the catalytic efficiency of the removal reaction can vary several hundred-fold in different sequence contexts and is most strongly affected by the nature of the base pair at the 3'-primer terminus and the six base pairs upstream of it. Similar effects of the upstream sequence were observed with primer-templates terminated with 2',3'-dideoxy-AMP, 2',3'-dideoxy-CMP, or 2',3'-dideoxy-GMP. However, the removal of 2',3'-dideoxy-TMP or 3'-azido-2',3'-dideoxy-TMP was much less influenced by upstream primer-template sequence, and the rate of excision of these thymidylate analogues was greater than or equal to that of the other chain-terminating residues in each sequence context tested. These results strongly indicate that the primer terminus and adjacent upstream base pairs interact with reverse transcriptase in a sequence-dependent manner that affects the removal reaction. We conclude that primer-template sequence context is a major factor to consider when evaluating the removal of different chain terminators by HIV-1 reverse transcriptase.
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PMID:Effects of primer-template sequence on ATP-dependent removal of chain-terminating nucleotide analogues by HIV-1 reverse transcriptase. 1530 46

Amdoxovir [(-)-beta-D-2,6-diaminopurine dioxolane, DAPD], the prodrug of dioxolane guanosine (DXG), is currently in Phase I/II clinical development for the treatment of HIV-1 infection. In this study, we examined the phosphorylation pathway of DXG using 15 purified enzymes from human (8), animal (6), and yeast (1) sources, including deoxyguanosine kinase (dGK), deoxycytidine kinase (dCK), high Km 5'-nucleotidase (5'-NT), guanylate (GMP) kinase, nucleoside monophosphate (NMP) kinase, adenylate (AMP) kinase, nucleoside diphosphate (NDP) kinase, 3-phosphoglycerate (3-PG) kinase, creatine kinase, and pyruvate kinase. In addition, the metabolism of 14C-labeled DXG was studied in CEM cells. DXG was not phosphorylated by human dCK, and was a poor substrate for human dGK with a high Km (7 mM). Human 5'-NT phosphorylated DXG with relatively high efficiency (4.2% of deoxyguanosine). DXG-MP was a substrate for porcine brain GMP kinase with a substrate specificity that was 1% of dGMP. DXG-DP was phosphorylated by all of the enzymes tested, including NDP kinase, 3-PG kinase, creatine kinase, and pyruvate kinase. The BB-isoform of human creatine kinase showed the highest relative substrate specificity (47% of dGDP) for DXG-DP. In CEM cells incubated with 5 microM DXG for 24 h, 0.015 pmole/10(6) cells (approximately 7.5 nM) of DXG-TP was detected as the primary metabolite. Our study demonstrated that 5'-nucleotidase, GMP kinase, creatine kinase, and NDP kinase could be responsible for the activation of DXG in vivo.
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PMID:Anabolism of amdoxovir: phosphorylation of dioxolane guanosine and its 5'-phosphates by mammalian phosphotransferases. 1545 Sep 53

Dianthin antiviral protein (DAP) is a naturally occurring antiviral protein from the leaves of carnation (Dianthus caryophyllus) capable of depurinating HIV-1 RNA and inhibiting HIV-1 replication in human peripheral blood mononuclear cells. Escherichia coli-derived recombinant DAP (rDAP, amino acids 1-254) was purified to homogeneity for structural and functional studies. In the following paper the X-ray crystal structure of rDAP as well as its complexes with cyclic AMP and adenyl-guanosine (ApG) as substrate analogs at 1.7 A resolution are reported. Molecular modeling studies of the interactions of DAP and the structurally similar pokeweed antiviral protein (PAP) with a single-stranded RNA heptamer predicted a more potent anti-HIV activity for rDAP due to its unique surface topology and more favorable charge distribution in its 20 A-long RNA binding active center cleft. In accordance with the predictions of the modeling studies, rDAP was more potent than rPAP in depurinating HIV-1 RNA. To the knowledge of the authors, this is the first structural and functional characterization of recombinant DAP.
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PMID:High resolution X-ray structure and potent anti-HIV activity of recombinant dianthin antiviral protein. 1555 10

A gene expression profile of the human brain cortex was performed in people with HIV-1-associated dementia (HAD) using Affymetrix HG-U133 chips. Messenger RNA transcripts in middle frontal gyrus from subjects with HAD or milder neurocognitive dysfunction were compared to HIV-negative people. The analysis focused on ionic conductance carriers that control membrane excitation. Overexpressed ionic channel genes in brain cortex of subjects with dementia included (1) a calcium-driven K+ channel that prolongs afterhyperpolarization (AHP) current, (2) a leak type of K+ channel that prolongs the AHP, (3) an adenosine receptor that modulates cationic current via G proteins, (4) a G protein-coupled serotonin receptor that modulates cyclic AMP-linked current transduction, (5) a G protein-coupled dopamine receptor, (6) a GABA receptor subunit that conducts chloride current. Underexpressed current generators in the demented subjects included (1) two voltage-gated K+ channels that influence refractory periods and the onset of AHP, (2) a Na+ channel subunit that modifies current inactivation and the onset of the AHP, (3) a neuronal type of voltage-sensitive Ca+ channel that controls postsynaptic membrane excitability, (4) a metabotropic glutamate receptor that regulates cationic gating via G protein coupling, (5) A specific Galpha protein that transduces metabotropic cationic current, (6) an NMDA receptor subunit, (7) a glycine receptor subunit that modulates chloride current. These gene expression shifts probably occurred in neurons because they were not present in gyral white matter. Acquired neuronal channelopathies were not associated with a generalized shift of neuronal or glial cell markers, which suggest that they were not an artifact produced by neurodegeneration and/or glial cell proliferation. Channelopathies were not correlated with a generalized increase of inflammatory cell transcripts and were present in demented people without, and with HIV encephalitis (HIVE). We surveyed experimentally induced perturbations of these channels to determine the implications for brain function. Eleven experimental channelopathies produced decreased neuronal firing frequencies and pacemaker rates in model neurons; seven channelopathies increase neuronal firing rates experimentally. The implied disruption of neuronal excitability is consistent with some features of HAD, including its potential reversibility after HIV-1 replication is suppressed, the abnormal electroencephalographic recordings, the lack of clear-cut correlation with neurodegeneration and the lack of strict correlation with brain inflammation. The channelopathy concept may have wide relevance to the subcortical dementias.
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PMID:Acquired neuronal channelopathies in HIV-associated dementia. 1557 87

Primary isolates of human immunodeficiency virus type 1 (HIV-1) predominantly use chemokine receptor CCR5 to enter target cells. The natural ligands of CCR5, the beta-chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES, interfere with HIV-1 binding to CCR5 receptors and decrease the amount of virions entering cells. Although the inhibition of HIV-1 entry by beta-chemokines is well documented, their effects on postentry steps of the viral life cycle and on host cell components that control the outcome of infection after viral entry are not well defined. Here, we show that all three beta-chemokines, and MIP-1alpha in particular, inhibit postentry steps of the HIV-1 life cycle in primary lymphocytes, presumably via suppression of intracellular levels of cyclic AMP (cAMP). Productive HIV-1 infection of primary lymphocytes requires cellular activation. Cell activation increases intracellular cAMP, which is required for efficient synthesis of proviral DNA during early steps of viral infection. Binding of MIP-1alpha to cognate receptors decreases activation-induced intracellular cAMP levels through the activation of inhibitory G proteins. Furthermore, inhibition of one of the downstream targets of cAMP, cAMP-dependent PKA, significantly inhibits synthesis of HIV-1-specific DNA without affecting virus entry. These data reveal that beta-chemokine-mediated inhibition of virus replication in primary lymphocytes combines inhibitory effects at the entry and postentry levels and imply the involvement of beta-chemokine-induced signaling in postentry inhibition of HIV-1 infection.
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PMID:Macrophage inflammatory protein 1alpha inhibits postentry steps of human immunodeficiency virus type 1 infection via suppression of intracellular cyclic AMP. 1582 77

The CD94/NKG2A heterodimer is a natural killer receptor (NKR), which inhibits cell-mediated cytotoxicity upon interaction with MHC class I gene products. It is expressed by NK cells and by a small fraction of activated T cells, predominantly of CD8+ phenotype. Abnormal upregulation of the CD94/NKG2A inhibitory NKR on cytotoxic T cells (CTLs) could be responsible for a failure of immunosurveillance in cancer or HIV infection. In an attempt to identify the mechanisms leading to inhibitory NKR upregulation on T cells, we analyzed the expression of the CD94/NKG2A heterodimer on human CTLs activated with anti-CD3 mAb in the presence of PGE2 or with 8-CPT-cAMP, an analogue of cyclic AMP. As previously described, anti-CD3 mAb-mediated activation induced the expression of CD94/NKG2A on a small fraction of CD8+ T cells. Interestingly, when low concentrations of PGE2 or 8-CPT-cAMP were present during the culture, the proportion of CD8+ T cells expressing CD94/NKG2A was two- to five-fold higher. This upregulation was partially prevented by PKA inhibitors, such as KT5720 and Rp-8-Br-cAMP (type I selective). We also report that cAMP induces upregulation of NKG2A at the mRNA level. We further demonstrated that cross-linking of CD94 on CD8+ T cells expressing the CD94/NKG2A heterodimer inhibits their cytotoxic activity in a bispecific antibody redirected lysis assay. Our findings clearly demonstrate that the PGE2/cAMP/PKA type I axis is involved in the expression of CD94/NKG2A receptor on human CD8+ T lymphocytes.
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PMID:Prostaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type I pathway. 1597 47

Natural toxins are the product of a long-term evolution, and have captured crucial events in the most essential and vital processes of living organisms. They can attack components of the protein synthesis machinery (as in the case of Diphteria and Shiga toxins, and Ribosome inactivating proteins), actin polymerization (Clostridium botulinum type C, C2, toxins and Enterotoxin A), signal transduction pathways (Cholera toxin, Heat-labile enterotoxins, Pertussis and Adenylate cyclase toxins), intracellular trafficking of vesicules (for Tetanus and Botulinum neurotoxin type C) as well as immune and/or inflammatory responses (Pyrogenic exotoxins, Cholera and Pertussis toxins). Of interest is the fact that several bacterial and vegetal toxins can either kill selectively cells infected with the human immunodeficiency virus (HIV) or exert inhibitory effects on its life cycle. In particular both pertussis toxin (PTX) and its nontoxic B-oligomeric component (PTX-B) can block the infectious process in vitro at multiple levels, by preventing the entry of CCR5-dependent (R5) HIV strains and by inhibiting both R5 and CXCR4-dependent HIVs at post-entry level(s). In addition, some toxins possess immunostimulating properties that have been exploited in terms of adjuvancy and induction of specific cytotoxic T lymphocytes responses to different vaccine preparations, including some experimental vaccine against HIV infection. Thus, toxins may represent a relatively unexplored exhibition of powerful biological agents that could either prevent infection or attack HIV-infected cells.
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PMID:Bacterial toxins: potential weapons against HIV infection. 1610 45


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