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)

Cocaine abuse has been implicated as a cofactor in human immunodeficiency virus (HIV)-1-associated dementia (HAD). In this study, we tested the hypothesis that exposure of microglial cells, the resident macrophages of the brain, to cocaine would potentiate HIV-1 expression. Because kappa-opioid receptor (KOR) agonists have been shown to suppress neurochemical and neurobehavioral responses to cocaine and to inhibit HIV-1 expression in microglial cell cultures, we also postulated that KOR ligands would inhibit cocaine-induced potentiation of HIV-1 expression. Human microglial cells were infected with HIV-1(SF162), an R5 isolate, and viral expression was quantified by measurement of p24 antigen in culture supernatants. Treatment of microglia with the KOR agonists trans-(+/-)-3,4-dichlor-N-methyl-N-(2[1-pyrrolidnyl])benzeneacetamide methanesulfonate and 8-carboxamidocyclazocine inhibited viral expression (maximal suppression of 42 and 48%, respectively). Consistent with the hypotheses, treatment of microglia with cocaine promoted HIV-1 expression (maximal enhancement of 54%), and pretreatment of microglia with these KOR agonists as well as with the KOR-selective antagonist nor-binaltorphimine abrogated cocaine-induced potentiation of viral expression. Results of flow cytometry studies suggested that the mechanism whereby KOR ligands inhibit cocaine's stimulatory effect on viral expression involves the suppression of cocaine-induced activation of extracellular signal-regulated kinase1/2, thereby blunting cocaine-enhanced up-regulation of the HIV-1 entry chemokine coreceptor CCR5. The findings of this study suggest that in addition to its neurotoxic effects, cocaine could foster development of HAD by potentiating viral expression in the brain and that this phenomenon is inhibited by KOR ligands.
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PMID:Kappa-opioid receptor ligands inhibit cocaine-induced HIV-1 expression in microglial cells. 1475 49

Both the chemokine SDF-1alpha and the human immunodeficiency virus-1 (HIV-1) coat protein gp120 can bind to CXCR4 chemokine receptors but with different signaling consequences. To understand the molecular basis for these differences, we tagged the rat CXCR4 receptor with enhanced cyan (ECFP) and yellow (EYFP) derivatives of the green fluorescent protein and investigated CXCR4 receptor dimerization in human embryonic kidney (HEK)-tsA201 cells using fluorescence resonance energy transfer (FRET). Elevated FRET was detected under basal conditions from EYFP-CXCR4 and ECFP-CXCR4 receptor-transfected cells indicating a high level of CXCR4 receptor dimerization. In comparison, EYFP-CXCR4 and ECFP-mu-opioid receptor-cotransfected cells displayed a much lower FRET signal. The FRET signal resulting from EYFP-CXCR4- and ECFP-CXCR4-expressing cells could be attenuated by coexpressing nontagged CXCR4 receptors suggesting competition with fluorophore-tagged receptors in the membrane. Nontagged mu-opioid, kappa-opioid, and muscarinic receptors also decreased the FRET between the tagged CXCR4 receptor pairs but to a lesser extent. Application of the CXCR4 receptor agonist SDF-1alpha (50 nM) further increased the FRET signal from tagged CXCR4 receptors, an effect that was inhibited by the CXCR4 antagonist AMD3100. SDF-1alpha had no effect when EYFP-CXCR4 and ECFP-mu-opioid receptors were coexpressed. The effect of gp120IIIB on CXCR4 FRET was dependent on the coexpression of human CD4 (hCD4) when it increased the FRET signal, and this was decreased by AMD3100 pretreatment. FRET analysis of tagged hCD4 constructs demonstrated that there was significant association of hCD4 and CXCR4, as well as hCD4 dimerization. These data suggest that CXCR4 dimerization is involved in SDF-1alpha- and gp120-induced signaling events.
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PMID:Regulation of CXCR4 receptor dimerization by the chemokine SDF-1alpha and the HIV-1 coat protein gp120: a fluorescence resonance energy transfer (FRET) study. 1501 35

Recent evidence suggests that injection drug users who abuse heroin are at increased risk of CNS complications from human immunodeficiency virus (HIV) infection. Opiate drugs may intrinsically alter the pathogenesis of HIV by directly modulating immune function and by directly modifying the CNS response to HIV. Despite this, the mechanisms by which opiates increase the neuropathogenesis of HIV are uncertain. In the present study, we describe the effect of morphine and the HIV-1 protein toxin Tat(1-72) on astroglial function in cultures derived from ICR mice. Astroglia maintain the blood-brain barrier and influence inflammatory signaling in the CNS. Astrocytes can express mu-opioid receptors, and are likely targets for abused opiates, which preferentially activate mu-opioid receptors. While Tat alone disrupts astrocyte function, when combined with morphine, Tat causes synergistic increases in [Ca(2+)](i). Moreover, astrocyte cultures treated with morphine and Tat showed exaggerated increases in chemokine release, including monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES), as well as interleukin-6 (IL-6). Morphine-Tat interactions were prevented by the mu-opioid receptor antagonist beta-funaltrexamine, or by immunoneutralizing Tat(1-72) or substituting a nontoxic, deletion mutant (Tat(Delta31-61)). Our findings suggest that opiates may increase the vulnerability of the CNS to viral entry (via recruitment of monocytes/macrophages) and ensuing HIV encephalitis by synergistically increasing MCP-1 and RANTES release by astrocytes. The results further suggest that astrocytes are key intermediaries in opiate-HIV interactions and disruptions in astroglial function and inflammatory signaling may contribute to an accelerated neuropathogenesis in HIV-infected individuals who abuse opiates.
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PMID:Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. 1563 Jul 4

Opioid use may be associated with an increased risk of neurological disease in human immunodeficiency virus (HIV) infection through effects on immune cell function. Studies were performed to examine the effects of specific retinoid receptor activation on mu opioid receptor (MOR) production by phytohemagglutinin (PHA)-stimulated U937 cells, a mononuclear cell line. PHA stimulation increased activation of the MOR promoter as well as levels of MOR mRNA, total receptor protein in cell lysates, and surface and cytoplasmic receptor expression. Retinoid X receptor (RXR) agonist and retinoic acid receptor (RAR) antagonist further increased MOR expression by the PHA-stimulated cells. In contrast, MOR expression was suppressed by RAR agonist and by RXR antagonist. Finally, opioid receptor binding was also increased by RXR agonist and RXR antagonist; no increase in binding occurred in the presence of RAR agonists and RXR antagonist. All together, these studies suggest that MOR expression in U937 cells can be differentially regulated by specific retinoid receptor activation. Such effects may have important clinical relevance for opioid users with HIV infection, including individuals with neurological disease.
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PMID:Retinoid-induced mu opioid receptor expression by phytohemagglutinin-stimulated U937 cells. 1603 94

Opiates exacerbate human immunodeficiency virus type 1 (HIV-1) Tat(1-72)-induced release of key proinflammatory cytokines by astrocytes, which may accelerate HIV neuropathogenesis in opiate abusers. The release of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), in particular, is potentiated by opiate-HIV Tat interactions in vitro. Although MCP-1 draws monocytes/macrophages to sites of CNS infection, and activated monocytes/microglia release factors that can damage bystander neurons, the role of MCP-1 in neuro-acquired immunodeficiency syndrome (neuroAIDS) progression in opiate abusers, or nonabusers, is uncertain. Using a chemotaxis assay, N9 microglial cell migration was found to be significantly greater in conditioned medium from mouse striatal astrocytes exposed to morphine and/or Tat(1-72) than in vehicle-, mu-opioid receptor (MOR) antagonist-, or inactive, mutant Tat(delta31-61)-treated controls. Conditioned medium from astrocytes treated with morphine and Tat caused the greatest increase in motility. The response was attenuated using conditioned medium immunoneutralized with MCP-1 antibodies, or medium from MCP-1(-/-) astrocytes. In the presence of morphine (time-release, subcutaneous implant), intrastriatal Tat increased the proportion of neural cells that were astroglia and F4/80+ macrophages at 7 days post-injection. This was not seen after treatment with Tat alone, or with morphine plus inactive Tat(delta31-61) or naltrexone. Glia displayed increased MOR and MCP-1 immunoreactivity after morphine and/or Tat exposure. The findings indicate that MCP-1 underlies most of the response of microglia, suggesting that one way in which opiates exacerbate neuroAIDS is by increasing astroglial-derived proinflammatory chemokines at focal sites of CNS infection and promoting macrophage entry and local microglial activation. Importantly, increased glial expression of MOR can trigger an opiate-driven amplification/positive feedback of MCP-1 production and inflammation.
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PMID:HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines. 1620 61

Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO2 response curves and pupillary response in the presence of TPV and/or RTV.
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PMID:Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers. 1630 51

Acute and chronic alcohol abuse impairs various functions of the immune system and thus, has been implicated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) disease progression. We determined whether naltrexone, an opioid receptor antagonist widely used in the treatment of alcoholism, inhibits alcohol-mediated enhancement of HIV infection of T cells. Alcohol enhanced HIV infection of peripheral blood lymphocytes (PBL) and a human lymphoid cell line (CEMX174). Alcohol increased HIV X4 envelope (Env), not murine leukemia virus Env-pseudotyped infection of CEMX174 cells. Naltrexone antagonized the enhancing effect of alcohol on HIV infection of PBL and CEMX174 cells. The specific mu-opioid receptor antagonist, Cys2, Tyr3, Arg5, Pen7 (CTAP) amide, also blocked the enhancing effect of alcohol on HIV infection. Investigation of the underlying mechanism for the alcohol action showed that alcohol significantly increased endogenous beta-endorphin production and induced mu-opioid receptor mRNA expression in PBL and CEMX174 cells. The role of beta-endorphin in alcohol-mediated enhancement of HIV infection was indicated by the observations that naltrexone and CTAP antagonized ether alcohol- or exogenous beta-endorphin-mediated enhancement of HIV infection. These findings suggest a biological mechanism for the potential therapeutic benefit of naltrexone in treating HIV-infected alcoholics.
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PMID:Naltrexone inhibits alcohol-mediated enhancement of HIV infection of T lymphocytes. 1657 67

Lymphocytes are antinociceptive and can modulate visceral pain perception in mice. Previously, we have shown that adoptive transfer of CD4+ T cells to severe combined immune-deficient (SCID) mice normalized immunodeficiency-related visceral hyperalgesia. Pain attenuation was associated with an increase in beta-endorphin release by T cells and an upregulation of beta-endorphin in the enteric nervous system. In this study, we investigated the relationship between T cells and opioid expression in the myenteric plexus. We examined opioid peptide and receptor expression in the myenteric plexus in the presence and absence of mucosal T cells. We found a positive association between T cells and beta-endorphin expression; this was accompanied by a downregulation of the micro-opioid receptor (MOR). In vitro, T helper (Th) type 1 and type 2 cytokine stimulation of CD4+ T cells or isolation of T cells from in vivo Th-polarized mice did not increase T cell release of beta-endorphin or the induction of beta-endorphin expression in the myenteric plexus. However, exogenous beta-endorphin did upregulate beta-endorphin expression, and both cycloheximide and naloxone methiodide inhibited peptide upregulation. Therefore, our results suggest that nonpolarized CD4+ T cells release beta-endorphin, which, through an interaction with MOR, stimulates an upregulation of beta-endorphin expression in the myenteric plexus. Thus, we propose that the mechanism underlying lymphocyte modulation of visceral pain involves T cell modulation of opioid expression in the enteric nervous system.
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PMID:Lymphocyte-mediated regulation of beta-endorphin in the myenteric plexus. 1695 49

The chemokine receptor CXCR4 regulates neuronal survival and differentiation and is involved in a number of pathologies, including cancer and human immunodeficiency virus (HIV). Recent data suggest that chemokines act in concert with neurotransmitters and neuropeptides, such as opioids. This study aimed to determine whether mu-opioid agonists alter the effect of CXCL12 (the specific CXCR4 ligand) on central neurons. Neuronal expression of CXCR4 and micro-opioid receptors (MORs) was analyzed by Western blot, immunostaining, and flow cytometry. Single-cell studies showed that all CXCR4-positive neurons coexpress MORs. Treatment of neuronal cultures with the selective MOR agonist DAMGO or the endogenous peptide endomorphin-1 inhibited intracellular signaling pathways (ERK1/2 and Akt) activated by CXCL12. Furthermore, DAMGO abolished the neuroprotective effect of CXCL12 in N-methyl-d-aspartate (NMDA) neurotoxicity studies. The effects of DAMGO and endomorphin-1 were inhibited by a general or a micro-specific opioid receptor antagonist, and not caused by changes in neuronal CXCR4 levels. DAMGO did not affect CXCL12-induced internalization of CXCR4. The authors propose that interactions between MOR and CXCR4 signaling can modulate the action of CXCL12 on neuronal survival-which may have important implications to neuroAIDS as well as other neuroinflammatory disorders.
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PMID:Modulation of neuronal CXCR4 by the micro-opioid agonist DAMGO. 1716 64

Recent evidence suggests that human immunodeficiency virus (HIV)-induced pathogenesis is exacerbated by opioid abuse and that the synergistic toxicity may result from direct actions of opioids in immature glia or glial precursors. To assess whether opioids and HIV proteins are directly toxic to glial-restricted precursors (GRPs), we isolated neural stem cells from the incipient spinal cord of embryonic day 10.5 ICR mice. GRPs were characterized immunocytochemically and by reverse transcriptase-polymerase chain reaction (RT-PCR). At 1 day in vitro (DIV), GRPs failed to express mu opioid receptors (MOR or MOP) or kappa-opioid receptors (KOR or KOP); however, at 5 DIV, most GRPs expressed MOR and KOR. The effects of morphine (500 nM) and/or Tat (100 nM) on GRP viability were assessed in GRPs at 5 DIV by examining the apoptotic effector caspase-3 and cell viability (ethidium monoazide exclusion) at 96 h following continuous exposure. Tat or morphine alone or in combination caused significant increases in GRP cell death at 96 h, but not at 24 h, following exposure. Although morphine or Tat caused increases in caspase-3 activity at 4 h, this was not accompanied with increased cleaved caspase-3 immunoreactive or ethidium monoazide-positive dying cells at 24 h. The results indicate that prolonged morphine or Tat exposure is intrinsically toxic to isolated GRPs and/or their progeny in vitro. Moreover, MOR and KOR are widely expressed by Sox2 and/or Nkx2.2-positive GRPs in vitro and the pattern of receptor expression appears to be developmentally regulated. The temporal requirement for prolonged morphine and HIV-1 Tat exposure to evoke toxicity in glia may coincide with the attainment of a particular stage of maturation and/or the development of particular apoptotic effector pathways and may be unique to spinal cord GRPs. Should similar patterns occur in vivo then we predict that immature astroglia and oligodendroglia may be preferentially vulnerable to HIV-1 infection or chronic opiate exposure.
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PMID:Glial-restricted precursors: patterns of expression of opioid receptors and relationship to human immunodeficiency virus-1 Tat and morphine susceptibility in vitro. 1747 53


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