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)

Mechanisms underlying human immunodeficiency virus-1 encephalopathy are not completely known; however, recent studies suggest that the viral protein gp41 may be neurotoxic via activation of inducible nitric oxide synthase (iNOS) in glial cells. In the present study, we investigated the NO-generating activity of primary human fetal astrocytes in response to gp41 and the relationship to microglial cell production of interleukin-1 (IL-1). Gp41 failed to trigger iNOS mRNA expression in highly enriched (>99%) astrocyte or microglial cell cultures. However, gp41-treated microglia released a factor(s) that triggered iNOS mRNA expression and NO production in astrocytes. Because IL-1 receptor antagonist protein blocked gp41-induced NO production, a pivotal role was suggested for microglial cell IL-1 production in astrocyte iNOS expression. Also, gp41 induced IL-1beta mRNA expression and IL-1 production in microglial cell but not astrocyte cultures. Using specific inhibitors, we found that gp41-induced IL-1beta production in microglia was mediated via a signaling pathway involving protein-tyrosine kinase. These data support the hypothesis that gp41 induces astrocyte NO production indirectly by triggering upregulation of microglial cell IL-1 expression.
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PMID:Gp-41-mediated astrocyte inducible nitric oxide synthase mRNA expression: involvement of interleukin-1beta production by microglia. 1041 75

The regional expression of immune-mediated and neurotoxic events in the human immunodeficiency virus (HIV)-infected brain in relationship to the acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) and brain pathology remains uncertain. The extent of gp41, inducible nitric oxide synthase (iNOS), and HLA-DR expression was examined in the frontal lobe and basal ganglia of 25 patients at varying stages of ADC. The expression of gp41 and iNOS was present predominantly in perivascular cells and most often in the basal ganglia. Staining for gp41 correlated significantly with iNOS in the basal ganglia, whereas the severity of staining for gp41 and iNOS in the basal ganglia and white matter was significantly greater in subjects with moderate to severe dementia compared with those with milder impairment. The degree of macrophage staining in the white matter and basal ganglia also correlated significantly with ADC severity and was more abundant than gp41 or iNOS staining, particularly in the white matter. Logistic regression analysis revealed that staining for iNOS and gp41 increased linearly with ADC severity and was significantly more abundant in the basal ganglia compared with the white matter. Double-immunolabeling studies colocalized iNOS predominantly to macrophage/microglia and to gp41-positive cells. The expression of iNOS and gp41 in the basal ganglia combined with immune activation contributes to the development and progression of the clinical syndrome.
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PMID:Human immunodeficiency virus infection, inducible nitric oxide synthase expression, and microglial activation: pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex. 1044 86

In order to establish whether the neurotoxicity of the human immunodeficiency virus type 1 (HIV-1) regulatory protein Tat could be related to the production of potentially toxic substances by microglial cells, we examined the ability of recombinant HIV-1 Tat protein to stimulate the release of NO in purified rat microglial cultures. We found that the exposure of microglia to Tat led to a dose dependent expression of the inducible isoform of nitric oxide (iNOS) and NO production. The effect was remarkably enhanced by pretreatment or cotreatment with the proinflammatory cytokine interferon-gamma (IFN-gamma), but not with bacterial lipopolysaccharide (LPS). The high concentrations of Tat required (>100 ng/ml) suggested the viral protein induced transactivation of the iNOS gene, rather than acting through a receptor-mediated mechanism, that generally requires lower concentrations. Indeed, the induction of the iNOS gene by Tat was largely prevented by a specific inhibitor of the nuclear factor-kB (NF-kB), a transcription factor known to be involved in the induction of iNOS by LPS. The activation of NF-kB could largely account for the ability of Tat to induce iNOS expression and to act in synergism with IFN-gamma, which utilizes a different transduction system. On the other hand, the convergence of Tat and LPS on the same target (NF-kB) could explain the lack of synergism between these substances. We propose that the induction of iNOS in microglial cells and the consequent release of high and sustained levels of NO during HIV-1 cerebral infection may be an important step in the cascade of pathological events triggered by Tat. Furthermore, the NO-dependent damage may be exacerbated by the presence of IFN-gamma, which is likely to occur in pathological conditions characterized by glial activation and inflammatory cell infiltration.
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PMID:Human immunodeficiency virus type 1 Tat protein stimulates inducible nitric oxide synthase expression and nitric oxide production in microglial cultures. 1044 7

Ross River virus (RRV) is an indigenous Australian arthropod-borne alphavirus responsible for epidemic polyarthritis (EPA), myalgia, and lethargy in humans. Macrophages and monocytes have been associated with human RRV disease, and previous studies have shown that RRV is capable of infecting macrophages via both a natural virus receptor and by Fc receptor-mediated antibody-dependent enhancement (ADE). Similar to other viruses, such as human immunodeficiency virus and dengue virus, ADE infection results in dramatic RRV growth increases for in vitro macrophage cultures. This study demonstrates that RRV could resist lipopolysaccharide (LPS)-induced antiviral activity in macrophage cultures when infection was via the ADE pathway. Investigation of this infection pathway found that RRV was able to suppress the transcription and translation of key antiviral genes (tumor necrosis factor and inducible nitric oxide synthase) in LPS-stimulated macrophages by disrupting the transcription into mRNA of the genes coding for the associated transcription factors IRF-1 and NF-kappaB. The transcription of non-antiviral control genes was not perturbed by RRV-ADE infection, and de novo protein synthesis also was not significantly affected in RRV-ADE infected cells. The ADE pathway of infection allowed RRV to specifically target antiviral genes in macrophages, resulting in unrestricted virus replication. As ADE has been observed for several virus families and associated with disease and adverse vaccination outcomes, these findings may have broad relevance to viral disease formation and antiviral vaccination strategies.
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PMID:Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection. 1095 37

Macrophages are suspected to play a major role in human immunodeficiency virus (HIV) infection pathogenesis, not only by their contribution to virus dissemination and persistence in the host but also through the dysregulation of immune functions. The production of NO, a highly reactive free radical, is thought to act as an important component of the host immune response in several viral infections. The aim of this study was to evaluate the effects of HIV type 1 (HIV-1) Ba-L replication on inducible nitric oxide synthase (iNOS) mRNA expression in primary cultures of human monocyte-derived macrophages (MDM) and then examine the effects of NO production on the level of HIV-1 replication. Significant induction of the iNOS gene was observed in cultured MDM concomitantly with the peak of virus replication. However, this induction was not accompanied by a measurable production of NO, suggesting a weak synthesis of NO. Surprisingly, exposure to low concentrations of a NO-generating compound (sodium nitroprusside) and L-arginine, the natural substrate of iNOS, results in a significant increase in HIV replication. Accordingly, reduction of L-arginine bioavailability after addition of arginase to the medium significantly reduced HIV replication. The specific involvement of NO was further demonstrated by a dose-dependent inhibition of viral replication that was observed in infected macrophages exposed to N(G)-monomethyl L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME), two inhibitors of the iNOS. Moreover, an excess of L-arginine reversed the addition of L-NAME, confirming that an arginine-dependent mechanism is involved. Finally, inhibitory effects of hemoglobin which can trap free NO in culture supernatants and in biological fluids in vivo confirmed that endogenously produced NO could interfere with HIV replication in human macrophages.
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PMID:Nitric oxide synthesis enhances human immunodeficiency virus replication in primary human macrophages. 1098 33

Addition of nitric oxide (NO) donors to mitogen-activated human immunodeficiency virus type 1 (HIV-1)-infected peripheral blood mononuclear cultures produced a significant increase in virus replication, and this effect was not associated with a change in cell proliferation. This effect was only observed with T-tropic X4 or X4R5 virus but not with R5 virus. Moreover, HIV-1 replication in mitogen-stimulated cultures was partially prevented by the specific inhibitors of the inducible nitric oxide synthase (iNOS). NO donors also enhanced HIV-1 infection of the human T-cell lines, Jurkat and MT-2. We have also observed that NO leads to an enhancement of HIV-1 replication in resting human T cells transfected with a plasmid carrying the entire HIV-1 genome and activated with phorbol ester plus ionomycin. Thus, in those cultures NO donors strongly potentiated HIV-1 replication in a dose-dependent manner, up to levels comparable to those with tumor necrosis factor alpha (TNF-alpha) stimulation. Furthermore, iNOS inhibitors decreased HIV-1 replication in HIV-1-transfected T cells to levels similar to those obtained with neutralizing anti-TNF-alpha antibodies. Moreover, HIV-1 replication induced iNOS and TNF-alpha transcription in T cells and T-cell lines. Interestingly, NO donors also stimulated long terminal repeat (LTR)-driven transcription whereas iNOS inhibitors partially blocked TNF-alpha-induced LTR transcription. Therefore, our results suggest that NO is involved in HIV-1 replication, especially that induced by TNF-alpha.
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PMID:Regulation of human immunodeficiency virus type 1 replication in human T lymphocytes by nitric oxide. 1131 36

Tuberculosis (TB) is the most common opportunistic infection in human immunodeficiency virus type 1 (HIV-1)-infected patients globally and occurs throughout the course of HIV-1 disease. Here the production of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells (PBMC) of HIV-1-infected versus -uninfected patients with newly diagnosed pulmonary TB (PTB) was compared. Findings were correlated with cytokine profiles, clinical presentation, and expression of inducible nitric oxide (iNOS). Most HIV-1/PTB patients with a CD4 cell count of 200-500 cells/microL had high IFN-gamma production and radiographic evidence of atypical PTB. Low IFN-gamma production and radiographic evidence of reactivated PTB characterized both HIV-1/PTB patients with a CD4 cell count >or=500 cells/microL and HIV-1-uninfected patients. TNF-alpha levels were similar in all HIV-1/PTB patients, regardless of CD4 cell count. Induction of iNOS in PBMC was low and was associated with low IFN-gamma production. These data underscore the potential pathogenic role of macrophage-activating cytokines in TB in HIV-1-infected patients.
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PMID:Macrophage-activating cytokines in human immununodeficiency virus type 1-infected and -uninfected patients with pulmonary tuberculosis. 1137 35

The interferons (IFNs) belong to the body's natural defensive response mechanisms directed against virus infections including also the human immunodeficiency virus (HIV) infection. This review discusses the current knowledge concerning the role of IFNs types I and II during the HIV infection. The author analyzes the HIV-driven process of endogenous IFNs induction in different cell types as well as the development of unusual acid-labile IFN following the HIV infection, its nature and clinical significance. Possible action mechanisms of different exogenous IFN types against the HIV-infection are reviewed taking into consideration the stages of HIV replication accompanied by these mechanisms of action and describing both positive and negative roles of IFNs during this disease. The author discusses also some well-known IFN-inducible antiviral pathways participating in the anti-HIV mechanisms and enzymes realizing antiviral action (PKR, 2'5'-OAS, iNOS, IDO, Mx and 9-27 proteins). A problem of HIV defense against the anti-HIV IFN action as well as some aspects of HIV-accelerating IFN effects are also examined in detail.
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PMID:Endogenous and exogenous interferons in HIV-infection. 1177 39

Immune stimulants, such as the bacterial endotoxin, lipopolysaccharide (LPS), the human immunodeficiency virus-1 coat protein gp120, or beta-amyloid peptides, lead to glial activation and production of various immune mediators, such as nitric oxide (NO) and proinflammatory cytokines in the brain. These mediators appear to contribute to neuronal cell death in neurodegenerative diseases. However, the signaling pathways, which mediate the neurotoxic effect by the endotoxin, are not understood. The purpose of this study was to determine the role of mitogen-activated protein kinase (MAPK) in LPS-induced neurodegeneration using mesencephalic dopaminergic neuron/glia cultures. We have found that the p38 MAPK is important in LPS-induced death of mesencephalic neurons in rat neuron-glia mixed cultures. Upon treatment with 10 ng/ml LPS, the number of dopaminergic neurons decreased by 80% within 48 h, preceded by a significant production of NO by glia. Neuroprotection by selective inhibition of p38 MAPK activity paralleled a decrease in LPS-induced inducible nitric oxide synthase (iNOS) expression. These events were significantly reduced by the selective p38 MAPK inhibitor, SB202190, but not by the inactive analogue SB202474. Inhibition of iNOS activity and NO production by treatment with GW274150 was also neuroprotective. Although the p38 MAPK inhibitor afforded significant neuroprotection from LPS toxicity in the neuron-glia mixed culture, it failed to protect dopaminergic neurons from 6-hydroxy-dopamine-induced toxicity, which acts directly on dopaminergic neurons by inducing hydroxyl radical formation from the mitochondria. The results suggest that p38 MAPK in glia plays a significant role in the LPS-induced death of mesencephalic neurons through induction of nitric oxide synthase and resulting NO production.
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PMID:p38 MAP kinase is involved in lipopolysaccharide-induced dopaminergic neuronal cell death in rat mesencephalic neuron-glia cultures. 1207 85

Chemokine receptor 5 (CCR5) binds macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, RANTES, and members of the monocyte chemotactic protein family and is also a receptor for human immunodeficiency virus (HIV). CCR5 ligands can suppress HIV-1 entry into cells. In humans, homozygous mutations of the ccr5 gene confer resistance to HIV-1 infection. The role of CCR5 in defense against microbial infection is unclear. In this study we examined the innate and adaptive immune responses of CCR5-deficient mice to the intracellular bacterial pathogen Listeria monocytogenes. We found that migration of monocytic cells, formation of L. monocytogenes-containing lesions, and bacterial clearance occurred normally in the spleens and livers of CCR5-deficient animals. Activation of macrophages and dendritic cells during the first 3 days postinfection was normal in the absence of CCR5, as demonstrated by intact expression of inducible nitric oxide synthase (iNOS) and production of the cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-12. Priming of L. monocytogenes-specific CD8 T cells also occured independently of CCR5 expression. Previously immunized, CCR5-deficient animals mounted normal secondary CD8 T-cell responses and cleared bacteria from infected organs similarly to wild-type controls, suggesting that CCR5 is dispensable for migration and activation of memory CD8 T cells. Our data indicate that CCR5-mediated chemotaxis is not required for defense against infection with L. monocytogenes.
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PMID:Chemokine receptor 5 is dispensable for innate and adaptive immune responses to Listeria monocytogenes infection. 1474 53


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