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)

Mitochondrial parameters in peripheral blood mononuclear cells (PBMC) and their relationship with mitochondrially-driven PBMC apoptosis were investigated in a group of HIV-1-infected long-term nonprogressors (LTNP) and compared with untreated asymptomatic HIV-1 infected typical progressors (TP) and uninfected healthy controls (HC). Twenty-six LTNP, 27 TP and 31 HC were evaluated. Studies were performed in PBMCs. Mitochondrial DNA content (mtDNA) was assessed by quantitative real-time PCR. Activities of mitochondrial respiratory chain complexes (MRC) II, III and IV were determined by spectrophotometry. Caspase-3 activity was assessed by fluorimetry, and caspase-9 activation and Bcl-2 levels were assessed by immunoblotting. mtDNA abundance (p<0.05), MRC complex II (p<0.001), complex III (p<0.01) and complex IV (p=0.01) were lower in the TP group than in the HC group. In the LTNP group these parameters were similar to those of the HC group except for complex II, which was decreased (p<0.01). The PBMC of TP showed the highest overall apoptotic activation, since their caspase-3 activity was greater than that of HC (p<0.05) and LTNP. In the case of LTNP, however, the difference was non-significant. Caspase-9 and the caspase-9/Bcl-2 ratio were both over-expressed in TP compared to HC (p<0.01) and LTNP (p<0.05). Both of these measurements indicate that mitochondrially-driven apoptosis in TP is greater than in LTNP and HC. A relationship between mitochondrial damage and apoptotic activation was found in TP. Mitochondrial damage is associated with increased PBMC apoptosis in patients with active HIV-1 replication (TP). These abnormalities are slight or not present in LTNP.
Curr HIV Res 2007 Sep
PMID:HIV-1-infected long-term non-progressors have milder mitochondrial impairment and lower mitochondrially-driven apoptosis in peripheral blood mononuclear cells than typical progressors. 1789 66

Previous work has demonstrated that the surface glycoprotein (gp120) of human immunodeficiency virus-1 (HIV-1) can induce damage and apoptosis of neurons both in vitro and in vivo. In this report, we provide evidence that double-stranded RNA-activated protein kinase (PKR), a stress kinase, is involved in HIV/gp120-associated neurodegeneration. In cultures of mixed cortical cells, HIV/gp120 increased the protein level of PKR. Additionally, PKR was phosphorylated in neurons but not glia after exposure to gp120. The use of two independent pharmacological inhibitors of PKR activity abrogated neuronal cell death induced by gp120. Cortical neurons from PKR knock-out mice were significantly protected from neurotoxicity induced by gp120, further validating the pivotal proapoptotic function of PKR. gp120-induced phosphorylated PKR localized prominently to neuronal nuclei; PKR inhibition or the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] abrogated this effect. PKR inactivation also inhibited gp120-induced caspase-3 activation, consistent with its neuroprotective effect. Finally, brain tissue from individuals diagnosed with HIV-associated dementia (HAD), but not HIV infection alone, contained the activated form of PKR, which localized predominantly to neuronal nuclei. Together, these results identify PKR as a critical mediator of gp120 neurotoxicity, suggesting that activation of PKR contributes to the neuronal injury and cell death observed in HAD.
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PMID:Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons. 1792 46

We aimed to evaluate the frequency of Kaposi sarcoma (KS)-associated herpesvirus (KSHV) infection in KS lesions in patients from Brazil. In addition, expression of human bcl-2, cleaved caspase-3, and KSHV latency-associated nuclear antigen (LANA)-1 in tumors was evaluated using immunohistochemical analysis. We studied 64 KS cases, classified as follows: classical, 20 (31%); iatrogenic, 2 (3%); AIDS-associated, 25 (39%); and not otherwise specified (lack of information about HIV status), 17 (27%). KSHV was detected by polymerase chain reaction (PCR) in 61 cases (95%); 40 cases (63%) were KSHV+ by PCR and immunohistochemical analysis for LANA-1. Immunoexpression of bcl-2 was detected in 47 cases (73%). Only a few cells in 15 cases (23%) of KS had demonstrable immunostaining for cleaved caspase-3. These results further support the association of KSHV with all KS forms. Cleaved caspase-3 in KS tumors was infrequent, which may reflect the inhibition of apoptosis owing to bcl-2 overexpression observed in the majority of KS tumors.
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PMID:Human bcl-2 expression, cleaved caspase-3, and KSHV LANA-1 in Kaposi sarcoma lesions. 1795 Dec 2

Neutrophils from human immunodeficiency virus-positive (HIV+) patients have an increased susceptibility to undergo programmed cell death (PCD), which could explain neutropenia during advanced disease. In this work, key steps of PCD have been evaluated in neutrophils from HIV+ patients. The role of caspase-3, caspase-8, mitogen activated protein kinase (MAPK) and reactive oxygen species (ROS) was analysed. Spontaneous neutrophil death is dependent upon caspase-3 but independent of caspase-8, suggesting that the intrinsic pathway is involved as a pathogenic mechanism of PCD. Inhibition of ROS decreased spontaneous PCD and caspase-3 hydrolysis, connecting oxidative stress and caspase-3 activation with neutrophil PCD in HIV-infected patients. Additionally, an increased neutrophil death was observed in HIV+ patients, following inhibition of p38 MAPK, suggesting a role for p38 MAPK in cell survival during the disease. We conclude that oxidative stress secondary to HIV infection can accelerate neutrophil death.
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PMID:Mechanisms of neutrophil death in human immunodeficiency virus-infected patients: role of reactive oxygen species, caspases and map kinase pathways. 1795 81

The present study was aimed at clarifying the effects of an anti-apoptotic protein for modulating symptoms in acute lung injury (ALI). From Bcl-x(L), a Bcl-2 family member, we constructed an artificial protein (FNK) and fused it with the protein transduction domain (PTD) of the HIV/Tat protein (PTD-FNK) to facilitate its permeation into cells. ALI was induced by intratracheal infusion of lipopolysaccharide (LPS) into Sprague-Dawley male rats. PTD-FNK was injected into the peritoneal cavity of the animals either 2 h before, or 3 h or 6 h after LPS challenge. All rats were sacrificed 24 h after the last treatment. Cell differential ratios and albumin concentration were estimated in bronchoalveolar lavage fluid. We examined histological change, myeloperoxidase activity, TUNEL assay, caspase-3/caspase-3-like activity and immunohistochemical reaction for caspase 3 (active form). In animals with PTD-FNK treatment, the albumin leakage was significantly attenuated with protection of tissue damage. Also, the apoptosis of alveolar wall cells was reduced by PTD-FNK treatment, while a total cell number and the neutrophil ratio were not changed. Human umbilical vein endothelial cells (HUVEC) and cells of an alveolar epithelial cell line (A549) were exposed to LPS or TNF-alpha with or without PTD-FNK treatment in vitro. Cell survival rates examined by trypan-blue exclusion assay were increased by PTD-FNK treatment in a concentration-dependent manner. Thus, PTD-FNK could play a protective role in ALI by suppressing apoptosis of alveolar epithelial cells and capillary endothelial cells despite of some effect on neutrophil activity.
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PMID:Anti-apoptotic PTD-FNK protein suppresses lipopolysaccharide-induced acute lung injury in rats. 1795 70

Our overall goal is to understand how viral envelope proteins mediate membrane fusion and pathogenesis. Membrane fusion is a crucial step in the delivery of the viral genome into the cell resulting in infection. On the other hand, fusion activity of viral envelope glycoproteins expressed in infected cells may cause the demise of uninfected bystander cells by apoptosis. Our general approach is to kinetically resolve steps in the pathway of viral envelope glycoprotein-mediated membrane fusion and to uncover physical parameters underlying those steps using a variety of biochemical, biophysical, virological, and molecular and cell biological techniques. Since HIV fusion involves a complex cascade of interactions of the envelope glycoprotein with two receptors, membrane organization plays an important role and interfering with it may modulate entry. To study this phenomenon, we have either examined cell lines with differential expression of sphingolipids (such as GM3), or altered membrane organization by modifying levels of cholesterol, ceramides, or glycosphingolipids. We show that the localized plasma membrane lipid microenvironment (and not the specific membrane lipids) in the vicinity of CD4 controls receptor mobility and HIV-1 fusion. The complex cascade of conformational changes that must occur to allow virus entry is also a very important target for therapy and vaccine development. We have recently designed and tested peptide analogs composed of chemical spacers and reactive moieties positioned strategically to promote permanent attachment. Using a temperature-arrested state in vitro assay we show evidence for the trapping of a pre-six-helix bundle fusion intermediate by a covalent reaction with the inhibitory reactive peptide. Also, using photo-reactive hydrophobic probes we have found ways to inactivate viral envelope glycoproteins while leaving their overall structures intact. Finally, in order to study the envelope glycoprotein effects on pathogenesis, we have used an in vitro model of co-culture of envelope-expressing cells as effectors and CD4+ T cells as targets. We delineated that apoptosis mediated by envelope glycoprotein in bystander cells correlates with transmembrane subunit (gp41)-induced hemifusion. The apoptotic pathway initiated by this interaction involves caspase-3-dependent mitochondrial depolarization and reactive oxygen species production, which depends on the phenotype of the envelope glycoprotein associated with the virus. Taken as a whole, our studies have many different important implications for antiviral therapies and vaccine development.
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PMID:HIV-1 envelope glycoprotein-mediated fusion and pathogenesis: implications for therapy and vaccine development. 1824 97

OX40, a member of the tumor necrosis factor receptor (TNF-R) superfamily, has been shown to play an important role in the survival of antigen-specific CD4(+) T cells. We have previously reported that stimulation of the OX40-expressing and HIV-1 chronically infected T cell line, ACH-2/OX40, with either OX40 ligand (OX40L)-expressing cells or with TNF resulted in the activation of HIV-1 followed by apoptotic cell death. In the present study we found that costimulation via OX40 and TNF-R in OX40-expressing HIV-1-infected T cell lines leads to a marked reduction of HIV-1 production associated with rapid cell death. Since HIV-1-negative OX40(+) T cell lines underwent rapid apoptotic cell death after OX40L and TNF stimulation, it was reasoned that the ACH-2/OX40 cell death was unlikely to be due to HIV-1 infection. Furthermore, we found that the OX40-mediated apoptosis of the CD4(+) T cell line, Molt-4/CCR5-OX40 (M/R5-OX40), required (1) signals mediated via the cytoplasmic tail of OX40, (2) activation of the caspase cascade, including caspase-8 and caspase-3, and (3) induction of endogenous TNF-alpha, but not of TNF-beta, FasL, or TNF-related apoptosis-inducing ligand (TRAIL), suggesting that this apoptosis occurred indirectly via the TNF/TNF-R system. Finally, a fraction of primary activated CD4(+) T cells, expressing high levels of OX40, underwent apoptosis, as revealed by annexin V staining, after cocultivation with OX40L(+) cells. These results suggest a new biological role of the OX40L/OX40 system in controlling the fate of activated CD4(+) T cells and of controlling HIV-1 infection in inflammatory environments.
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PMID:Enhancement of OX40-induced apoptosis by TNF coactivation in OX40-expressing T cell lines in vitro leading to decreased targets for HIV type 1 production. 1832 75

Caspase-3 is the executioner caspase of apoptosis whose activation in mammalian cells represents the last stage of the programmed cell death signaling pathway and the initiation of the lethal digestion of cell proteins. Active caspase-3 is a tetramer composed of two p12 and two p17 subunits derived from cleavage of procaspase-3 during activation. Here, we armed GFP-fusion proteins of both the caspase-3 p12 and p17 subunits with signals from Ig-kappa light chain that allows its efficient secretion from the cells (Sec) and from HIV-1 Tat that facilitates its uptake and nuclear translocation by other cells (NLS). We found that treatment of cells with conditioned media from cells expressing both Sec-GFP-p17-NLS and Sec-GFP-p12-NLS was able to transduce active caspase-3 with consequent cell death of treated cultures. Use of various combinations of constructs demonstrated that both subunits were required and that each one needed to possess both Sec and NLS. Our observations introduce a bidirectional protein transduction system with the ability to introduce active caspase-3 into cells and cause apoptosis. This system may have important therapeutic applications.
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PMID:Development of a bidirectional caspase-3 expression system for the induction of apoptosis. 1850 60

HIV encephalitis (HIVE) is accompanied by brain inflammation, leukocyte infiltration, and glial activation, and HIV patients who abuse opiates are more likely to develop HIVE. To better understand how opiates could alter HIV-related brain inflammation, the expression of astrocyte (GFAP immunoreactivity) and macrophage/microglial (F4/80 or Mac1 immunoreactivity) markers in the striatum, and the percentage of 3-nitrotyrosine (3-NT) positive macrophages/microglia, was determined following a 2-day exposure to morphine (5 mg/kg/day via time-release, subcutaneous implant) and doxycycline in GFAP-driven, doxycycline-inducible HIV-1 Tat transgenic mice. Data show that both morphine and Tat induction via doxycycline increased astrocyte activation, with significant additive increases achieved with combined morphine and doxycycline exposure. By contrast, combined Tat induction and morphine exposure, but neither manipulation alone, significantly increased the proportion of macrophages/microglia present in the striatum of transgenic mice, although morphine exposure was necessary to elevate 3-NT co-detection in Mac1-positive macrophages/microglia. Finally, Tat induction increased the percentage of neurons expressing active caspase-3, and this was even more significantly elevated by co-administration of morphine. In spite of elevations in caspase-3, neuronal TUNEL reactivity was unchanged in all groups, even after 10 days of Tat induction. Importantly, co-administration of naltrexone completely antagonized the effects of morphine. These findings indicate that morphine rapidly and significantly increases the activation of astrocytes and macrophages/microglia in the brains of inducible Tat transgenic mice, supporting the theory that early inflammatory changes in glia could underlie the development of HIVE in opiate-abusing AIDS patients.
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PMID:Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 Tat transgenic mice. 1855 26

There is an urgent need of novel approaches to drugs in the cancer, HIV, and bacterial areas. Increasing resistance to conventional therapies is observed. This minireview provides novel insights for drugs in these three areas. The agents PAC-1 (anticancer), DHBNH (anti-HIV), AHL (autoinducer), and UCS1025A (anticancer) have recently attracted attention due to considerable potential based on new approaches. PAC-1 activates procaspase-3 to caspase-3, resulting in induction of apoptosis in tumor cells. DHBNH binds to a newly revealed site on HIV reverse transcriptase. The drug mainly inhibits RNase H (RNA-cleaving). AHLs comprise an important class that participates in bacterial cell communication. UCS1025A is a fungus-derived inhibitor of the enzyme telomerase, present in cancer cells, which is crucially involved in tumor cell immortality. All four agents possess chelating sites for metal binding, which has not been appreciated. In PAC-1 and DHBNH, the coordinating portion is similar to salicylaldehyde semicarbazone. For AHL and UCS1025A, the metal-binding moiety is a beta -ketoamide. Metal complexes of heavier metals are well-known electron transfer (ET) functionalities that can generate reactive oxygen species. Hence, it is reasonable to hypothesize a commonality in mechanism based on metal ET. Differences in receptor binding can result, in part, in diverse physiological responses. There is considerable literature that addresses involvement of signal transduction with the various physiologically active agents discussed herein. Thus, cell communication appears to play an important role in the biochemistry of these endogenous and exogenous substances. Details of cell signaling are presented for complexes of metals (Fe, Cu, Ni, and As), telomerase, caspase-3, and RNase. In addition, practical medical aspects are discussed.
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PMID:Does structural commonality of metal complex formation by PAC-1 (anticancer), DHBNH (anti-HIV), AHL (autoinducer), and UCS1025A (anticancer) denote mechanistic similarity? Signal transduction and medical aspects. 1856 22


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