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)

The third reading frame of the envelope gene from HIV-1 codes for a protein homologous to the human selenoprotein glutathione peroxidase (GPX). Cells stably or transiently transfected with a HIV-1 GPX construct are protected against the loss of the mitochondrial transmembrane potential and subsequent cell death induced by exogenous reactive oxygen species (ROS) as well as mitochondrion-generated ROS. However, HIV-1 GPX does not confer a general apoptosis resistance, because HIV-1 GPX-transfected cells were not protected against cell death induced by staurosporine or oligomycin. The inhibition of cell death induced by the ROS donor tert-butylhydroperoxide was also observed in cells depleted from endogenous glutathione (GSH), suggesting that GSH is not the sole electron acceptor for HIV-1 GPX. Clinical HIV-1 isolates from long-term non-progressors (untreated patients with diagnosed HIV-1 infection for > 10 years, with CD4 T cell count of > 500 cells/mm3) mostly possess an intact GPX gene (with only 18% of loss-of-function mutations), while HIV-1 isolates from patients developing AIDS contain non-functional GPX mutants in 9 out of 17 cases (53%). Altogether, these data suggest that HIV-1 GPX possesses a cytoprotective, pathophysiologically relevant function.
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PMID:Anti-apoptotic activity of the glutathione peroxidase homologue encoded by HIV-1. 1500 15

HIV-1 encodes for one of the human glutathione peroxidases. As a consequence, as it is replicated, its genetic needs cause it to deprive HIV-1 seropositive individuals not only of glutathione peroxidase, but also of the four basic components of this selenoenzyme, namely selenium, cysteine, glutamine, and tryptophan. Eventually this depletion process causes severe deficiencies of all these substances. These, in turn, are responsible for the major symptoms of AIDS which include immune system collapse, greater susceptibility to cancer and myocardial infarction, muscle wasting, depression, diarrhea, psychosis and dementia. As the immune system fails, associated pathogenic cofactors become responsible for a variety of their own unique symptoms. Any treatment for HIV/AIDS must, therefore, include normalization of body levels of glutathione, glutathione peroxidase, selenium, cysteine, glutamine, and tryptophan. Although various clinical trials have improved the health of AIDS patients by correcting one or more of these nutritional deficiencies, they have not, until the present, been addressed together. Physicians involved in a selenium and amino-acid field trial in Botswana, however, are reporting that this nutritional protocol reverses AIDS in 99% of patients receiving it, usually within three weeks.
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PMID:How HIV-1 causes AIDS: implications for prevention and treatment. 1505 Jan 5

Homologues of the selenoprotein glutathione peroxidase (GPx) have been previously identified in poxviruses and in RNA viruses including HIV-1 and hepatitis C virus (HCV). Sequence analysis of the NS4 region of Japanese encephalitis virus (JEV) suggests it may encode a structurally related but functionally distinct selenoprotein gene, more closely related to the iron-binding protein ferredoxin than to GPx, with three highly conserved UGA codons that align with essential Cys residues of ferredoxin. Comparison of the probe JEV sequence to an aligned family of ferredoxin sequences gave an overall 30.3% identity and 45.8% similarity, and was statistically significant at 4.9 S.D. (P < 10(-6)) above the average score computed for randomly shuffled sequences. A 3-dimensional model of the hypothetical JEV protein (JEV model) was constructed by homology modeling using SYBYL, based upon a high resolution X-ray structure of ferredoxin (PDB code: 1awd). The JEV model and the model from 1awd were subsequently subjected to molecular dynamics simulations in aqueous medium using AMBER 6. The solution structure of the JEV model indicates that it could fold into a tertiary structure globally similar to ferredoxin 1awd, with RMSD between the averaged structures of 1.8 A for the aligned regions. The modeling and MD simulations data also indicate that this structure for the JEV protein is energetically favorable, and that it could be quite stable at room temperature. This protein might play a role in JEV infection and replication via TNF and other cellular stimuli mediated via redox mechanisms.
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PMID:Structure and dynamics of a predicted ferredoxin-like selenoprotein in Japanese encephalitis virus. 1553 Aug 18

The blood-brain barrier (BBB) has an important role in the development of AIDS dementia. The HIV-1 envelope glycoprotein (gp120) and transregulatory protein (Tat) of HIV-1 are neurotoxic and cytotoxic and have been implicated in the development of HIV dementia. They are known to cause oxidative stress and are associated with disruption of the BBB. Here, we used an immortalized endothelial cell line from rat brain capillaries, RBE4, to determine whether gp120 and Tat can induce oxidative stress in an in vitro model of the BBB. RBE4 cells were exposed to gp120 or Tat and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG), catalase (CAT) activity, glutathione peroxidase (GPx) activity, and glutathione reductase (GR) activity, and malondialdehyde (MDA) used as measures of oxidative stress. Both gp120 and Tat significantly decreased the levels of intracellular GSH, GPx, and GR and increased the levels of MDA in RBE4 cells, showing that the cells were oxidatively challenged. The ratio of GSH/GSSG, a widely accepted indicator of oxidative stress, was also significantly decreased. These studies show that both of these viral proteins can induce oxidative stress in immortalized BBB endothelial cells.
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PMID:HIV-1 viral proteins gp120 and Tat induce oxidative stress in brain endothelial cells. 1591 Jul 62

Ribosomal frameshifting is used by various organisms to maximize protein coding potential of genomic sequences. It is commonly exploited by RNA viruses to overcome the constraint of their limited genome size. Frameshifting requires specific RNA structural features, such as a suitable heptanucleotide "slippery" sequence and an RNA pseudoknot. Previous genomic analysis of HIV-1 indicated the potential for several hidden genes encoded through frameshifting; one of these, overlapping the envelope gene, has an RNA pseudoknot just downstream from a slippery sequence, AAAAAGA that features an adenine quadruplet prior to a potential hungry arginine codon (AGA). This env-frameshift (env-fs) gene has been shown to encode a truncated glutathione peroxidase homologue, with both antioxidant and anti-apoptotic activities in transfected cells. Using a dual reporter cell-based frameshift assay, we demonstrate that the env-fs frameshift sequence is active in vitro. Furthermore, in arginine deficient media, env-fs frameshifting increased over 100% (p<0.005), consistent with the hypothesized hungry codon mechanism. As a response to arginine deficiency, increased expression of the antioxidant viral GPx gene (env-fs) by upregulation of frameshifting could be protective to HIV-infected cells, as a countermeasure to the increased oxidative stress induced by arginine deficiency (because NO is a known scavenger of hydroxyl radical).
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PMID:A -1 frameshift in the HIV-1 env gene is enhanced by arginine deficiency via a hungry codon mechanism. 1605 59

Human immunodeficiency virus-1 (HIV-1) infection in the central nervous system (CNS) may lead to neuronal loss and progressively deteriorating CNS function: HIV-1 gene products, especially gp120, induce free radical-mediated apoptosis. Reactive oxygen species (ROS), are among the potential mediators of these effects. Neurons readily form ROS after gp120 exposure, and so might be protected from ROS-mediated injury by antioxidant enzymes such as Cu/Zn-superoxide dismutase (SOD1) and/or glutathione peroxidase (GPx1). Both enzymes detoxify oxygen free radicals. As they are highly efficient gene delivery vehicles for neurons, recombinant SV40-derived vectors were used for these studies. Cultured mature neurons derived from NT2 cells and primary fetal neurons were transduced with rSV40 vectors carrying human SOD1 and/or GPx1 cDNAs, then exposed to gp120. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. Transduction efficiency of both neuron populations was >95%, as assayed by immunostaining. Transgene expression was also ascertained by Western blotting and direct assays of enzyme activity. Gp120 induced apoptosis in a high percentage of unprotected NT2-N. Transduction with SV(SOD1) and SV(GPx1) before gp120 challenge reduced neuronal apoptosis by >90%. Even greater protection was seen in cells treated with both vectors in sequence. Given singly or in combination, they protect neuronal cells from HIV-1-gp120 induced apoptosis. We tested whether rSV40 s can deliver antioxidant enzymes to the CNS in vivo: intracerebral injection of SV(SOD1) or SV(GPx1) into the caudate putamen of rat brain yielded excellent transgene expression in neurons. In vivo transduction using SV(SOD1) also protected neurons from subsequent gp120-induced apoptosis after injection of both into the caudate putamen of rat brain. Thus, SOD1 and GPx1 can be delivered by SV40 vectors in vitro or in vivo. This approach may merit consideration for therapies in HIV-1-induced encephalopathy.
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PMID:Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis. 1687 Dec 33

In an alternate reading frame overlapping the viral envelope gene, HIV-1 has been shown to encoded a truncated glutathione peroxidase (GPx) module. Essential active site residues of the catalytic core regions of mammalian GPx sequences are conserved in the putative viral GPx (vGPx, encoded by the env-fs gene). Cells transfected with an HIV-1 env-fs construct show up to a 100% increase in GPx enzyme activity, and are protected against the loss of mitochondrial transmembrane potential and subsequent cell death induced by exogenous oxidants or mitochondrial reactive oxygen species. An intact vGPx gene was observed to be more common in HIV-1-infected long-term non-progressors, as compared to HIV-1 isolates from patients developing AIDS. An antioxidant/antiapoptotic protective role of the vGPx is also consistent with the observation that -1 frameshifting induced by the HIV-1 env-fs sequence AAAAAGA (which contains a potential "hungry" arginine codon, AGA) increases during arginine deficiency, which has been associated with increased oxidative stress. Under arginine-limited conditions, nitric oxide synthase generates superoxide, which rapidly combines with NO to form peroxynitrite, which can cause activated T-cells to undergo apoptosis. Thus, biosynthesis of the HIV-1 GPx as an adaptive response to low arginine conditions might delay oxidant-induced apoptotic cell death, providing an enhanced opportunity for viral replication.
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PMID:Functional studies of an HIV-1 encoded glutathione peroxidase. 1701 67

HIV-1 proteins, especially gp120 and Tat, elicit reactive oxygen species (ROS) and cause neuron apoptosis. We used antioxidant enzymes, Cu/Zn superoxide dismutase (SOD1) and glutathione peroxidase (GPx1) to study signaling and neuroprotection from Tat-induced apoptosis. SOD1 converts superoxide to peroxide; GPx1 converts peroxide to water. Primary human neurons were transduced with SV40-derived vectors carrying SOD1 and GPx1, then HIV-1 Tat protein was added. Both SV(SOD1) and SV(GPx1) delivered substantial transgene expression. Tat decreased endogenous cellular, but not transduced, SOD1 and GPx1. Tat rapidly increased neuron [Ca(2+)](i), which effect was not altered by SV(SOD1) or SV(GPx1). However, both vectors together blocked Tat-induced [Ca(2+)](i) fluxes. Similarly, neither SV(SOD1) nor SV(GPx1) protected neurons from Tat-induced apoptosis, but both vectors together did. Tat therefore activates multiple signaling pathways, in one of which superoxide acts as an intermediate while the other utilizes peroxide. Gene delivery to protect neurons from Tat must therefore target both.
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PMID:Preventing HIV-1 Tat-induced neuronal apoptosis using antioxidant enzymes: mechanistic and therapeutic implications. 1733 61

Human immunodeficiency virus-1 (HIV-1) is the most frequent cause of dementia in adults under 40. We sought to use gene delivery to protect from HIV-1-related neuron loss. Because HIV-1 envelope (Env) gp120 elicits oxidant stress and apoptosis in cultured neurons, we established reproducible parameters of Env-mediated neurotoxicity in vivo, then tested neuroprotection using gene delivery of antioxidant enzymes. We injected 100-500 ng mul(-1)gp120 stereotaxically into rat caudate-putamens (CP) and assayed brains for apoptosis by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) 6-h to 14-day post-injection. Peak apoptosis occurred 1 day after injection of 250 and 500 ng microl(-1)gp120. TUNEL-positive cells mostly expressed neuronal markers (NeuroTrace), although some expressed CD68 and so were most likely microglial cells. Finally, we compared neuroprotection from gp120-induced apoptosis provided by localized and generalized intra-central nervous system (CNS) gene delivery. Recombinant SV40 vectors carrying Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) were injected into the CP, where gp120 was administered 4-24 weeks later. Alternatively, we inoculated the vector into the lateral ventricle (LV), with or without prior intraperitoneal (i.p.) administration of mannitol. Intracerebral injection of SV(SOD1) or SV(GPx1) significantly protected neurons from gp120-induced apoptosis throughout the 24-week study. Intraventricular vector administration protected from gp120 neurotoxicity comparably, particularly if preceded by mannitol i.p. Thus, HIV-1 gp120 is neurotoxic in vivo, and intracerebral or intra-ventricular administration of rSV40 vectors carrying antioxidant enzymes is neuroprotective. These findings suggest the potential utility of both localized and widespread gene delivery in treating neuroAIDS and other CNS diseases characterized by excessive oxidative stress.
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PMID:Protecting neurons from HIV-1 gp120-induced oxidant stress using both localized intracerebral and generalized intraventricular administration of antioxidant enzymes delivered by SV40-derived vectors. 1791 6

A homeostatic balance exists between the cellular generation of oxidant species and endogenous antioxidants under normal physiological conditions. Human Immunodeficiency Virus (HIV) infection is known to affect this balance causing oxidative stress. However, the interaction of HIV infection with a substance abuse on cellular oxidant/antioxidant system is sparse. This study was designed in order to investigate the interactive effect of morphine abuse and Simian Immunodeficiency Virus/ Simian Human Immunodeficiency Virus (SIV/SHIV) infection on plasma oxidant/antioxidant balance in rhesus macaques. Six rhesus macaques adapted to morphine dependence (20 weeks) along with three controls were infected with mixture of SHIV(KU-1B), SHIV(89.6P), and SIV(17E-Fr). Plasma samples from morphine-dependent and control macaques were analyzed for an array of oxidative stress indices after 16 weeks of infection. Morphine-dependence significantly increased plasma malondialdehyde (MDA) and 8-isoprostane levels (8-fold and 2-fold), but these animals showed higher MDA and 8-isoprostane levels after viral infection (18-fold and 4-fold) which was directly correlated with increase in viral load and decline in CD4+ cells. Plasma glutathione (GSH) level depleted (55%) with morphine dependence that was further depleted (25%) by the infection. Activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were increased by 30% and 110%, respectively with morphine dependence, but that was decreased by the infection. Catalase (CAT) activity declined (25%) with morphine dependence that was further declined by infection. Our results clearly suggest that morphine interaction with SIV/SHIV infection causes higher oxidative tissue injury that might have implication in the pathogenesis of AIDS in morphine-dependent macaques.
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PMID:Interaction of SIV/SHIV infection and morphine on plasma oxidant/antioxidant balance in macaque. 1793


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