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)

Bovine immunodeficiency-like virus (BIV) is a recently identified lentivirus that infects cattle. The virus has structural and genetic similarities to human HIV. The present study demonstrates that BIV can be activated by bovine herpesvirus type 1 (BHV-1), a pathogen frequently associated with cattle diseases. Activation of BIV expression can be detected as increased BIV reverse transcriptase activity, increased in the number of syncytia induced by BIV, and increased in the steady state level of BIV-specific RNA upon BHV-1 super-infection. Additional transactivation studies using the BIV-LTR (long terminal repeat) were conducted. The BIV-LTR was linked to the chloramphenicol acetyl transferase gene (CAT) and transfected into bovine cell cultures in order to quantitate the levels of BIV-LTR expression. When the transfected cells were infected by BHV-1, there was an increase in CAT expression, indicating transactivation of the BIV-LTR by BHV-1. Most of the transactivation activities were abolished with an LTR construct that has deleted the NF-kappa B-like sequence located in the U3 region of the LTR. In order to further demonstrate that activation of the BIV-LTR involves factors that may bind to the LTR sequences, gel retardation assays were carried out using the BIV-LTR U3 region as probe. Our results showed that BHV-1 infection resulted in an induction of factor(s) that binds to the NF-kappa B-like sequence on the BIV-LTR. This suggests that transactivation of BIV by BHV-1 may be mediated by a bovine NF-kappa B-like protein that binds to the target sequence in the BIV promoter region.
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PMID:Activation of bovine immunodeficiency-like virus expression by bovine herpesvirus type 1. 131 80

Visna virus is a pathogenic lentivirus of sheep that is distantly related to the primate lentiviruses, including the human immunodeficiency virus type 1 (HIV-1). Replication of HIV-1 in cell culture requires the expression of a virus-encoded protein, Tat, which is a potent trans-activator of viral gene expression. Visna virus encodes an analogous Tat protein that greatly increases gene expression directed by the visna viral LTR. This report uses a stable vero cell line that constitutively expresses visna virus Tat to investigate the molecular mechanism of action of Tat on viral gene expression. Transient expression assays, using the visna virus LTR to drive transcription of the bacterial gene for chloramphenicol acetyltransferase (CAT), demonstrate that Tat trans-activates gene expression by increasing steady-state mRNA levels. The increase in steady-state mRNA levels is sufficient to account for the increase in protein observed and is due, in part, to an increase in the rate of transcription initiation. Tat mediates the accumulation of mRNA through AP-4 and AP-1 binding sites located in the U3 region of the LTR. Deletion of the upstream AP-1 and AP-4 binding sites results in a residual low level of trans-activation by Tat. Further experiments, using LTRs with R-U5 sequences deleted to +10, demonstrate AP-1 and AP-4 mediated responses to TAT at the RNA level, but no increase was observed in CAT protein.
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PMID:Molecular mechanisms of visna virus Tat: identification of the targets for transcriptional activation and evidence for a post-transcriptional effect. 131 69

We previously described the molecular cloning of a replication-defective variant of feline leukemia virus (FeLV) that induced fatal immunodeficiency in cats. Eighteen proviruses have now been molecularly cloned from cats inoculated with the original isolate (FeLV-FAIDS) or its in vivo passages. Three were replication-competent and each of these was noncytopathic for the feline T-cell line, 3201. Replication of the prototype, FeLV-61E, in cats was associated with development of T cell tumors in some cats. The remaining 15 proviruses were replication-defective, but each of six of these tested was found to be cytopathic for 3201 cells when rescued with the noncytopathic helper virus, 61E. Three defective/helper virus mixtures were inoculated into cats and all induced fatal immunodeficiency, but with varied efficiency and kinetics. Each of these virus mixtures was attenuated relative to a mixture containing 61E and the intestine-targeted, FeLV-FAIDS-61C prototype defective molecular clone. Furthermore, one replication-competent virus chimera generated using the envelope and LTR of the defective pathogenic variant was incapable of inducing viremia in cats. The observed differences in the biological activity between the defective viruses could be attributed to no more than 10 scattered amino acid changes in envelope and either one or two nucleotide changes in the LTR.
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PMID:Structure and pathogenicity of individual variants within an immunodeficiency disease-inducing isolate of FeLV. 131 74

The abnormal isoforms of the normal cellular prion protein (PrP), also termed Scrapie-associated fibril protein, are assumed to be one causative factor of spongiform encephalopathies. The mRNA of PrP contains stem-loop structures which are very similar to the human immunodeficiency virus-1 (HIV-1) cis-acting sequence TAR within the LTR; both structures contain the pentanucleotide CUGGG in the loop, and the uridine- and adenine-bulge in the stem. In this study, using purified HIV-encoded trans-activator, Tat, and HIV-1 TAR-RNA or PrP-mRNA containing the stem-loop structure, we demonstrate by use of gel-retardation and filter binding assays that Tat binds to TAR- and PrP-RNA with the dissociation constants of 2.9 or 37.0 nM, respectively, at a molar ratio of 0.7 mol of Tat to 1 mol of RNA fragment. The Tat-RNA (TAR or PrP) complexes bind to protein(s) in the nuclear matrix, isolated from human astrocytes (glial fibrillary acidic protein positive brain cells). Infection of astrocytes with HIV-1 resulted in an increased level of PrP mRNA. The data presented led us to assume that certain sequences in the PrP mRNA might be targets for proteins acting in trans.
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PMID:Accumulation of transcripts coding for prion protein in human astrocytes during infection with human immunodeficiency virus. 135 48

Quinolinic acid (QUIN) is an neurotoxic N-methyl-D-aspartate receptor agonist and an L-tryptophan metabolite of the kynurenine pathway. Increased concentrations of QUIN occur in both cerebrospinal fluid (CSF) and blood of patients infected with human immunodeficiency virus (HIV)-1, particularly those with neurologic disturbances. In the present study of HIV-1 infected patients in Walter Reed stages 4, 5 and 6, reductions in L-tryptophan accompanied proportional increases in L-kynurenine and QUIN in both serum and CSF. Further, close inter-correlations exist between QUIN kynurenic acid and L-kynurenine with both beta 2-microglobulin and neopterin in CSF and serum. These correlations support the hypotheses that the kynurenine pathway is activated in association with inflammation and induction of indoleamine-2,3-dioxygenase. There were no relationships between CSF QUIN, L-kynurenine or kynurenic acid with the ratio of serum:CSF albumin concentrations, which indicates that the increases in CSF QUIN, L-kynurenine or kynurenic acid were not dependent on a breakdown of the blood-brain barrier. Kynurenic acid is also a kynurenine pathway metabolite that can attenuate the excitotoxic effects of QUIN when present in higher molar concentrations. While CSF kynurenic acid levels were increased in HIV-1-infected patients, the magnitude of the increases were smaller than those of QUIN and the molar concentrations of kynurenic acid were consistently lower than QUIN by at least one order of magnitude. We conclude that immune activation increases the levels of neuroactive kynurenines within the central nervous system of HIV-1-infected patients secondary to activation of indoleamine-2,3-dioxygenase.
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PMID:Inter-relationships between quinolinic acid, neuroactive kynurenines, neopterin and beta 2-microglobulin in cerebrospinal fluid and serum of HIV-1-infected patients. 138 55

Ro 5-3335, 7-chloro-5-(2-pyrryl)-3H-1,4-benzo-diazepin-2-(H)-one, has been shown to inhibit gene expression controlled by the human immunodeficiency virus-1 (HIV-1) LTR promoter. The inhibition was specific for the viral transcriptional transactivator Tat. The compound did not inhibit the basal activity of the HIV-1 LTR or the activity of promoters not responsive to Tat. Consistent with its mode of action, Ro 5-3335 inhibited HIV-1 replication (IC50 = 0.1-1 microM) by reducing viral RNA synthesis in acutely, as well as chronically, infected cells in vitro. The compound was active against HIV-1 and HIV-2, and AZT-resistant clinical isolates.
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PMID:Discovery and characterization of an HIV-1 Tat antagonist. 139 54

The Epstein-Barr virus latent membrane protein (LMP) is an integral membrane protein that is expressed in cells latently infected with the virus. LMP is believed to play an important role in Epstein-Barr virus transformation and has been shown to induce expression of several cellular proteins. We performed a series of experiments that demonstrated that LMP is an efficient transactivator of expression from the human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR). Mutation or deletion of the NF-kappa B elements in the LTR abolished the transactivation, indicating that the LMP effect on HIV expression was due to induction of NF-kappa B activity. Experiments in which the HIV-1 Tat protein was coexpressed in cells together with LMP showed that Tat was able to potentiate the transactivation. Surprisingly, a synergistic effect of the two proteins was observed even in the absence of the recognized target region for Tat (TAR) in the HIV-1 LTR.
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PMID:Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-kappa B activity. 140

We have previously identified a T lymphocyte protein which binds to a site within the LTR of the human immunodeficiency virus type 1 (HIV-1) and exerts an inhibitory effect on virus gene expression. The palindromic site (site B) recognized by this protein is related to the palindromic binding sites of members of the steroid/thyroid hormone receptor family. Here we characterize the T cell protein binding to this site as a 100 kD protein which is most abundant in T cells and which binds to site B as a 200 kD complex. This protein is distinct from other members of the steroid/thyroid hormone receptor family including the COUP protein which has a closely related DNA binding specificity.
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PMID:Characterization of a novel T lymphocyte protein which binds to a site related to steroid/thyroid hormone receptor response elements in the negative regulatory sequence of the human immunodeficiency virus long terminal repeat. 143 60

We have shown that the interaction of pepstatin A with human immunodeficiency virus-1 protease (HIV-1 protease) can be characterized by a high-affinity mode (Ki = 478 +/- 27 nM), resulting in pure competitive inhibition of the hydrolytic activity of HIV-1 protease toward the fluorogenic substrate. Binding of pepstatin in this mode induces a blue shift in the endogenous fluorescence arising from the tryptophan residues in HIV-1 protease. This shift is maximal in the presence of 10 microM pepstatin. Haloperidol, in contrast, interacts with HIV-1 protease with weaker affinity (Ki = 19 +/- 1 microM) in a mode which results in pure noncompetitive inhibition of the hydrolytic activity of HIV-1 protease. Binding of haloperidol in this mode induces a red shift in the endogenous fluorescence arising from the tryptophan residues in HIV-1 protease. This shift is maximal in the presence of 200 microM haloperidol. Addition of both pepstatin and haloperidol at concentrations in the range of their Ki values results in additive inhibition of the hydrolytic activity of HIV-1 protease, as well as an additive effect on the tryptophan fluorescence of protease. However, at saturating concentrations of pepstatin and haloperidol, the effect of haloperidol was predominant, as measured by the changes in the intrinsic fluorescence of HIV-1 protease.
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PMID:Inhibitors of human immunodeficiency virus-1 protease. 149 58

Increased concentrations of the excitotoxin quinolinic acid (QUIN) have been implicated in the neurologic deficits and brain atrophy that may accompany infection with the human immunodeficiency virus type-1. Key neuropathologic features of the AIDS encephalitis are replicated in some macaques following infection with the simian immunodeficiency virus (SIV). In the present studies, cerebrospinal fluid (CSF) QUIN concentrations increased within 2 weeks following infection of 11 rhesus macaques (Macaca mulatta) with a neurotropic sooty mangabey isolate of the simian immunodeficiency virus (SIVsm) and were sustained to greater than 2 standard deviations above uninfected control macaques. Highest CSF QUIN concentrations (up to 400-fold above pre-inoculation levels) were observed in 6 SIVsm-infected macaques with motor and behavioral abnormalities during life, brain atrophy on MRI scan and inflammatory lesions within the brain and meninges. Four of the 6 neurologic macaques deteriorated rapidly within 12 weeks after inoculation and had substantially larger increases in CSF QUIN levels than 2 other neurologic macaques and 5 macaques without neurologic signs which survived for longer than 37 weeks. Increases in serum QUIN and CSF kynurenic acid also occurred but generally to a lesser degree than the increases in CSF QUIN. In some animals, increases in serum L-kynurenine concentrations and reductions in CSF and serum L-tryptophan occurred and were consistent with activation of indoleamine-2, 3-dioxygenase, the first enzyme of the kynurenine pathway in extrahepatic tissues. CSF QUIN exceeded serum QUIN in 8.8% of samples from macaques with neurologic signs, supporting increased QUIN synthesis within the central nervous system. Production of [13C6]QUIN was demonstrated in one SIVsm-infected macaque and one uninfected control macaque following an intracisternal injection of [13C6]L-tryptophan and suggests that L-tryptophan is a substrate for QUIN synthesis within the nervous system or meninges, although the cellular localization of QUIN synthesis remain to be determined. We conclude that increases in kynurenine pathway metabolism occur in SIV-infected macaques and are most prominent in macaques with neurologic signs. Macaques infected with SIV offer a model to investigate the relationship between the metabolism of neuroactive kynurenines and neurologic disturbances associated with retroviral infection.
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PMID:Relationship of neurologic status in macaques infected with the simian immunodeficiency virus to cerebrospinal fluid quinolinic acid and kynurenic acid. 153 32


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