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)

Binding of human immunodeficiency virus type 1 (HIV-1) transactivator (Tat) protein to Tat-responsive RNA (TAR) is essential for viral replication and is considered a promising starting point for the design of anti-HIV drugs. NMR spectroscopy indicated that the aminoglycosides neomycin B and ribostamycin bind to TAR and that neomycin is able to inhibit Tat binding to TAR. The solution structure of the neomycin-bound TAR has been determined by NMR spectroscopy. Chemical shift mapping and intermolecular nuclear Overhauser effects define the binding region of the aminoglycosides on TAR and give strong evidence for minor groove binding. Based on 15 nuclear Overhauser effect-derived intermolecular distance restraints, a model structure of the TAR-neomycin complex was calculated. Neomycin is bound in a binding pocket formed by the minor groove of the lower stem and the uridine-rich bulge of TAR, which adopts a conformation different from those known. The neamine core of the aminoglycoside (rings I and II) is covered with the bulge, explaining the inhibition of Tat by an allosteric mechanism. Neomycin reduces the volume of the major groove in which Tat is bound and thus impedes essential protein-RNA contacts.
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PMID:Structural rearrangements of HIV-1 Tat-responsive RNA upon binding of neomycin B. 1074 64

Human TIP30 is a cofactor that specifically enhances human immunodeficiency virus-1 (HIV-1) Tat-activated transcription. The sequence of TIP30 is identical to that of CC3, a protein associated with metastasis suppression. TIP30/CC3 is a member of the short-chain dehydrogenases/reductases (SDR) family. Of the several experimentally determined SDR structures, Escherichia coli uridine diphosphate (UDP) galactose-4 epimerase is most similar to TIP30/CC3. Because the direct sequence similarity between TIP30/CC3 and E. coli UDP galactose-4 epimerase is low, we used the transitive nature of homology and employed two Aquifex aeolicus proteins as intermediaries in the homology modeling process. Comparison of our structural model with that of known SDRs reveals that TIP30/CC3 contains several well-conserved features, including a beta alpha beta fold at the amino terminus, which we predict binds NADP(H). TIP30/CC3 contains characteristic motifs at the catalytic site of SDRs, including a serine, tyrosine, and lysine that are important in catalyzing hydride transfer between substrate and cofactor. We also predict that a unique 20-amino acid sequence found at the amino terminus is an alpha-helix. Because this region contains several positively and negatively charged amino acids, it may dock TIP30/CC3 to other proteins. Our structural model points to this alpha-helix and the SDR-like part of TIP30/CC3 for mutagenesis experiments to elucidate its role in HIV-1 Tat-activated transcription, metastasis suppression, and other cellular functions.
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PMID:Three-dimensional model of human TIP30, a coactivator for HIV-1 Tat-activated transcription, and CC3, a protein associated with metastasis suppression. 1089 49

The retroviral primary transcription product is a multifunctional RNA that is utilized as pre-mRNA, mRNA, and genomic RNA. The relationship between human immunodeficiency virus type 1 (HIV-1) unspliced transcripts used as mRNA for viral protein synthesis and as virion precursor RNA (vpRNA) for encapsidation remains an important question. We developed a biochemical assay to evaluate the hypothesis that prior utilization as mRNA template for protein synthesis is necessary to generate vpRNA. HIV-1-infected T cells were treated with translation inhibitors under conditions that maintain virus production. Immunoprecipitation of newly synthesized HIV-1 Gag protein revealed that de novo translation is not necessary to sustain assembly, release, or processing of Gag structural protein. Both newly synthesized protein and steady-state Gag are competent for assembly, and the extracellular accumulation of Gag is proportional to the intracellular abundance of Gag. As early as 2 h after transcription, newly synthesized RNA is detectable in cell-free virions and encapsidation is sustained upon inhibition of host cell translation. Results of both [(3)H]uridine incorporation assays and HIV-1-specific RNase protection assays (RPAs) indicate that translation inhibition reduces the absolute amounts of both cytoplasmic and virion-associated RNA. Evaluation of encapsidation efficiency by RPA revealed that the cytoplasmic availability of vpRNA is increased, indicating that HIV-1 unspliced mRNA can be rerouted to function as vpRNA. Our data contrast with results from the HIV-2 and murine leukemia virus systems and indicate that HIV-1 unspliced RNA constitutes a single functional pool that can function interchangeably as mRNA and as vpRNA.
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PMID:Translation is not required To generate virion precursor RNA in human immunodeficiency virus type 1-infected T cells. 1109 Jan 50

In the present study, one has determined the relative role of plasma membrane equilibrative (Na+-independent) ENT nucleoside transport proteins (particularly ENT2) in the uptake of antiviral nucleoside analogues for comparison with the previously reported drug transport properties of concentrative (Na+-dependent) CNT nucleoside transport proteins. The human and rat nucleoside transport proteins hENT1, rENT1, hENT2 and rENT2 were produced in Xenopus oocytes and investigated for their ability to transport three 3'-deoxy-nucleoside analogues, ddC (2'3'-dideoxycytidine), AZT (3'-azido-3'-deoxythymidine) and ddI (2'3'-dideoxyinosine), used in human immunodeficiency virus (HIV) therapy. The results show, for the first time, that the ENT2 transporter isoform represents a mechanism for cellular uptake of these clinically important nucleoside drugs. Recombinant h/rENT2 transported ddC, ddI and AZT, whilst h/rENT1 transported only ddC and ddI. Relative to uridine, h/rENT2 mediated substantially larger fluxes of ddC and ddI than h/rENT1. Transplanting the amino-terminal half of rENT2 into rENT1 rendered rENT1 transport-positive for AZT and enhanced the uptake of both ddC and ddI, identifying this region as a major site of 3'-deoxy-nucleoside drug interaction.
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PMID:Transport of antiviral 3'-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. 1146 8

As part of our on-going study of the analysis of anti-human immunodeficiency virus (HIV) nucleosides, a capillary electrochromatography (CEC) method has been developed for the concurrent analysis of nucleoside HIV reverse transcriptase inhibitors (NRTIs) in a pool of endogenous nucleosides. Up to now, beta-cyclodextrin-bonded silica stationary phases have mainly been dedicated to the separation of enantiomers; however, these polysaccharides can be also be used in achiral way. This work aims at showing how CEC performed on a beta-cyclodextrin-bonded silica stationary phase can be used to concurrently resolve zidovudine (AZT), lamivudine (3TC), didanosine (ddA) and its administrated form (ddI), stavudine (d4T) and hivid (ddC) in a mixture of adenosine (A), cytidine (C), guanosine (G), thymidine (T) and uridine (U). The influence of several parameters (pH buffer, ionic strength, acetonitrile content, temperature and voltage) on both the retention times and the retention factors has been investigated using the short-end injection technique to achieve baseline separation in a short-time analysis before quantitation. Moreover, the retention factors of the charged solutes in short-end injection-CEC were calculated using theoretically derived equations, allowing for the actual voltage drop in the packed section of the semipacked CEC capillary.
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PMID:Concurrent analysis of nucleoside reverse transcriptase inhibitors in a pool of endogenous nucleosides by short-end injection-capillary electrochromatography on a beta-cyclodextrin-bonded stationary phase. 1200 25

We have partially reconstituted 20S proteasome/RNA complexes using oligonucleotides corresponding to ARE (adenosine- and uridine-rich element) (AUUUA)4 and HIV-TAR (human immunodeficiency virus-Tat transactivation response element), a stem-loop structure in the 5' UTR (untranslated region) of HIV-mRNAs. We demonstrate that these RNAs which associate with proteasomes are degraded by proteasomal endonuclease activity. The formation of these 20S proteasome/RNA substrate complexes is rather specific since 20S proteasomes do not interfere with truncated TAR that is not cleaved by proteasomal endonuclease. In addition, affinity of proteasomes for (AUUUA)4 is much stronger as it is for HIV-TAR. These results provide further arguments for our hypothesis that proteasomes could be involved in the destabilisation of cytokines mRNAs containing AUUUA sequences as well as viral mRNAs.
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PMID:Substrate affinity and substrate specificity of proteasomes with RNase activity. 1268 29

For the simultaneously visual detection of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus type-1 (HIV-1), a qualitative DNA chip method, combining multiplex and nested polymerase chain reaction (PCR) with arrayed anchored primer PCR and a biotin-avidin alkaline phosphatase (Av-AP) indicator system, was developed. After pretreatment of infected blood samples and reverse transcription of the RNA virus genome, PCR was performed in a single tube by using the outer primer pairs. Second round nested multiplex PCR was performed on the DNA chip, on which the primers array had already been prepared. During the arrayed anchored multiplex PCR, 5[N-(N-biotinylaminocaproyl)-epsilon-3-aminoallyl]-2-deoxy-uridine-5-triphosphate (biotin-11-dUTP) was incorporated into the extended DNA chains in order to bind avidin alkaline phosphatase via avidin and biotin. To produce purple precipitates on the chips, the enzyme substrate 5-bromo-4-chloro-3-indolyl phosphate (BCIP) was used in conjunction with the enhancer, nitro blue tetrazolium (NBT). Blood samples containing the three viruses were tested using this DNA chip and about 1 pg of specific viral DNA fragments were detected on the chip wells after nested PCR.
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PMID:A visual DNA chip for simultaneous detection of hepatitis B virus, hepatitis C virus and human immunodeficiency virus type-1. 1470 86

Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) is poorly understood and innate immune receptors for ssRNA are unknown. We report that guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus-1 (HIV-1) stimulate dendritic cells (DC) and macrophages to secrete interferon-alpha and proinflammatory, as well as regulatory, cytokines. By using Toll-like receptor (TLR)-deficient mice and genetic complementation, we show that murine TLR7 and human TLR8 mediate species-specific recognition of GU-rich ssRNA. These data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8.
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PMID:Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. 1500 68

Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross-resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment-naive patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment-experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate-glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22-47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor-containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. John's wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once-daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.
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PMID:Atazanavir for the treatment of human immunodeficiency virus infection. 1558 41

Substrate properties of various morpholinonucleoside triphosphates in the reaction of DNA elongation catalyzed by DNA polymerase beta, reverse transcriptase of human immunodeficiency virus (HIV-1 RT), and reverse transcriptase of Moloney murine leukemia virus (M-MuLV RT) were compared. Morpholinonucleoside triphosphates were utilized by DNA polymerase beta and HIV-1 reverse transcriptase as substrates, which terminated further synthesis of DNA, but were virtually not utilized by M-MuLV reverse transcriptase. The kinetic parameters of morpholinoderivatives of cytosine (MorC) and uridine (MorU) were determined in the reaction of primer elongation catalyzed by DNA polymerase beta and HIV-1 reverse transcriptase. MorC was a more effective substrate of HIV-1 reverse transcriptase and significantly less effective substrate of DNA polymerase beta than MorU. The possible use of morpholinonucleoside triphosphates as selective inhibitors of HIV-1 reverse transcriptase is discussed.
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PMID:Analysis of interactions of DNA polymerase beta and reverse transcriptases of human immunodeficiency and mouse leukemia viruses with dNTP analogs containing a modified sugar residue. 1570 Oct 45


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