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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In primate cells, assembly of a single HIV-1 capsid involves multimerization of thousands of Gag polypeptides, typically at the plasma membrane. Although studies support a model in which HIV-1 assembly proceeds through complexes containing Gag and the cellular adenosine triphosphatase ABCE1 (also termed HP68 or ribonuclease L inhibitor), whether these complexes constitute true assembly intermediates remains controversial. Here we demonstrate by pulse labeling in primate cells that a population of Gag associates with endogenous ABCE1 within minutes of translation. In the next approximately 2 h, Gag-ABCE1 complexes increase in size to approximately that of immature capsids. Dissociation of ABCE1 from Gag correlates closely with Gag processing during virion maturation and occurs much less efficiently when the HIV-1 protease is inactivated. Finally, quantitative double-label immunogold electron microscopy reveals that ABCE1 is recruited to sites of assembling wild-type Gag at the plasma membrane but not to sites of an assembly-defective Gag mutant at the plasma membrane. Together these findings demonstrate that a population of Gag present at plasma membrane sites of assembly associates with ABCE1 throughout capsid formation until the onset of virus maturation, which is then followed by virus release. Moreover, the data suggest a linkage between Gag-ABCE1 dissociation and subsequent events of virion production.
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PMID:Host ABCE1 is at plasma membrane HIV assembly sites and its dissociation from Gag is linked to subsequent events of virus production. 1723 57

Human immunodeficiency virus type 1 (HIV-1) carries a variety of host proteins in addition to virus-encoded structural proteins, both in its envelope and inside the viral particle. Previous studies have reported that the HIV-1 life-cycle is affected by such virus-associated host cell surface proteins. The nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), also known as CD39, is a plasma membrane-bound ectoenzyme that hydrolyzes extracellular ATP and ADP to AMP. It has been shown that CD39 inhibits platelet function, and is thus a critical thromboregulatory molecule. We demonstrate here that host-derived CD39 is acquired by both laboratory-adapted and clinical variants of HIV-1 produced in cellular reservoirs of the virus. Moreover, purified CD39-bearing virions, but not isogenic viruses lacking CD39, display strong ATPase and ADPase activities. It is of particular interest that virions bearing this cellular enzyme can inhibit ADP-induced platelet aggregation, an effect blocked by an NTPDase inhibitor. On the basis of published and the present data on the functionality of human cellular proteins embedded within HIV-1, it can be proposed that these proteins might contribute to some of the immunologic deficiencies seen in infected individuals.
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PMID:The nucleoside triphosphate diphosphohydrolase-1/CD39 is incorporated into human immunodeficiency type 1 particles, where it remains biologically active. 1756 Jun 7

Ligand regulated localization controllable protein constructs were optimized in this study. Several constructs were made from a classical nuclear export signal (HIV-rev, MAPKK, or progesterone receptor) in combination with a SV40 T-antigen type nuclear import signal. Different ligand binding domains (LBDs from glucocorticoid receptor or progesterone receptor) were also tested for their ability to impart control over localization of proteins. This study was designed to create constructs which are cytoplasmic in the absence of ligand and nuclear in the presence of ligand, and also to regulate the amount of protein translocating to the nucleus on ligand induction. The balance between the strengths of import and export signals was critical for overall localization of proteins. The amount of protein entering the nucleus was also affected by the dose of ligand (10-100 nM). However, the overall import characteristics were determined by the strengths of localization signals and the inherent localization properties of the LBD used. This study established that the amount of protein present in a particular compartment can be regulated by the use of localization signals of various strengths. These optimized localization controllable protein constructs can be used to correct for diseases due to aberrant localization of proteins.
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PMID:Optimizing the protein switch: altering nuclear import and export signals, and ligand binding domain. 1757 89

We have made adamantylGSLs by substituting the fatty acids of primarily, globotriaosyl ceramide(Gb(3)) and sulfogalactosyl ceramide(SGC), with the rigid alpha-adamantane hydrocarbon frame. These analogues have proven to be remarkably water-soluble but retain the receptor function of the parent membrane GSL. AdaGb(3) prevents the binding of verotoxins to target cells but increased pathology in vivo, likely due to the partitioning into receptor negative target cells to provide pseudo-receptors. Preincubation of HIV with adaGb(3) prevents cellular infection in vitro and viral-host cell fusion. Cellular accumulation of Gb(3) reduces HIV susceptibility in vitro, whereas lack of Gb(3) promotes infection, suggesting that Gb(3) expression could be a novel risk factor for HIV susceptibility. AdaGb(3) has proven to be a new inhibitor for the MDR1 drug pump (P-glycoprotein) and can reverse drug resistance in cell culture. AdaSGC is bound by hsp70/hsc70 within the N-terminal ATPase domain and inhibits chaperone function. When added to cells transfected with the DeltaF508 CFTR mutant, adaSGC was able to decrease ER degradation of this mutant protein, an hsc70 dependent process. Our finding that DeltaF508 CFTR expressing cells show reduced SGC biosynthesis suggests that SGC could be an additional natural regulator of the hsp70 chaperone ATPase cycle.
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PMID:The medium is the message: glycosphingolipids and their soluble analogues. 1802

The maintenance of pH homeostasis in the CNS is of key importance for proper execution and regulation of neurotransmission, and deviations from this homeostasis are a crucial factor in the mechanism underlying a spectrum of pathological conditions. The first few sections of the review are devoted to the brain operating under normal conditions. The article commences with an overview of how extrinsic factors modelling the brain at work: neurotransmitters, depolarising stimuli (potassium and voltage changes) and cyclic nucleotides as major signal transducing vehicles affect pH in the CNS. Further, consequences of pH alterations on the major aspects of CNS function and metabolism are outlined. Next, the major cellular events involved in the transport, sequestration, metabolic production and buffering of protons that are common to all the mammalian cells, including the CNS cells. Since CNS function reflects tight interaction between astrocytes and neurons, the pH regulatory events pertinent to either cell type are discussed: overwhelming evidence implicates astrocytes as a key player in pH homeostasis in the brain. The different classes of membrane proteins involved in proton shuttling are listed and their mechanisms of action are given. These include: the Na+/H+ exchanger, different classes of bicarbonate transporters acting in a sodium-dependent- or -independent mode, monocarboxylic acid transporters and the vacuolar-type proton ATPase. A separate section is devoted to carbonic anhydrase, which is represented by multiple isoenzymes capable of pH buffering both in the cell interior and in the extracellular space. Next, impairment of pH regulation and compensatory responses occurring in brain affected by different pathologies: hypoxia/ischemia, epilepsy, hyperammonemic encephalopathies, cerebral tumours and HIV will be described. The review is limited to facts and plausible hypotheses pertaining to phenomena directly involved in pH regulation: changes in pH that accompany metabolic stress but have no distinct implications for the pH regulatory mechanisms are not dealt with. In most cases, the vast body of knowledge derived from in vitro studies remains to be verified in in vivo settings.
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PMID:Regulation of pH in the mammalian central nervous system under normal and pathological conditions: facts and hypotheses. 1806 8

The HIV-1 ribonucleoprotein (RNP) contains the major structural protein, pr55(Gag), viral genomic RNA, as well as the host protein, Staufen1. In this report, we show that the nonsense-mediated decay (NMD) factor UPF1 is also a component of the HIV-1 RNP. We investigated the role of UPF1 in HIV-1-expressing cells. Depletion of UPF1 by siRNA resulted in a dramatic reduction in steady-state HIV-1 RNA and pr55(Gag). Pr55(Gag) synthesis, but not the cognate genomic RNA, was efficiently rescued by expression of an siRNA-insensitive UPF1, demonstrating that UPF1 positively influences HIV-1 RNA translatability. Conversely, overexpression of UPF1 led to a dramatic up-regulation of HIV-1 expression at the RNA and protein synthesis levels. The effects of UPF1 on HIV-1 RNA stability were observed in the nucleus and cytoplasm and required ongoing translation. We also demonstrate that the effects exerted by UPF1 on HIV-1 expression were dependent on its ATPase activity, but were separable from its role in NMD and did not require interaction with UPF2.
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PMID:Unexpected roles for UPF1 in HIV-1 RNA metabolism and translation. 1836 87

The objective was to examine the influence of Pluronic block-copolymers on the interaction between the drug efflux transporter, P-glycoprotein and HIV-1 protease inhibitors (PIs). The ATPase assay determined the effect of various Pluronics on PI-stimulated P-gp ATPase activity. Cellular accumulation studies were conducted using MDCKII and LLC-PK1 cells transfected with human MDR1 to assess Pluronic modulation of PI efflux. Pluronic P85 inhibited both basal and nelfinavir-stimulated P-gp ATPase activity, while Pluronic F127 had no effect. In cell accumulation studies, Pluronic P85 restored the accumulation of nelfinavir in MDCKII-MDR1 cells while Pluronic F127 and F88 had no effect. Pluronic P85 increased saquinavir accumulation in wild-type and MDR1-transfected cells in both the MDCKII and LLC-PK1 cell models, suggesting inhibition of multiple transporters, including MRPs. In conclusion, this study provides evidence that a block-copolymer, Pluronic P85, effectively inhibits the interaction of P-gp with nelfinavir and saquinavir. These data indicate that effective inhibition of HIV-1 PI efflux by Pluronic P85 may influence the distribution of antiretroviral agents to sites protected by efflux mechanisms, such as the blood-brain barrier, and possibly increase the brain exposure of these drugs resulting in suppression of viral replication and reduction in the incidence of drug resistant mutants.
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PMID:Interactions of pluronic block copolymers on P-gp efflux activity: experience with HIV-1 protease inhibitors. 1839 90

Members of the Nedd4 family of E3 ubiquitin ligases bind the L domain in avian sarcoma virus (ASV) Gag and facilitate viral particle release. Translational fusion of ASV Gag with an L domain deletion (Deltap2b) to proteins that comprise ESCRT-I, -II, and -III (the endocytic sorting complexes required for transport) rescued both Gag ubiquitination and particle release from cells. The ESCRT-I factors Vps37C or Tsg101 were more effective in rescue of Gag/Deltap2b budding than the ESCRT-II factor Eap20 or the ESCRT-III component CHMP6. Thus ESCRT components can substitute for Nedd4 family members in ASV Gag release. Unlike wild type, ASV Gag/Deltap2b -ESCRT chimeras failed to co-immunoprecipitate with co-expressed hemagglutinin-tagged Nedd4, indicating that Nedd4 was not stably associated with these Gag fusions. Release of the Gag-ESCRT-I or -II fusions was inhibited by a dominant negative mutant of Vps4 ATPase similar to wild type ASV Gag. In contrast to ASV Gag, HIV-1 Gag containing an L domain inactivating mutation (P7L) was efficiently rescued by fusion to a component of ESCRT-III (Chmp6) but not ESCRT-II (Eap20). Depletion of the endogenous pool of Eap20 (ESCRT-II) had little effect on HIV-1 Gag release but blocked ASV Gag release. In contrast, depletion of the endogenous pool of Vps37C (ESCRT-I) had little effect on ASV but blocked HIV-1 Gag release. Furthermore, an N-terminal fragment of Chmp6 inhibited both HIV-1 and ASV Gag release in a dominant negative manner. Taken together, these results indicate that ASV and HIV-1 Gag utilize different combinations of ESCRT proteins to facilitate the budding process, although they share some common elements.
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PMID:Avian sarcoma virus and human immunodeficiency virus, type 1 use different subsets of ESCRT proteins to facilitate the budding process. 1872 11

HIV-1 replication has been inhibited by using a compound able to target the human cellular cofactor DEAD-box ATPase DDX3, essential for HIV-1 RNA nuclear export. This compound, identified by means of a computational protocol based on pharmacophoric modeling and molecular docking calculations, represents the first small molecule with such a mechanism of action and could lay the foundations for a pioneering approach for the treatment of HIV-1 infections.
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PMID:Pharmacophore modeling and molecular docking led to the discovery of inhibitors of human immunodeficiency virus-1 replication targeting the human cellular aspartic acid-glutamic acid-alanine-aspartic acid box polypeptide 3. 1883 10

The ESCRT (endosomal sorting complexes required for transport) pathway functions in vesicle formation at the multivesicular body, the budding of enveloped RNA viruses such as HIV-1, and the final abscission stage of cytokinesis. As the only known enzyme in the ESCRT pathway, the AAA ATPase (ATPase associated with diverse cellular activities) Vps4 provides the energy required for multiple rounds of vesicle formation. Like other Vps4 proteins, yeast Vps4 cycles through two states: a catalytically inactive disassembled state that we show here is a dimer and a catalytically active higher-order assembly that we have modeled as a dodecamer composed of two stacked hexameric rings. We also report crystal structures of yeast Vps4 proteins in the apo- and ATPgammaS [adenosine 5'-O-(3-thiotriphosphate)]-bound states. In both cases, Vps4 subunits assembled into continuous helices with 6-fold screw axes that are analogous to helices seen previously in other Vps4 crystal forms. The helices are stabilized by extensive interactions between the large and small AAA ATPase domains of adjacent Vps4 subunits, suggesting that these contact surfaces may be used to build both the catalytically active dodecamer and catalytically inactive dimer. Consistent with this model, we have identified interface mutants that specifically inhibit Vps4 dimerization, dodecamerization, or both. Thus, the Vps4 dimer and dodecamer likely form distinct but overlapping interfaces. Finally, our structural studies have allowed us to model the conformation of a conserved loop (pore loop 2) that is predicted to form an arginine-rich pore at the center of one of the Vps4 hexameric rings. Our mutational analyses demonstrate that pore loop 2 residues Arg241 and Arg251 are required for efficient HIV-1 budding, thereby supporting a role for this "arginine collar" in Vps4 function.
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PMID:Biochemical and structural studies of yeast Vps4 oligomerization. 1892 72


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