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)

Full-sized gen vif of human immunodeficiency virus has been synthesized and cloned into plasmid pGEX-2T. Vif-gene expression was found in Escherichia coli cells resulting in production of a hybrid GST-protein. The recombinant protein studied by the immunoblotting technique reacted with 8 of 22 probes of human HIV-positive sera. The recombinant protein is specifically cut by thrombin in two proteins corresponding to GST and VIF-proteins in molecular mass.
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PMID:[Expression of the vif gene of human immunodeficiency virus type 1 in Escherichia coli and study of the immunoreactivity of the vif protein]. 828 43

We have cloned and expressed HIV-1 gag p15 nucleocapsid protein (NCp15) in the form of a 41-kDa fusion polypeptide with glutathione-S-transferase (GST-NCp). The recombinant protein was rapidly degraded in bacterial lysates unless Zn2+ and Cd2+ were present in the extraction buffer. Inclusion of these metals stabilized the protein, allowing facile purification of GST-NCp by affinity chromatography. The native NCp15 was readily prepared from GST-NCp by proteolytic cleavage with thrombin. Both GST-NCp and the processed NCp15 were able to bind RNA containing sequences from the 5'-end of the HIV-1 genome. This binding was unaffected by the absence or the presence of Zn2+; however, the binding of RNA was absolutely dependent on the presence of K+. The GST-NCp fusion protein was nonselective in the binding of RNA, with all transcripts, including antisense and non-HIV RNA, binding with equal efficiency. In contrast, NCp15 was highly selective in binding of RNA. Sequences within nucleotides 1244-1412 of the HIV-1 proviral genome were found necessary for maximal binding of RNA to NCp15.
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PMID:Expression, purification, and RNA-binding properties of HIV-1 p15gag nucleocapsid protein. 837 99

It has been suggested that the V3 domain of human immunodeficiency virus type 1 (HIV-1) isolates has to interact with a cell-surface-associated or endosomal proteinase during virus entry into susceptible cells. To investigate this hypothesis, we examined the effect of several mutations in the V3 loop on its susceptibility to proteolytic cleavage by thrombin and cathepsin E and compared it with the effect of these mutations on viral infectivity. The data obtained indicate that, if an interaction between the V3 loop and a proteinase is indeed crucial for viral entry, the substrate requirements for such a proteinase(s) would have to be very complex. In particular, it seems unlikely that a single enzyme with a unique specificity would be able to interact with all of the different HIV-1 and HIV-2/SIV strains isolated so far. Therefore, one would have to postulate the involvement of several cellular proteinases, or proteases with multiple specificities, in V3-based viral tropism.
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PMID:Effect of mutations in the V3 loop of HIV-1 gp120 on infectivity and susceptibility to proteolytic cleavage. 845 83

We have studied perturbation of the gp120/gp41 envelope complex of HIV-1 in the presence of the mannose-specific lectin succinyl Con A (SC) and compared the effect with that observed in the presence of soluble CD4 (sCD4). SC did not inhibit the binding of gp120 to CD4. Both sCD4 and SC inhibited syncytium formation induced by HIV-1-infected Molt3/HIV-1IIIB cells. The infectivity of HIV-1 was markedly reduced when the virions were preincubated with SC or when SC was mixed simultaneously with virus and cells. The conformation of gp120 was altered in the presence of SC as evidenced by an increased susceptibility of the principal neutralizing epitope (V3 loop) to thrombin digestion. SC treatment of [35S]-methionine-labeled virions derived from Molt3/HIV-1IIIB cells resulted in the dissociation of gp120 from the viral membrane. The effect was less pronounced than that observed with sCD4. These results suggest that although interacting with different regions of gp120, the mannose-specific lectin alters the conformation of the glycoprotein in a manner similar to that induced by sCD4, causing destabilization of the gp120/gp41 complex.
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PMID:Conformational perturbation of the envelope glycoprotein gp120 of human immunodeficiency virus type 1 by soluble CD4 and the lectin succinyl Con A. 850 88

Inflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma are increased in sera and lesions of Kaposi's sarcoma (KS) patients. Previous data have indicated that the combination of these cytokines as found in conditioned media from activated T cells induces normal endothelial cells to acquire the features of KS spindle cells (KS cells) including spindle morphology, marker expression, and the responsiveness to the effects of HIV-1 Tat protein. Conditioned media from activated T cells or the single cytokines also induce AIDS-KS cells to produce and release basic fibroblast growth factor (bFGF). bFGF is highly expressed also by in situ KS cells and mediates KS-like lesion formation after inoculation of the cells in nude mice. Here we show that both large and small vessel endothelial cells chronically exposed to inflammatory cytokines produce and release bioactive bFGF in the absence of cell death. In addition, after this treatment, endothelial cells acquire angiogenic capability and induce KS-like lesions after inoculation in nude mice. Production and release of bFGF is induced in a synergistic fashion by TNF-alpha, IL-1beta, and IFN-gamma, and its release is further promoted by low cell density and by the serine proteases plasmin and thrombin. These results indicate that inflammatory cytokines induce endothelial cells to export bFGF and to acquire angiogenic properties, a key feature of the KS cell phenotype, and suggest a mechanism by which these cytokines can cooperate in the induction of KS.
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PMID:Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi's sarcoma-like lesions in nude mice. 902 30

Previously, we have described inhibition of HIV-1 infection by T30177, 5'-(GTGGTGGGTGGGTGGGT)-3', an oligonucleotide that is a potent inhibitor of HIV-1 integrase in vitro (Mazumder et al. (1996) Biochemistry 35, 13762). Here a family of oligonucleotides, analogs of T30177, has been studied. On the basis of thermal denaturation, we show that a folded structure of T30177 is much more stable than that of the thrombin binding aptamer, which only differs with T30177 in the loop sequence. Sequence changes reveal that loop interactions are solely responsible for this observed stability difference. In the presence of K+ ion, the fold of T30695, a designed 16mer derivative, is indeed more stable than T30177. Loop folding within T30695 is very ion selective. Quantitative analysis of thermal denaturation suggests that the loops of T30695, 5'-(GGGTGGGTGGGTGGGT)-3', and T30177 confer the ability to coordinate three equivalents of K+ ion (one bound to the core octet and two bound to the loops); however, the thrombin binding aptamer is shown to bind only one K+ equivalent. Folding kinetics and CD titration demonstrate that K+-induced folding of T30695 and T30177 is a two-step process, consistent with a sequential model in which a first equivalent of K+ binds to the octet core, followed by slow K+-induced rearrangement of the loop domains. Comparing structural stability with the capacity of the folded oligomers to inhibit the HIV-1 integrase enzyme in vitro or HIV-1 infection in cell culture, we have found that the folding and activity data are highly correlated, suggesting that formation of an orderly, ion-coordinated loop structure similar to that in T30177 or T30695 may be a prerequisite for both integrase inhibition and anti-HIV-1 activity.
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PMID:Ion selective folding of loop domains in a potent anti-HIV oligonucleotide. 937 54

The influence of HIV Env glycosylation on the conformation of the third variable domain (V3) of Env was studied by both deglycosylation of mature Env and the use of Env produced by recombinant systems in which alpha-glucosidase activity was inhibited by either deoxynojirimycin (DNM) or mutation. Selective deglycosylation affected anti-V3 antibody binding. The immunoreactivity and sensitivity to thrombin cleavage of V3 presented on Env produced in baby hamster kidney cells were changed by DNM treatment. In contrast, Env expressed in alpha-glucosidase I-deficient Chinese hamster ovary cells or in their parental cells treated by DNM fully retained these V3 properties. These results are discussed in relation to the inconsistent data obtained on V3 property changes resulting from Env glycosylation changes.
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PMID:Effect of changes in the glycosylation of the human immunodeficiency virus type 1 envelope on the immunoreactivity and sensitivity to thrombin of its third variable domain. 945 27

Major discoveries have been made of new type-I and type-III peptidomimetic inhibitors of peptide-derived systems. Innovative reversible inhibitors of cysteine proteases and renin, and additional examples of peptidomimetic inhibitors of interleukin-1 beta-converting enzyme, neutral endopeptidase, herpes simplex virus protease, thrombin, HIV protease, Ras farnesyltransferase, the RGD motif, Factor Xa and various aspartic proteases have been discovered.
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PMID:Peptidomimetic design. 973 16

Various coagulation abnormalities were reported in HIV-infected patients. Cases of severe thrombocytopenia were first observed in contaminated homosexual males, as well as prolonged APTT due to the presence of lupus-like anticoagulant with a frequency in the range 8 to 70% of the studied patients. Even if lupus anticoagulant could be evidenced in asymptomatic patients, it frequently occurred during acute opportunistic infections such as Pneumocystis carinii. More recently, increased prevalence of protein S and heparin cofactor II deficiency, two physiological coagulation inhibitors were demonstrated in HIV-infected patients. The same applied for hypoalbuminemia-related fibrin polymerization defects which induced prolonged thrombin and reptilase clotting times. Abnormalities of the fibrinolytic system were also reported, such as increased levels of both tissue-type plasminogen activator and type 1 plasminogen activator inhibitor or decreased levels of histidine-rich glycoprotein. Even if the acute phase response could play a key-role, the pathogenesis of these abnormalities is not fully understood, so far. In addition, their clinical consequences have not been extensively investigated, but hemorrhage appeared to be uncommon. Moreover, D-dimer levels were found increased in HIV-infected patients, suggesting that HIV-infection might be associated with a so-called prethrombotic state, which could lead to clinical thrombosis in some HIV-infected patients (2%).
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PMID:[Hemostasis and human immunodeficiency virus (HIV) infection]. 975 40

If no structural information about a particular target protein is available, methods of rational drug design try to superimpose putative ligands with a given reference, e.g., an endogenous ligand. The goal of such structural alignments is, on the one hand, to approximate the binding geometry and, on the other hand, to provide a relative ranking of the ligands with respect to their similarity. An accurate superposition is the prerequisite of subsequent exploitation of ligand data by either 3D QSAR analyses, pharmacophore hypotheses, or receptor modeling. We present the automatic method FLEXS for structurally superimposing pairs of ligands, approximating their putative binding site geometry. One of the ligands is treated as flexible, while the other one, used as a reference, is kept rigid. FLEXS is an incremental construction procedure. The molecules to be superimposed are partitioned into fragments. Starting with placements of a selected anchor fragment, computed by two alternative approaches, the remaining fragments are added iteratively. At each step, flexibility is considered by allowing the respective added fragment to adopt a discrete set of conformations. The mean computing time per test case is about 1:30 min on a common-day workstation. FLEXS is fast enough to be used as a tool for virtual ligand screening. A database of typical drug molecules has been screened for potential fibrinogen receptor antagonists. FLEXS is capable of retrieving all ligands assigned to platelet aggregation properties among the first 20 hits. Furthermore, the program suggests additional interesting candidates, likely to be active at the same receptor. FLEXS proves to be superior to commonly used retrieval techniques based on 2D fingerprint similarities. The accuracy of computed superpositions determines the relevance of subsequently performed ligand analyses. In order to validate the quality of FLEXS alignments, we attempted to reproduce a set of 284 mutual superpositions derived from experimental data on 76 protein-ligand complexes of 14 proteins. The ligands considered cover the whole range of drug-size molecules from 18 to 158 atoms (PDB codes: 3ptb, 2er7). The performance of the algorithm critically depends on the sizes of the molecules to be superimposed. The limitations are clearly demonstrated with large peptidic inhibitors in the HIV and the endothiapepsin data set. Problems also occur in the presence of multiple binding modes (e.g., elastase and human rhinovirus). The most convincing results are achieved with small- and medium-sized molecules (as, e.g., the ligands of trypsin, thrombin, and dihydrofolate reductase). In more than half of the entire test set, we achieve rms deviations between computed and observed alignment of below 1.5 A. This underlines the reliability of FLEXS-generated alignments.
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PMID:FLEXS: a method for fast flexible ligand superposition. 980 90


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