Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purposes of this study were to map the targets for neutralizing Abs in the HIV-2 glycoproteins with particular emphasis on the role of the V3 region. Sera obtained from guinea pig immunized with peptides representing five immunogenic regions of the envelope proteins were used in cross-neutralization experiments with nine HIV-2 isolates. Broad cross-neutralizing activity was elicited by immunization with two peptides representing the central and COOH-terminal portions of the HIV-2 V3 loop. Murine mAbs were established from animals immunized with two corresponding overlapping peptides. Six mAbs showed neutralizing activity against the homologous virus isolate SBL-6669. Peptide absorption experiments were performed to define the target regions for human neutralizing Abs in the HIV-2 envelope glycoproteins. A significant blocking of neutralizing activity of five HIV-2 Ab-positive sera was seen in the presence of two peptides corresponding to the V3 region. Two overlapping deletion sets of peptides, representing amino acids Ser311 and Arg337, were used to identify the role of individual HIV-2 V3 amino acids in the binding of polyclonal and mAbs. Two distinct antigenic sites were identified in this region, the first corresponding to a region including the conserved motif Phe-His-Ser (amino acid 315-317) and the second in proximity of the COOH-terminal cysteine Trp-Cys-Arg (amino acid 329-331). Potentially these two sites can interact to represent a single discontinuous antigenic site. Taken together, these results indicate that V3 is an important neutralizing domain of HIV-2.
 ...
PMID:Two neutralizing domains in the V3 region in the envelope glycoprotein gp125 of HIV type 2. 812 Mar 99

The proteases expressed by the HIV-1 and HIV-2 viruses process the polyproteins encoded by the viral genomes into the mature proteins required for virion replication and assembly. Eight analogs of haloperidol have been synthesized that cause time-dependent inactivation of the HIV-1 protease and, in six cases, HIV-2 protease. The IC50 values for the analogues are comparable to that of haloperidol itself. Enzyme inactivation is due to the presence of an epoxide in two of the analogues and carbonyl-conjugated double or triple bonds in the others. Irreversible inactivation is confirmed by the failure to recover activity when one of the inhibitors is removed from the medium. At pH 8.0, the agents inactivate the HIV-1 protease 4-80 times more rapidly than the HIV-2 protease. Faster inactivation of the HIV-1 protease is consistent with alkylation of cysteine residues because the HIV-1 protease has four such residues whereas the HIV-2 protease has none. Inactivation of the HIV-2 protease requires modification of non-cysteine residues. The similarities in the rates of inactivation of the HIV-2 protease by six agents that have intrinsically different reactivities toward nucleophiles suggest that the rate-limiting step in the inactivation process is not the alkylation reaction itself. At least five of the agents inhibit polyprotein processing in an ex vivo cell assay system, but they are also toxic to the cells.
 ...
PMID:Haloperidol-based irreversible inhibitors of the HIV-1 and HIV-2 proteases. 812 7

Human immunodeficiency viruses HIV-1 and HIV-2 encode a Tat protein that specifically activates transcription from the viral long terminal repeat. To characterize the properties of the Tat proteins, we have expressed them in Escherichia coli. The purified Tat protein was biochemically analyzed and tested for activity upon electroporation into human cell lines. This protein electroporation was used for the intracellular analysis of in vitro modified Tat protein. Our results indicate that the transcriptionally active form of the Tat protein is a monomer. Furthermore, we found that Tat activity is dramatically inhibited by preincubation of the protein with strongly reducing agents. In contrast, no inhibitory effect was measured upon incubation with metal-chelating reagents. These results suggest that the cysteine residues of Tat are involved in the formation of intramolecular disulfide bonds.
 ...
PMID:Intracellular analysis of in vitro modified HIV Tat protein. 813 60

The irreversible inhibition of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) proteases by 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) and eight haloperidol derivatives has been studied. EPNP specifically inhibits HIV-1 and HIV-2 proteases with a stoichiometry of one EPNP molecule/dimeric enzyme. The site of modification of HIV-2 protease by EPNP has been unambiguously identified as Asp-25 using high performance tandem mass spectrometry. The haloperidol derivatives assayed consist of epoxides, ynones, and alpha,beta-unsaturated ketones. The Kinact values for these haloperidol derivatives range from 10.7 to 521 microM for HIV-1 protease and from 8.6 to 283 microM for the HIV-2 enzyme, being in some cases approximately 1000-fold more potent irreverisble inhibitors of HIV proteases than EPNP. This potency results from the haloperidol character of the compounds and the chemical reactivity of the groups capable of forming a covalent bond with the enzyme. Covalent modification of HIV-2 protease by a radiolabeled epoxide derivative of haloperidol, UCSF 84, is prevented by EPNP and the peptidomimetic transition state analog U-85548. In similar experiments, incorporation of UCSF 84 into HIV-1 protease is partially prevented by these active-site inhibitors. In contrast, a mutant HIV-1 protease, HIV-1 PR C95M, in which Cys-95 has been replaced by Met, is labeled 50% less than HIV-1 protease and is fully protected by EPNP and U-85548. These results indicate the presence of 2 reactive residues in HIV-1 protease: Cys-95 and another located in the active site of the enzyme. The alpha,beta-unsaturated ketone derivative of haloperidol, UCSF 191, which is stable over a broad pH range, was used to study the pH profile of inactivation of HIV-1 and HIV-2 proteases. Comparison of the profiles of inactivation of wild-type HIV-1 protease, HIV-1 PR C95M, and HIV-1 PR C67L as well as HIV-2 protease (which has no cysteine residues) reveals the contribution of Cys-95 to the reactivity of these irreversible inhibitors. The inhibitors UCSF 70, UCSF 84, UCSF 115, UCSF 142, and UCSF 191 reduce p55gag polyprotein processing when assayed in a mammalian cell line that produces HIV-1 viral particles lacking the envelope.
 ...
PMID:In vitro characterization of nonpeptide irreversible inhibitors of HIV proteases. 814 59

Neutrophils from asymptomatic HIV-infected patients have an increased Nitroblue tetrazolium (NBT) reduction, that is an increased production of oxygen radicals. Plasma from these patients can activate normal neutrophils to an increased NBT-reduction and the neutrophil activating factor thus seems to be mainly plasma bound. Further, the patients also have increased levels of plasma malondialdehyde and thus an increased lipid peroxidation. Plasma cysteine levels are low, a sign of increased consumption of antioxidants. Treatment of the asymptomatic HIV-infected patients with N-acetylcysteine corrected the plasma cysteine levels and had some beneficial effects, but did not inhibit the increased radical production by the neutrophils.
 ...
PMID:Oxygen radical release by neutrophils of HIV-infected patients. 819 30

Deficiency in antioxidant micronutrients have been observed in patients with AIDS. These observations concerning only some isolated nutrients demonstrate a defect in zinc, selenium, and glutathione. An increase in free radical production and lipid peroxidation has been also found in these patients, and takes a great importance with recent papers presenting an immunodeficiency and more important an increase in HIV-1 replication secondary to free radicals overproduction. We have assessed different studies, trying to obtain a global view of the antioxidant status of these patients. In adults we observe a progressive decrease for zinc, selenium, and vitamin E with the severity of disease, except that selenium remains normal at stage II. However, the main dramatic decrease concerns carotenoids whose level at stage II is only half the normal value. To understand if these decreases in antioxidant and increases in oxidative stress occur secondary to the aggravation of the disease or, conversely, are responsible for it, we undertook a longitudinal survey of asymptotic patients. The preliminary results of this evaluation are presented. Paradoxically, lipid peroxidation is higher at stage II than at stage IV. This may be consecutive to a more intense overproduction of oxygen free radicals by more viable polymorphonuclear (PMN) at the asymptomatic stage. The free radicals production and lipid peroxidation seem secondary to a direct induction by the virus of PMN stimulation and cytokines secretion. N-Acetyl cysteine or ascorbate have been demonstrated in cell culture to be capable of blocking the expression of HIV-1 after oxidative stress and N-acetyl cysteine inhibits in vitro TNF-induced apoptosis of infected cells. In regard to all these experimental data, few serious and large trials of antioxidants have been conducted in HIV-infected patients, although some preliminary studies using zinc or selenium have been performed. In our opinion it is now time to evaluate in humans the beneficial effect of antioxidants. The more promising candidates for presenting synergistic effects when associated with N-acetyl cysteine seem to be beta-carotene, selenium and zinc.
 ...
PMID:Antioxidant status and lipid peroxidation in patients infected with HIV. 819 33

The product of the vpr open reading frame of human immunodeficiency virus type 1 (HIV-1) is a 15-kDa, arginine-rich protein that is present in virions in molar quantities equivalent to that of Gag. We report here the results of our investigations into the mechanism by which Vpr is incorporated into virions during assembly in infected cells. For these studies we used an expression vector encoding a Vpr molecule fused at its amino terminus to a nine-amino-acid peptide from influenza virus hemagglutinin. The tagged Vpr expression vector and a vpr mutant HIV-1 provirus were used to cotransfect COS cells, and the resulting virions were tested for the presence of the tagged protein on immunoblots probed with monoclonal antibody against the hemagglutinin peptide. The COS-produced virions were found to contain readily detectable amounts of tagged Vpr and smaller amounts of a putative tagged Vpr dimer. Infectivity of the particles was not altered by incorporation of tagged Vpr. Our results using this system in combination with mutant HIV-1 proviruses suggested that incorporation of Vpr into virions requires the carboxy-terminal Gag protein of HIV-1 (p6) but not gp160, Pol, or genomic viral RNA. In addition, analysis of mutated, tagged Vpr molecules suggested that amino acids near the carboxy terminus (amino acids 84 to 94) are required for incorporation of Vpr into HIV-1 virions. The single cysteine residue near the carboxy terminus was required for production of a stable protein. Arginine residues tested were not important for incorporation or stability of tagged Vpr. These results suggested a novel strategy for blocking HIV-1 replication.
 ...
PMID:Incorporation of Vpr into human immunodeficiency virus type 1 virions: requirement for the p6 region of gag and mutational analysis. 823 Apr 45

N-acetyl-L-cysteine (NAC) is known to antagonize the PMA- or cytokine-stimulated HIV-1 replication in latently and acutely infected monocytic and lymphocytic cell lines, and to reduce the virus multiplication in acutely infected, PHA-stimulated PBMC. We here report on the modulatory effects of NAC on the HIV-1 multiplication in both chronically and acutely infected lymphocytes that produce high virus levels independently from cytokine activation. In both cases, NAC doses of 0.12 and 0.25 mM decreased, whereas doses of 0.5-2 mM increased the infectious HIV-1 yield. At these concentrations, the modulatory effect of NAC on the HIV-1 multiplication paralleled that on cell proliferation, suggesting a close correlation between the two phenomena; in fact, under conditions where NAC could not modulate the cell growth, the drug also failed to modulate the HIV-1 multiplication. High NAC concentrations (4-16 mM), which were able to increase the proliferative rate of both chronically infected H9/IIIB and normal T lymphocytes, increased up to 6-fold the virus multiplication in H9/IIIB cells but were inhibitory to HIV-1 in acutely infected cells. This inhibition was due to the fact that, like dextran sulfate, NAC interfered with an early event in the virus growth cycle. The finding that high NAC doses were also capable of preventing syncytium formation in H9/IIIB and C8166 (or MT-4) cocultures further indicated an interference of the drug with receptor-binding-related events.
 ...
PMID:Modulatory effect of N-acetyl-L-cysteine on the HIV-1 multiplication in chronically and acutely infected cell lines. 825 May 42

Human immunodeficiency virus type 2 (HIV-2) trans-activator (Tat) is an important trans-regulator of viral gene expression. It differs from the related HIV-1 Tat in certain aspects of its structure and function. HIV-2 Tat is composed of 130 amino acids versus 86 amino acids for HIV-1 Tat. Apart from certain conserved regions, there is little homology between the two Tats. They also differ in their ability to trans-activate HIV-2 and HIV-1 long terminal repeat (LTR)-directed gene expression. As an aid to understanding its mechanism of action, the functional domains important for HIV-2 Tat trans-activation of HIV-2 and HIV-1 LTR-directed gene expression were investigated. Like HIV-1 Tat, HIV-2 Tat contains conserved cysteine- and arginine-rich domains important for its function. However, HIV-2 Tat differs from HIV-1 Tat in that about 20% of the HIV-2 Tat at the amino terminus was not essential for its trans-activation function while HIV-1 Tat amino terminus is reportedly a part of its activation domain. Similarly, about 30% of the protein at the carboxy terminus of HIV-2 Tat was not essential. A domain critical for HIV-2 Tat-mediated trans-activation was located just upstream of the cysteine-rich domain. This segment is predicted to adopt an alpha-helical conformation and also contains acidic amino acid residues; thus, it may resemble amphipathic helix-type activation domains found in some transcriptional factors. A region with predicted hydrophobic alpha-helical character located between the cysteine- and arginine-rich domains was also important for HIV-2 Tat function. HIV-2 Tat mutants that were analogs of HIV-1 Tat trans-dominant negative mutants did not display such a phenotype.
 ...
PMID:Human immunodeficiency virus type 2 (HIV-2) trans-activator (Tat): functional domains and the search for trans-dominant negative mutants. 825 33

The formation of dimers or higher-order multimers is critical to the biological activity of many eukaryotic regulatory proteins. However, biochemical analyses of the multimerization capacity of the Tat trans activator of human immunodeficiency virus types 1 (HIV-1) and 2 (HIV-2) have yielded contradictory results. We used the two-hybrid genetic assay for protein-protein interactions in the eukaryote Saccharomyces cerevisiae (S. Fields and O.-K. Song, Nature [London] 340:245-246, 1989) to examine the multimerization of Tat in vivo. Both HIV-1 and HIV-2 Tat are shown to form specific homo- but not heteromultimers in the yeast cell nucleus. Mutational analysis indicates a critical role for the essential core motif of Tat in mediating this interaction but demonstrates that efficient Tat multimerization does not require an intact cysteine motif. These data raise the possibility that the multimerization of Tat may be important for Tat function in higher eukaryotes.
 ...
PMID:Genetic evidence that the Tat proteins of human immunodeficiency virus types 1 and 2 can multimerize in the eukaryotic cell nucleus. 833 38


<< Previous 1 2 3 4 5 6 7 8 9 10