UMLS:C0021051 - FACTA Search

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human immunodeficiency virus type 1 (HIV-1) Gag protein precursor, Pr55Gag, contains at its C-terminal end a proline-rich, 6-kDa domain designated p6. Two functions have been proposed for p6: incorporation of the HIV-1 accessory protein Vpr into virus particles and virus particle production. To characterize the role of p6 in the HIV-1 life cycle and to map functional domains within p6, we introduced a number of nonsense and single and multiple amino acid substitution mutations into p6. Following the introduction of the mutations into the full-length HIV-1 molecular clone pNL4-3, the effects on Gag protein expression and processing, virus particle production, and virus infectivity were analyzed. The production of mutant virus particles was also examined by transmission electron microscopy. The results indicate that (i) p6 is required for efficient virus particle production from a full-length HIV-1 molecular clone; (ii) a Pro-Thr-Ala-Pro sequence, located between residues 7 and 10 of p6, is critical for virus particle production; (iii) mutations outside the Pro-Thr-Ala-Pro motif have little or no effect on virus assembly and release; (iv) the p6 defect is manifested at a late stage in the budding process; and (v) mutations in p6 that severely reduce virion production in HeLa cells also block or significantly delay the establishment of a productive infection in the CEM (12D-7) T-cell line. We further demonstrate that mutational inactivation of the viral protease reverses the p6 defect, suggesting a functional linkage between p6 and the proteolytic processing of the Gag precursor protein during the budding of progeny virions.
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PMID:p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease. 747 93

A series of inhibitors of human immunodeficiency virus type 1 (HIV-1) proteinase containing the 2-aralkyl-amino-substituted statine moiety as a novel transition-state analog was synthesized, with the aim to obtain compounds which combine anti-HIV potency with oral bioavailability. The reduced-size 2-aminobenzylstatine derivative SDZ PRI 053, which contains 2-(S)-amino-3-(R)-hydroxyindane in place of an amino acid amide, is a potent and orally bioavailable inhibitor of HIV-1 replication. The antiviral activity of SDZ PRI 053 was demonstrated in various cell lines, in primary lymphocytes, and in primary monocytes, against laboratory strains as well as clinical HIV-1 isolates (50% effective dose = 0.028 to 0.15 microM). Cell proliferation was impaired only at 100- to 300-fold-higher concentrations. The mechanism of antiviral action of the proteinase inhibitor SDZ PRI 0.53 was demonstrated to be inhibition of gag precursor protein processing. The finding that the inhibitory potency of SDZ PRI 053 in chronic virus infection, determined by p24 release, was considerably lower than that in de novo infection may be explained by the fact that the virus particles produced in the presence of SDZ PRI 053 are about 50-fold less infectious than those from untreated cultures. Upon intravenous administration, half-lives in blood of 100 and 32 min in mice and rats, respectively, were measured. Oral bioavailability of SDZ PRI 053 in rodents was 20 to 60%, depending on the dose. In mice, rats, and dogs, the inhibitor levels after oral administration remained far above the concentrations needed to efficiently block HIV replication in vitro for a prolonged period. This compound is thus a promising candidate for clinical use in HIV disease.
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PMID:SDZ PRI 053, an orally bioavailable human immunodeficiency virus type 1 proteinase inhibitor containing the 2-aminobenzylstatine moiety. 749 76

The Pr55gag human immunodeficiency virus type 1 (HIV-1) precursor protein that is capable of auto-assembling was used as a carrier for a consensus sequence of the principal neutralization domain (PND) of the HIV-1 envelope. For this purpose, a modified HIV-1 gag gene with deletion of the sequence encoding a previously described p24 epitope (amino acids 196-228 of Pr55gag) was first obtained using PCR with degenerate primers, and then cloned. This deleted gag gene allowed in a second time the insertion of a synthetic oligonucleotide cassette encoding the North American/European consensus PND precisely in place of the p24 epitope. The chimeric gene was then inserted into a baculovirus transfer vector and expressed in insect cells. The construct formed 100-140 nm virus-like particles that were released into the extracellular medium. The use of a serum-free medium that supports growth of insect cells facilitated the downstream purification of the extracellular particles. The chimeric particles were recognized by monoclonal antibodies directed to V3 by Western blot but not by immune electron microscopy, suggesting that, although the inserted sequence was still antigenic it was not exposed at the surface of the particles. The results show the ability of Pr55gag to serve as a carrier for easy insertion, in a precisely defined region, of selected epitopes of gp120 surface envelope protein, and to still auto-assemble in virus-like particles. However, the data indicate that exposed epitopes of the mature p24 protein are not presented similarly in the Pr55 precursor, and therefore that different constructs with various insertions in different places must be generated. Such constructs offer an attractive approach for HIV vaccine development and will need evaluation for both antigenicity and immunogenicity.
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PMID:A simple procedure to generate chimeric Pr55gag virus-like particles expressing the principal neutralization domain of human immunodeficiency virus type 1. 753 50

The 96-amino acid Vpr protein is the only virion-associated regulatory protein encoded by the human immunodeficiency virus type 1 (HIV-1). Vpr incorporation into the viral particle is most likely due to an interaction with a viral structural protein. Recent data have shown that DNA encoding for the p55 Gag precursor protein (Pr55gag) is the minimal viral genetic information necessary for Vpr incorporation. Other studies have suggested that the p6 portion of Pr55gag, which is unique to lentiviruses, is involved in Vpr incorporation. To investigate the mechanism of incorporation of Vpr into HIV-1 virions, COS-7 cells were cotransfected with ptrENV, an expression vector that encodes all of the HIV-1 regulatory proteins including Rev and Vpr, and different constructs of pIIIgagCAR, a rev-dependent Gag expression plasmid that encodes Pr55gag and the viral protease. Virions produced from gag constructs containing a premature p6 termination codon at positions Leu-1, Ser-17, Tyr-36, or Leu-44 lacked detectable Vpr. In contrast, gag constructs with double Pro-10-Pro-11 substitutions for Leu-10-Leu-11 or a premature termination codon at position Pro-49 of p6 were still able to incorporate Vpr, however, with lower efficiency than wild type. The mutations described in this study affected directly two short regions within the p6 domain, which are highly conserved among primate immunodeficiency viruses. Our results suggest that the conserved (P-T/S-A-P-P) and (L-X-S-L-F-G) motifs located near the N-terminus and C-terminus, respectively, of the p6 domain of Gag are critical for Vpr incorporation into HIV-1 virions.
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PMID:Incorporation of Vpr into human immunodeficiency virus type 1: role of conserved regions within the P6 domain of Pr55gag. 764 78

The entire envelope protein of the human T cell leukemia/lymphoma virus type I (HTLV-I)1711, obtained from the DNA of a West African healthy HTLV-I-infected patient, was expressed in the highly attenuated poxvirus vaccine vectors ALVAC and NYVAC. These live recombinant vaccine candidates were used to immunize New Zealand White rabbits. Immunization regimens included inoculation of the poxvirus recombinant alone as well as prime/boost protocols using gp63 HTLV-I envelope precursor protein in Alum as the subunit boost. All animals were exposed to an HTLV-I cell-associated challenge (5 x 10(4) cells) from a primary culture of the HTLV-IBOU isolate. The results indicated that two inoculations of the ALVAC-based HTLV-Ienv vaccine candidate protected animals against viral challenge 5 months following the last immunization. However, a combination protocol with ALVAC-env and two additional boosts of gp63 surprisingly failed to confer protection, suggesting that administration of the subunit preparation might be deleterious. Further, in the case of the NYVAC HTLV-Ienv recombinant, protection was afforded as early as 2 months following the first immunization. Last, all the protected animals in the NYVAC and ALVAC trials were challenged 5 months following the initial challenge exposure with 5 ml of blood from an HTLV-IBOU-infected animal, and subsequently became infected. Protection conferred by the attenuated HTLV-Ienv recombinant poxvirus vaccine in the rabbit model might be instrumental for optimizing the immunogenicity of poxvirus-based vaccine candidates against human immunodeficiency virus (HIV), particularly because of the need to enhance protection against cell-to-cell transmission.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Highly attenuated HTLV type Ienv poxvirus vaccines induce protection against a cell-associated HTLV type I challenge in rabbits. 774 44

Poliovirus genomes which contain small regions of the human immunodeficiency virus type 1 (HIV-1) gag, pol, and env genes substituted in frame for the P1 capsid region replicate and express HIV-1 proteins as fusion proteins with the P1 capsid precursor protein upon transfection into cells (W. S. Choi, R. Pal-Ghosh, and C. D. Morrow, J. Virol. 65:2875-2883, 1991). Since these genomes, referred to as replicons, do not express capsid proteins, a complementation system was developed to encapsidate the genomes by providing P1 capsid proteins in trans from a recombinant vaccinia virus, VV-P1. Virus stocks of encapsidated replicons were generated after serial passage of the replicon genomes into cells previously infected with VV-P1 (D. C. Porter, D. C. Ansardi, W. S. Choi, and C. D. Morrow, J. Virol. 67:3712-3719, 1993). Using this system, we have further defined the role of the P1 region in viral protein expression and RNA encapsidation. In the present study, we constructed poliovirus replicons which contain the complete 1,492-bp gag gene of HIV-1 substituted for the entire P1 region of poliovirus. To investigate whether the VP4 coding region was required for the replication and encapsidation of poliovirus RNA, a second replicon in which the complete gag gene was substituted for the VP2, VP3, and VP1 capsid sequences was constructed. Transfection of replicon RNA with and without the VP4 coding region into cells resulted in similar levels of expression of the HIV-1 Gag protein and poliovirus 3CD protein, as indicated by immunoprecipitation using specific antibodies. Northern (RNA) blot analysis of RNA from transfected cells demonstrated comparable levels of RNA replication for each replicon. Transfection of the replicon genomes into cells infected with VV-P1 resulted in the encapsidation of the genomes; serial passage in the presence of VV-P1 resulted in the generation of virus stocks of encapsidated replicons. Analysis of the levels of protein expression and encapsidated replicon RNA from virus stocks after 21 serial passages of the replicon genomes with VV-P1 indicated that the replicon which contained the VP4 coding region was present at a higher level than the replicon which contained a complete substitution of the P1 capsid sequences. These differences in encapsidation, though, were not detected after only two serial passages of the replicons with VV-P1 or upon coinfection and serial passage with type 1 Sabin poliovirus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Encapsidation of poliovirus replicons encoding the complete human immunodeficiency virus type 1 gag gene by using a complementation system which provides the P1 capsid protein in trans. 785 88

The human immunodeficiency virus type 2 gag precursor protein, pr41, self assembles as virus-like particles (VLP) when the gag gene is expressed in insect cells. To map the functional domains for HIV-2 gag VLP formation, a series of deletion mutants was constructed by removing sequentially the C-terminal region of HIV-2 gag precursor protein and expressing the truncated gag genes in SF9 insect cells by means of recombinant baculoviruses. We found that deletion of up to 143 amino acids at the C-terminus of HIV-2 gag, leaving 376 amino acids at the N-terminus of the protein, did not prevent VLP formation. However, an additional four amino acids deletion from the C-terminus, which represents 372 amino acids at the N-terminus, made gag protein fail to form VLP. There is a proline-rich region at amino acid positions 372 and 377 of HIV-2 gag. To analyze the role of these proline residues, we generated five mutants in which proline was changed sequentially into leucine. Our results showed that replacement of one or two prolines did not stop gag VLP formation, whereas replacement of all three prolines by leucine residues completely abolished VLP assembly. Our data demonstrate that the C-terminal p12 region of HIV-2 gag precursor protein and the zinc finger domain are dispensable for gag VLP assembly, but the presence of at least one of the three proline residues located between amino acid positions 372 and 377 of HIV-2NIH-Z is required.
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PMID:Mapping of functional domains for HIV-2 gag assembly into virus-like particles. 797 51

All foamy viruses give rise to a strong nuclear staining when infected cells are reacted with sera from infected hosts. This nuclear fluorescence distinguishes foamy viruses from all other retroviruses. The experiments reported here indicate that the foamy virus Gag precursor protein is transiently located in the nuclei of infected cells and this is the likely reason for the typical foamy virus nuclear fluorescence. By using the vaccinia virus expression system, a conserved basic sequence motif in the nucleocapsid domain of foamy virus Gag proteins was identified to be responsible for the nuclear transport of the gag precursor molecule. This motif was also found to be able to direct a heterologous protein, the Gag protein of human immunodeficiency virus, into the nucleus.
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PMID:Nuclear localization of foamy virus Gag precursor protein. 803 93

The dermaseptins are a family of broad spectrum antimicrobial peptides, 27-34 amino acids long, involved in the defense of the naked skin of frogs against microbial invasion. They are the first vertebrate peptides to show lethal effects against the filamentous fungi responsible for severe opportunistic infections accompanying immunodeficiency syndrome and the use of immunosuppressive agents. A cDNA library was constructed from skin poly(A+) RNA of the arboreal frog Phyllomedusa bicolor and screened with an oligonucleotide probe complementary to the COOH terminus of dermaseptin b. Several clones contained a full-length DNA copy of a 443-nucleotide mRNA that encoded a 78-residue dermaseptin b precursor protein. The deduced precursor contained a putative signal sequence at the NH2 terminus, a 20-residue spacer sequence extremely rich (60%) in glutamic and aspartic acids, and a single copy of a dermaseptin b progenitor sequence at the COOH terminus. One clone contained a complete copy of adenoregulin, a 33-residue peptide reported to enhance the binding of agonists to the A1 adenosine receptor. The mRNAs encoding adenoregulin and dermaseptin b were very similar: 70 and 75% nucleotide identities between the 5'- and 3'-untranslated regions, respectively; 91% amino acid identity between the signal peptides; 82% identity between the acidic spacer sequences; and 38% identity between adenoregulin and dermaseptin b. Because adenoregulin and dermaseptin b have similar precursor designs and antimicrobial spectra, adenoregulin should be considered as a new member of the dermaseptin family and alternatively named dermaseptin b II. Preprodermaseptin b and preproadenoregulin have considerable sequence identities to the precursors encoding the opioid heptapeptides dermorphin, dermenkephalin, and deltorphins. This similarity extended into the 5'-untranslated regions of the mRNAs. These findings suggest that the genes encoding the four preproproteins are all members of the same family despite the fact that they encode end products having very different biological activities. These genes might contain a homologous export exon comprising the 5'-untranslated region, the 22-residue signal peptide, the 20-24-residue acidic spacer, and the basic pair Lys-Arg.
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PMID:Precursors of vertebrate peptide antibiotics dermaseptin b and adenoregulin have extensive sequence identities with precursors of opioid peptides dermorphin, dermenkephalin, and deltorphins. 807 51

Human immunodeficiency virus (HIV), the retrovirus believed to be the cause of acquired immunodeficiency syndrome (AIDS), infects a variety of CD4+ cells, including lymphocytes and cells of the monocyte/macrophage lineage. Encoded in the HIV genome are several precursor proteins that must undergo proteolytic cleavage to yield functional proteins. The gag precursor protein of HIV (p55) is cleaved by a virally encoded aspartate protease (HIV protease). Because cleavage of p55 is required for viral maturation and infectivity, inhibition of HIV protease is an attractive target for therapy designed to block the progression of HIV infection. Inhibitors of HIV protease from a variety of chemical classes have been synthesized and antiviral activity has been demonstrated in lymphocytes and cells from the monocyte/macrophage lineage. A few HIV protease inhibitors have progressed to the clinic and some have shown promise in early trials. There are, however, several important issues that will affect the development of a successful HIV protease inhibitor, including cell and tissue distribution and immunotoxicity. These issues are tissue distribution and immunotoxicity. These issues are discussed, with an emphasis on the complexities posed by cells of the monocyte/macrophage lineage.
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PMID:HIV protease inhibitors: effects on viral maturation and physiologic function in macrophages. 808 11

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