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)

Mutants of feline immunodeficiency virus (FIV) were selected in cell culture in the continuous presence of 10 microM (each) 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI). These mutants (AIR-1 and AIR-3) displayed a 13-fold resistance to AZT but had less than a 2-fold decrease in susceptibility to ddI. Interestingly, the AIR mutants were cross-resistant to phosphonoformate (PFA) and were hypersensitive to 2',3'-dideoxycytidine (ddC). Mutants of FIV were also selected in the presence of 10 microM ddI alone (DIS-1, DIS-2c), and these displayed a two- to fourfold decrease in susceptibility to ddI. Like the mutants selected with the combination of AZT plus ddI, DIS-1 and DIS-2c were cross-resistant to PFA and were hypersensitive to ddC. However, they remained as susceptible as wild-type FIV to AZT. Thus, the mutants selected with the combination of AZT plus ddI have phenotypes which reflect those obtained by selection with these drugs individually.
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PMID:Multiple-drug-resistant mutants of feline immunodeficiency virus selected with 2',3'-dideoxyinosine alone and in combination with 3'-azido-3'-deoxythymidine. 803 Oct 60

The untranslated leader of the RNA genome of the human immunodeficiency virus type 1 (HIV-1) encodes multiple signals that regulate distinct steps of the viral replication cycle. The RNA secondary structure of several replicative signals in the HIV-1 leader is critical for function. Well-known examples include the TAR hairpin that forms the binding site for the viral Tat trans-activator protein and the DIS hairpin that is important for dimerization and subsequent packaging of the viral RNA into virion particles. In this study, we present evidence for the formation of a tertiary structure by the complete HIV-1 leader RNA. This conformer was recognized as a fast-migrating band on nondenaturing polyacrylamide gels, and such a migration effect is generally attributed to differences in compactness. Both the 5' and 3' domains of the 335-nt HIV-1 leader RNA are required for the formation of the compact RNA structure, and the presence of several putative interaction domains was revealed by an extensive analysis of the denaturing effect of antisense DNA oligonucleotides. The buffer conditions and sequence requirements for conformer formation are strikingly different from that of the RNA-dimerization reaction. In particular, the conformer was destabilized in the presence of Mg2+ ions and by the viral nucleocapsid (NC) protein. The presence of a stable RNA structure in the HIV-1 leader was also apparent when this RNA was used as template for reverse transcription, which yielded massive stops ahead of the structured leader domain. Formation of the conformer is a reversible event, suggesting that the HIV-1 leader is a dynamic molecule. The putative biological function of this conformational polymorphism as molecular RNA switch in the HIV-1 replication cycle is discussed.
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PMID:The leader of the HIV-1 RNA genome forms a compactly folded tertiary structure. 1068 66

The dimer initiation site/dimer linkage sequence (DIS/DLS) region of the human immunodeficiency virus type 1 (HIV-1) RNA genome is thought to play important roles at various stages of the virus life cycle. Recently we showed that the DIS/DLS region affects RNA-RNA interaction in intact virus particles, by demonstrating that duplication of the region in viral RNA caused the production of virus particles containing partially monomeric RNAs. We have extended this finding and succeeded for the first time in creating mutant particles which contain only monomeric RNAs without modifying any viral proteins. In terms of RNA encapsidation ability, virion density, and protein processing, the mutant particles were comparable to wild-type particles. The level of production of viral DNA by the mutant virus construct in infected cells was also comparable to that of the constructs that produced exclusively dimeric RNA, indicating that monomeric viral RNA could be the template for strand transfer. These results indicated that the RNA dimerization of HIV-1 could be separated from viral RNA packaging and was not absolutely required for RNA packaging, virion maturation, and reverse transcription.
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PMID:Dissociation of genome dimerization from packaging functions and virion maturation of human immunodeficiency virus type 1. 1177 71

The dimer initiation site/dimer linkage sequence (DIS/DLS) region in the human immunodeficiency virus type 1 (HIV-1) RNA genome is suggested to play important roles in various steps of the virus life cycle. However, due to the presence of a putative DIS/DLS region located within the encapsidation signal region (E/psi), it is difficult to perform a mutational analysis of DIS/DLS without affecting the packaging of RNA into virions. Recently, we demonstrated that duplication of the DIS/DLS region in viral RNA caused the production of partially monomeric RNAs in virions, indicating that the region indeed mediated RNA-RNA interaction. We utilized this system to assess the precise location of DIS/DLS in the 5' region of the HIV-1 genome with minimum effect on RNA packaging. We found that the entire lower stem of the U5/L stem-loop was required for packaging, whereas the region important for dimer formation was only 10 bases long within the lower stem of the U5/L stem-loop. The R/U5 stem-loop was required for RNA packaging but was completely dispensable for dimer formation. The SL1 lower stem was important for both dimerization and packaging, but surprisingly, deletion of the palindromic sequence at the top of the loop only partially affected dimerization. These results clearly indicated that the E/psi of HIV-1 is much larger than the DIS/DLS and that the primary DIS/DLS is completely included in the E/psi. Therefore, it is suggested that RNA dimerization is a part of RNA packaging, which requires multiple steps.
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PMID:Possible role of dimerization in human immunodeficiency virus type 1 genome RNA packaging. 1263 65

Specific packaging of human immunodeficiency virus type 1 (HIV-1) RNA is attributable to the high affinity of nucleocapsid (NC) sequence of Gag for the cis-acting RNA packaging signals located within the 5' un-translated region (5' UTR). Interestingly, we have previously reported that the T12I mutation (named MP2) within SP1 of Gag prevented incorporation of spliced viral RNA into mutated viruses that lacked the stem-loop 1 (SL1) RNA element (also named dimerization initiation site, DIS), suggesting a role for the SP1 sequence in viral RNA packaging. In this study, we have further tested this activity of MP2 in the context of a variety of mutations that affect viral RNA incorporation. The results showed that MP2 was able to effectively restrict packaging of spliced viral RNA into viruses containing either NC mutations R10A and K11A or mutated 5' UTR sequence, such as DeltaGU3 that lacked the 112-GUCUGUUGUGUG-123 sequence of U5, D1 that was deleted of a 27 nt fragment immediately downstream of the primer binding site (PBS), Delta(306-325) that had the SL3 RNA element removed and MD2 that was missing the 328-GGAG-331 sequence. As a result, MP2 contributed increased infectivity to the related viruses. Therefore, the MP2 mutation demonstrates a distinct role in HIV-1 RNA packaging that is neither pertained to the specific viral RNA packaging signal nor to the NC sequence.
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PMID:The T12I mutation within the SP1 region of Gag restricts packaging of spliced viral RNA into human immunodeficiency virus type 1 with mutated RNA packaging signals and mutated nucleocapsid sequence. 1622 79

It has been suggested that the dimer initiation site/dimer linkage sequence (DIS/DLS) region of the human immunodeficiency virus type 1 (HIV-1) RNA genome plays an important role at various stages of the viral life cycle. Recently we found that the duplication of the DIS/DLS region on viral RNA caused the production of partially monomeric RNAs in virions, indicating that this region indeed mediates RNA-RNA interaction. In this report, we followed up on this finding to identify the necessary and sufficient region for RNA dimerization in the virion of HIV-1. The region thus identified was 144 bases in length, extending from the junction of R/U5 and U5/L stem-loops to the end of SL4. The trans-acting responsive element, polyadenylation signal, primer binding site, upper stem-loop of U5/L, and SL2 were not needed for the function of this region. The insertion of this region into the ectopic location of the viral genome did not affect the level of virion production by transfection. However, the resultant virions contained monomerized genomes and showed drastic reductions in infectivity. A reduction was observed especially in the reverse transcription process. An attempt to generate a replication-competent virus with monomerized genome was performed by the long-term culture of mutant virus-infected cells. All recovered viruses were wild-type revertants, indicating a fatal defect of the mutation. These results suggest that genome dimerization or DIS/DLS itself also plays an important role in the early stages of virus infection.
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PMID:Minimal region sufficient for genome dimerization in the human immunodeficiency virus type 1 virion and its potential roles in the early stages of viral replication. 1750 64

We have characterized the viral RNA conformation in wild-type, protease-inactive (PR-) and SL1-defective (DeltaDIS) human immunodeficiency virus type 1 (HIV-1), as a function of the age of the viruses, from newly released to grown-up (>or=24 h old). We report evidence for packaging HIV-1 genomic RNA (gRNA) in the form of monomers in PR- virions, viral RNA rearrangement (not maturation) within PR- HIV-1, protease-dependent formation of thermolabile dimeric viral RNAs, a new form of immature gRNA dimer at about 5 h post virion release, and slow-acting dimerization signals in SL1-defective viruses. The rates of gRNA dimer formation were >or=3-fold and >or=10-fold slower in DeltaDIS and PR- viruses than in wild-type, respectively. Thus, the DIS, i.e. the palindrome in the apical loop of SL1, is a dimerization initiation signal, but its role can be masked by one or several slow-acting dimerization site(s) when grown-up SL1-inactive virions are investigated. Grown-up PR- virions are not flawless models for immature virions because gRNA dimerization increases with the age of PR- virions, indicating that the PR- mutation does not "freeze" gRNA conformation in a nascent primordial state. Our study is the first on gRNA conformation in newly released mutant or primate retroviruses. It shows for the first time that the packaged retroviral gRNA matures in more than one step, and that formation of immature dimeric viral RNA requires viral protein maturation. The monomeric viral RNAs isolated from budding HIV-1, as modeled by newly released PR- virions, may be seen as dimers that are much more fragile than thermolabile dimers.
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PMID:HIV-1 viral RNA is selected in the form of monomers that dimerize in a three-step protease-dependent process; the DIS of stem-loop 1 initiates viral RNA dimerization. 1759 54

The untranslated leader of the human immunodeficiency virus type 1 (HIV-1) RNA genome encodes essential sequence and structural motifs that control various replication steps. The 5' splice site or splice donor (SD) is embedded in a semistable hairpin, but the function of this structure is unknown. We stabilized this SD hairpin by creating an additional base pair and demonstrated a severe HIV-1 replication defect. A splicing defect was apparent in RNA analyses of virus-infected cells and cells transfected with appropriate reporter constructs. We selected multiple virus revertants in search for interesting second-site escape pathways. Most revertants acquired an additional mutation that modulated the stability of the mutant SD hairpin. One revertant acquired a single nucleotide change in the upstream DIS hairpin. We demonstrate that a novel SD site is created by this upstream mutation, which obviously reduces the number of leader nucleotides that are included in spliced HIV-1 transcripts. These results suggest a novel role of RNA structure in the regulation of HIV-1 splicing.
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PMID:RNA structure modulates splicing efficiency at the human immunodeficiency virus type 1 major splice donor. 1816 Apr 37

The dimer initiation site/dimer linkage sequence (DIS/DLS) region of the human immunodeficiency virus type 1 (HIV-1) RNA genome is suggested to play essential roles at various stages of the viral life cycle. Through a novel assay we had recently developed, we reported on the necessary and sufficient region for RNA dimerization in the HIV-1 virion. Using this system, we performed further detailed mapping of the functional base pairs necessary for HIV-1 DLS structure. Interestingly, the study revealed a previously unnoticed stem formation between two distantly positioned regions. Based on this and other findings on functional base pairing in vivo, we propose new 3D models of the HIV-1 DLS which contain a unique pseudoknot-like conformation. Since this pseudoknot-like conformation appears to be thermodynamically stable, forms a foundational skeleton for the DLS and sterically restricts the spontaneous diversification of DLS conformations, its unique shape may contribute to the viral life cycle and potentially serve as a novel target for anti-HIV-1 therapies.
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PMID:A proposal for a new HIV-1 DLS structural model. 2232 32