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)

Human immunodeficiency virus (HIV-1) gene expression is activated by the viral TAT protein that interacts with an RNA sequence, TAR, located at the 5' end of all viral mRNAs. TAT functions primarily as a transcriptional activator in mammalian cells. However, in Xenopus oocytes TAT functions primarily as a translational activator. TAR is an RNA structure comprising a partially base-paired stem, a tripyrimidine bulge in the upper stem, and an unpaired six-nucleotide loop. In vitro, TAT binds directly to the bulge with no requirement for the loop. In vivo, however, mutations in the loop abolish TAT activation of transcription and translation, implying a requirement for TAR-binding cellular factors. We now provide genetic evidence for the presence of two TAR-specific cellular factors in Xenopus oocytes. These factors display independent and mutually exclusive interactions with either the loop or the bulge region of TAR. Furthermore, by using in vivo RNA competition assays we show that the cellular factors regulate the accessibility of the TAT binding site. The fact that Xenopus oocytes contain factors that specifically interact with a human viral RNA sequence might indicate that the TAT/TAR interaction is subverting a conserved pathway in the cell.
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PMID:HIV-1 TAR RNA-binding proteins control TAT activation of translation in Xenopus oocytes. 842 67

The trans-activator of transcription or TAT gene from HIV-1 encodes a protein that increases the processivity of transcription from the HIV-1 genome. TAT protein can also affect cellular processes in the absence of its ribonucleic HIV target sequence trans activation response element and may be responsible for some aspects of HIV pathogenesis apart from infectious virus or other viral gene products. We have previously shown that TAT72 decreases CTL activity in TAT72-transgenic mice, and we now demonstrate aberrant regulation of mitogen-elicited IL-2 at both transcriptional and translational levels. In contrast, alloantigen stimulation resulted in increased IL-6 and IL-10 production in the TAT72-transgenic mice. Con A-stimulated cultures of splenic lymphocytes from TAT72-transgenic mice do not undergo clonal proliferation of CD4+ cells as compared with CD8+ cells monitored over 72 h. These results suggest that TAT is sufficient to induce some pathology associated with AIDS and is a potent immunologic manipulator apart from its function as trans-activator.
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PMID:Aberrant regulation of cytokines in HIV-1 TAT72-transgenic mice. 862 96

Cystic Fibrosis (CF) and AIDS are primary candidate disorders to be treated by gene therapy, owing to their lethality and the absence of efficient clinical treatments. Treatment of CF by gene therapy will require the transfer of the functional CFTR cDNA into the diseased human airway epithelia since mutations within the CFTR gene are responsible for CF. We have therefore cloned the human CFTR cDNA and developed a recombinant E1-deleted adenoviral vector carrying a CFTR expression cassette. We demonstrated in vitro the ability of this vector to efficiently transduce human lung cells isolated from CF patients and to correct their phenotype. Efficient in, vivo delivery of the CFTR cDNA to the airways of cotton rats and rhesus monkeys was also obtained and no dissemination of the recombinant viral vector in other tissues than the airways was observed. We have therefore designed a phase I clinical trial involving CF patients. In contrast to the monogenic CF disease, the mechanisms of AIDS pathogenesis still remain poorly understood. Such limited knowledge of the disease constitutes a serious restriction to the development of a rational gene therapy strategy for AIDS. Since HIV, the causative agent of AIDS, predominantly infects cells of the hematopoietic system, pluri- or multipotent stem cells may constitute potential targets for the introduction of a foreign anti-HIV gene that will inhibit HIV replication and/or spread. Reimplantation of the genetically modified stem cells into asymptomatic HIV-infected patients should theoretically allow the repopulation of the host's immune system with mature CD4+ cells expressing novel molecules that interfere with viral replication, thus slowing the progression of AIDS. We identified several new transdominant inhibitors derived from the viral TAT and REV proteins and showed their ability to confer to human CD4 lymphocytes resistance against HIV1 infection. Retroviral vectors carrying these potential therapeutic genes have been developed and are currently being tested in vivo in newly developed transgenic animal models, in humanized SCID mice and in macaques.
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PMID:[Gene therapy for hereditary and acquired human diseases]. 878 46

TAT protein is an essential regulatory protein of the human immunodeficiency virus type 1 (HIV-1). Inhibition of TAT activity blocks the virus cycle, and a drug that blocks TAT is one of the possibilities to cure AIDS. Circular dichroism (CD) was measured for TAT peptides covering the TAT sequence with overlaps. The CD spectrum of each peptide was measured in different solvents to evaluate the ability of each TAT region to form different secondary structures. The most variation or conformational heterogeneity is observed with the two regions adjacent to the TAT basic region. CD data show that the basic region can adopt an extended structure in a full TAT protein, which is not the case for the isolated peptide. TAT sequences from the different HIV-1 isolates were analyzed, and the results showed that the sequences could be gathered into six groups. Molecular modeling was done on the various isolates based on a TAT structure from two-dimensional NMR. After minimization and dynamic steps, the modeled three-dimensional structures were compared. The results showed structural variations of the TAT protein as a function of the HIV-1 isolates. These structural variations were mainly in the two regions adjacent to the basic region, confirming the conformational heterogeneity indicated by the CD measurements. Furthermore, Chou-Fasman analysis shows significant changes in propensities for each secondary structure only for regions III and V. This conformational heterogeneity should be essential for TAT activity and points out that regions III and V are a poor potential target to design a TAT ligand. We propose a target involving TAT structurally conserved regions, accessible whatever the size of the TAT C terminus.
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PMID:Conformational heterogeneity in two regions of TAT results in structural variations of this protein as a function of HIV-1 isolates. 879 35

Two methods of plasmid characterization, restriction digest patterns and incompatibility grouping, were used to study self-transmissible multi-drug resistance among non-typhi salmonellae (NTS). Resistance to ampicillin and other commonly applied beta-lactams was evaluated by iso-electric focusing and disc inactivation. Of the NTS isolated from blood, 75% were Salmonella typhimurium but those included several different phage types. Over 47% of isolates were resistant to three or more of the readily available drugs including ampicillin, cefuroxime, chloramphenicol, co-trimoxazole, streptomycin and tetracycline. Self-transferable resistance plasmids (c. 100 kb) were essentially of incompatibility group incFIIA, but their restriction fragment patterns revealed a diversity in relatedness. More than half of parent strains and their transconjugants produced beta-lactamases which co-electrophoresed with TEM-1 and OXA-1. This study has observed a disturbingly high prevalence of transmissible multi-drug resistance among NTS which are an important cause of morbidity in HIV-1 seropositive individuals.
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PMID:Multi-drug resistant non-typhi salmonellae in Kenya. 888 17

Upon prolonged treatment with various antiretroviral nucleoside analogs such as 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, (-)- beta-L-2', 3'dideoxy-3'thiacytidine and 2',3'-didehydro-3'-deoxythymidine, selection of human immunodeficiency virus type 1 (HIV-1) strains with mutations in the reverse transcriptase (RT) gene has been reported. We designed a reverse hybridization line probe assay (LiPA) for the rapid and simultaneous characterization of the following variations in the RT gene: M41 or L41; T69, N69, A69, or D69; K70 or R70; L74 or V74; V75 or T75; M184, I184, or V184; T215, Y215, or F215; and K219, Q219, or E219. Nucleotide polymorphisms for codon L41 (TTG or CTG), T69 (ACT or ACA), V75 (GTA or GTG), T215 (ACC or ACT), and Y215 (TAC or TAT) could be detected. In addition to the codons mentioned above, several third-letter polymorphisms in the direct vicinity of the target codons (E40, E42, K43, K73, D76, Q182, Y183, D185, G213, F214, and L214) were found, and specific probes were selected. In total, 48 probes were designed and applied to the LiPA test strips and optimized with a well-characterized and representative reference panel. Plasma samples from 358 HIV-infected patients were analyzed with all 48 probes. The amino acid profiles could be deduced by LiPA hybridization in an average of 92.7% of the samples for each individual codon. When combined with changes in viral load and CD4+ T-cell count, this LiPA approach proved to be useful in studying genetic resistance in follow-up samples from antiretroviral agent-treated HIV-1-infected individuals.
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PMID:Line probe assay for rapid detection of drug-selected mutations in the human immunodeficiency virus type 1 reverse transcriptase gene. 902 Nov 81

Transfer of "anti-HIV-1 genes" into hematopoietic stem cells of human immunodeficiency virus-1 (HIV-1)-infected individuals may be a potent therapeutic approach to render mature cells arising from transduced stem cells resistant to the destructive events associated with HIV-1 infection. To determine the feasibility of gene therapy for acquired immunodeficiency syndrome in individuals already infected with HIV-1, granulocyte colony-stimulating factor mobilized peripheral blood CD34+ cells were isolated from HIV-1-infected individuals and transduced with retroviral vectors containing three different anti-HIV-1-genes: the Rev binding domain of the Rev Responsive Element (RRE decoy) (L-RRE-neo), a double hammerhead ribozyme vector targeted to cleave the tat and rev transcripts (L-TR/TAT-neo), and the trans-dominant mutant of rev (M10) (L-M10-SN). As a control, a vector mediating only neomycin resistance (LN) was used. After 3 days of transduction on allogeneic stroma in the presence of stem cell factor, interleukin-6 (IL-6), and IL-3, the cultures were G418-selected, and then challenged with HIV-1(JR-FL) and a primary HIV-1 isolate. Compared with the control cultures, the L-RRE-neo-, L-TR/TAT-neo-, and L-M10-SN-transduced cultures displayed up to 1,000-fold inhibition of HIV-1 replication after challenge with HIV-1(JR-FL) and the primary HIV-1 isolate. Growth of the hematopoietic cells in long-term bone marrow culture was not perturbed by the presence of any of the anti-HIV-1 genes. This study shows that anti-HIV-1 genes can be introduced into CD34+ cells from individuals already infected with HIV-1, and strongly inhibit HIV-1 replication in primary monocytes derived from the CD34+ progenitors.
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PMID:Inhibition of human immunodeficiency virus-1 (HIV-1) replication after transduction of granulocyte colony-stimulating factor-mobilized CD34+ cells from HIV-1-infected donors using retroviral vectors containing anti-HIV-1 genes. 911 67

A M182T substitution was discovered as a second-site suppressor of a missense mutation in TEM-1 beta-lactamase. The combination of the M182T substitution with other substitutions in the enzyme indicates the M182T substitution is a global suppressor of missense mutations in beta-lactamase. The M182T substitution also is found in natural variants of TEM-1 beta-lactamase with altered substrate specificity that have evolved in response to antibiotic therapy. The M182T substitution may have been selected in natural isolates as a suppressor of folding or stability defects resulting from mutations associated with drug resistance. This pathway of protein evolution may occur in other targets of antimicrobial drugs such as the HIV protease.
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PMID:A natural polymorphism in beta-lactamase is a global suppressor. 923 58

Primary murine embryonic fibroblasts transfected with HIV-1 TAT demonstrated decreased levels of high energy phosphates (ATP, GTP, UTP/CTP), adenine nucleotides (ATP, ADP, AMP), and both NAD+/NADH redox pairs, resulting in a substantial loss of redox poise. A greater than 50% decrease in intracellular reduced glutathione (GSH) concentration was accompanied by the extracellular appearance of acidic fibroblast growth factor (FGF-1). Addition of either N-acetyl-L-cysteine or glutathione ester (GSE), but not L-2-oxothiazolidine 4-carboxylate, partially restored intracellular GSH levels and resulted in loss of extracellular FGF-1. Treatment of FGF-1-transduced cells with buthionine sulfoximine (BSO) resulted in a time- and dose-dependent decrease in total cellular GSH concentration that was accompanied by the extracellular appearance of FGF-1. Inclusion of GSE during BSO treatment eliminated the extracellular appearance of FGF-1. BSO treatment of cells transfected with a mutant form of FGF-1, in which all three cysteine residues were replaced with serines, also decreased total cellular GSH concentration but failed to induce the extracellular appearance of FGF-1. Collectively, these results suggest that HIV-1 TAT induces a condition of oxidative stress, which mediates cellular secretion of FGF-1, an observation relevant to the pathophysiologic development and progression of AIDS-associated Kaposi's sarcoma.
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PMID:Glutathione depletion associated with the HIV-1 TAT protein mediates the extracellular appearance of acidic fibroblast growth factor. 950 19

At present, treatment of HIV infection uses small inhibitory molecules that target HIV protease; however, the emergence of resistant HIV strains is increasingly problematic. To circumvent this, we report here a new 'Trojan horse' strategy to kill HIV-infected cells by exploiting HIV protease. We engineered a transducing, modified, apoptosis-promoting caspase-3 protein, TAT-Casp3, that substitutes HIV proteolytic cleavage sites for endogenous ones and efficiently transduces about 100% of cells, but remains inactive in uninfected cells. In HIV-infected cells, TAT-Casp3 becomes processed into an active form by HIV protease, resulting in apoptosis of the infected cell. This strategy could also be applied to other pathogens encoding specific proteases, such as hepatitis C virus, cytomegalovirus and malaria.
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PMID:Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein. 988 35


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