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)

Tat, the human immunodeficiency virus (HIV)-encoded transcription factor, is vital for HIV replication and transcription. Any drug that inhibits Tat's activity is a valuable candidate for chemotherapeutic applications. We show here that doxorubicin (Dox), a well-known anticancer drug and its derivative, daunomycin, inhibit the ability of Tat to activate the HIV-1 LTR. We contransfected HeLa cells with pSV40TAT and a chloramphenicol acetyltransferase gene driven by an HIV LTR promoter. CAT transcription was vigorously stimulated many fold by Tat production but the effect of Tat was inhibited by Dox in a dose-dependent manner. The transcriptional activation domain of Tat, located in its 67 amino terminal residues, remains Dox sensitive. A TAR-deleted reporter gene with a Gal binding domain is transactivated by a Gal-Tat fusion protein. This transcription complex retains a high level of activity in the presence of Dox, suggesting that Dox primarily affects RNA-Tat, rather than DNA-Tat, mediated transactivation. RNA gel mobility analysis reveals that Dox does not affect the binding of Tat to TAR-RNA in vitro but does increase the binding activity of cellular nuclear proteins with TAR-RNA. Induction or activation of such TAR-binding proteins in cells that might interfere with the activity of Tat could explain the observed inhibitory effects of Dox on Tat-activated transcription. These results suggest that Dox may have chemotherapeutic effects on HIV expression mediated through TAR RNA.
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PMID:Doxorubicin inhibits Tat-dependent transactivation of HIV type 1 LTR. 874 82

We compared the efficiency of human immunodeficiency virus (HIV-1) vectors that express a marker gene (chloramphenicol acetyltransferase, CAT) using different promoter elements. In one vector, CAT was expressed under the control of an internal murine leukemia virus (MuLV) long terminal repeat (LTR). In other vectors, CAT production was regulated by the HIV-1 LTR; these vectors also contained the HIV-1 tat gene and pol sequences reported to exert cis-acting positive effects on reverse transcription or gene expression. Vectors employing the Tat-driven HIV-1 LTR exhibited up to 500-fold greater CAT expression in Jurkat lymphocytes or human peripheral blood mononuclear cells compared with vectors using the internal MuLV LTR element as a promoter. This difference was not due to improved packaging of the vector RNA into virions, but to an improved level of gene expression in the target cells. Target cell CAT expression was two- to threefold higher for the vector containing the pol sequences and was only slightly less than that seen for a trans-complemented envdeleted provirus. These results indicate that defective HIV-1 vectors with efficiencies of gene transfer and expression comparable with that of HIV-1 itself are feasible.
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PMID:Use of cis- and trans-acting viral regulatory sequences to improve expression of human immunodeficiency virus vectors in human lymphocytes. 880 25

We have previously shown that long terminal repeats (LTRs) derived from various isolates of SIVAGM share a unique functional property. In the absence of viral Tat, all SIVAGM LTRs act as much more efficient promoters than any of the other LTRs derived from representative primate immunodeficiency viruses. In the presence of Tat, however, SIVAGM LTRs are activated relatively inefficiently. To map the elements that confer these features on the SIVAGM LTR, a number of deletion mutants were constructed, and their promoter activities were determined using a bacterial CAT gene as a marker. The results obtained indicated that various elements located in the U3 region may contribute to the high basal promoter activity and that no negative elements are present in the region. The Tat-responsive sequence TAR was localized to the R region as observed for the other LTRs. A mutant carrying a single nucleotide deletion in this region completely lost responsiveness to Tat protein.
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PMID:Functional analysis of simian immunodeficiency virus SIVAGM long terminal repeat. 887 17

The oxidative stress in human erythrocytes was studied in asymptomatic and symptomatic patients infected by the human immunodeficiency virus (HIV), and patients with the acquired immunodeficiency syndrome (AIDS). tert-Butyl hydroperoxide initiated chemiluminescence, superoxide dismutase and catalase activities, and total glutathione were evaluated in the erythrocytes and the total antioxidant capacity in the plasma of control, patients infected with HIV that have not yet developed acquired immunodeficiency syndrome, and patients in the later stage of AIDS. tert-Butyl hydroperoxide initiated chemiluminescence was increased by 33% in asymptomatic (stage A1) and symptomatic patients (stage B2) infected with HIV and 82% for patients with AIDS (stage B3) (P < 0.05). While catalase activity did not show any difference between patients and controls, other indices showed differences that, in some cases, reached statistical significance. Superoxide dismutase activity was increased by 24% in stages A1 and B2 of HIV infection and 65% in patients in stage B3 (P < 0.05). Glutathione was decreased by 20% in stages A1 and B2, and by 32% in stage B3 patients (P < 0.05). Total plasma antioxidant capacity was increased in 30 and 57% for the asymptomatic and AIDS patients groups, respectively (P < 0.05). The data indicate that erythrocyte's oxidative stress is associated with the progressive development of HIV disease. Parameters indicating oxidative stress could be an interesting form to screen the evolution of these patients and their response to anti-oxidant therapies.
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PMID:Oxidative stress in blood of HIV infected patients. 893 54

Infection with human immunodeficiency virus type 1 and 2 is associated with elevated concentrations of neopterin, released in large quantities by human macrophages on stimulation with interferon gamma. Evidence has suggested a potential role of neopterin derivatives in oxygen radical-mediated processes. Here we show that the redox-sensitive transcription factors AP-1 and NF-kappaB are activated by 7,8-dihydroneopterin, either directly (AP-1), or by the synergistic action with tumor necrosis factor alpha (NF-kappaB). We could further demonstrate that 7,8-dihydroneopterin enhances HIV-1 expression as shown in transient transfection assays using HIV-1 CAT promoter-reporter gene constructs. In sera of HIV+ patients 7,8-dihydroneopterin significantly correlated with neopterin and HIV-1 p24 antigen. On the basis of our data we therefore assume that 7,8-dihydroneopterin might augment progression to higher stages of HIV-associated disease.
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PMID:trans-Activation of the HIV type 1 promoter by 7,8-dihydroneopterin in vitro. 900 2

The human immunodeficiency virus type 1 (HIV-1) transactivator Tat protein is essential for efficient viral gene expression and virus replication. The Tat core domain, a stretch of 12 amino acids between the cysteine-rich and the basic domain, is conserved in all HIV isolates and required for interaction with a number of cellular transcriptional regulatory proteins. Here we demonstrate that soluble peptide analogs of the Tat core domain (amino acid 36-50) are able to effectively block LTR transactivation. In transfection experiments, Tat core peptide analogs containing amino acid substitutions at position 41 and 44 inhibited Tat transactivation of an HIV-1 LTR-CAT reporter construct up to 80-fold. In contrast, inhibition of other promoters such as HTLV-I and CMV was approximately 2-fold. Tat peptide analog 36-50 (41/44) inhibited HIV virus replication by 85% in latently infected U1 cells induced with Tat. Furthermore, U1 cells treated with the Tat peptide 36-50 (41/44) analog showed markedly delayed virus transmission when cocultivated with parental U937 cells. Interestingly, while both short and long peptide analogs (amino acids 36-50 vs 36-72) inhibited Tat transactivation in transient assays, the short peptides were more effective inhibitors of virus replication in U1 cells. The Tat peptide analog did not decrease expression of cellular genes including beta-actin, GAPDH, and histone H2B.
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PMID:Inhibition of HIV-1 transcription and virus replication using soluble Tat peptide analogs. 901 42

Transcription of the human immunodeficiency virus type 1 (HIV-1) genome takes place after integration of the provirus into human chromosomal DNA. HIV transcription is known to be modulated by viral and cellular factors but the influence of flanking chromosomal sequences on proviral gene expression has not been well defined. To investigate the activity of the integrated HIV promoter, we exploited the ability of recombinant adeno-associated virus (AAV-2) to transfer and stably integrate genes into the human genome at random or site-specifically. Chimeric AAV vectors were constructed containing an HIV-CAT reporter cassette; some vectors also contained the neomycin resistance gene to facilitate the isolation of positive clones. HeLa cells were infected with recombinant AAV, in some instances together with wild-type virus as a source of AAV rep function. We isolated 25 clones of G418-resistant cells which carried the integrated HIV-CAT cassette, generally occupying unique sites that did not correspond to the AAV-specific region of chromosome 19. The HIV promoter was transcriptionally active in most of the clones. Basal promoter activity varied substantially among the clones, and its responsivity to the HIV transactivator Tat was also variable. The integrated HIV promoter was transactivated to comparable degrees by the one-exon form and two-exon form of Tat. These findings provide evidence that the transcriptional activity of the HIV promoter can be greatly influenced by the site of proviral insertion.
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PMID:Transduction of the human immunodeficiency virus type 1 promoter into human chromosomal DNA by adeno-associated virus: effects on promoter activity. 923 45

Previously we documented the transposition of an intracisternal A particle (IAP) provirus to the interleukin 3 (IL-3) locus which resulted in autocrine transformation. In the present study, the effects of different long terminal repeats (LTRs) on IL-3 gene expression and autocrine transformation were investigated. LTRs from defective IAPs, and replication competent Moloney murine leukemia virus (MoMuLV), human T cell leukemia (HTLV), and immunodeficiency (HIV) viruses, were inserted 5' of the IL-3 promoter region, and their transforming abilities determined. Addition of the lymphocyte specific (LS) IAP-LTR to the germline IL-3 (gIL3) gene, the IAP-LTR present in the previously described transposition, resulted in a modified IL-3 gene that only infrequently transformed IL-3-dependent cells. In contrast, addition of plasmacytoma (PC) IAP-LTRs to the gIL3 gene, which were isolated from IAPs expressed in plasmacytomas, resulted in modified IL-3 genes that transformed IL-3-dependent cells more readily. The MoMuLV-LTR and the TCRdelta enhancer also stimulated high levels of IL-3 expression and autocrine transformation. In contrast, the HTLV-I, HTLV-II and HIV LTRs did not induce significant IL-3 synthesis or autocrine transformation. Consistent with these results, higher levels of CAT expression were observed in cells transiently transfected with PC-IAP-LTR or a TCR enhancer compared with LS-IAP and HTLV LTRs. In summary, the rank order for the effects of different LTRs on IL-3 expression and cell transformation is: TCRdelta-enhancer approximately MoMuLV-LTR > PC-IAP-LTRs >> LS-IAP-LTR >> HTLV-LTRs approximately HIV-LTR. These results indicate that the LS-IAP-LTR is very weak at inducing IL-3 gene transcription and additional genetic mutations may be necessary for LS-IAPs to induce autocrine transformation of hematopoietic cells. In contrast, the enhancers contained in PC-IAP-LTRs and TCR enhancers may be more effective in inducing abnormal gene expression and malignant transformation.
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PMID:Differential effects of retroviral long terminal repeats on interleukin-3 gene expression and autocrine transformation. 932 93

The Tat protein of human immunodeficiency virus type 1 (HIV-1) is a potent trans-activator of transcription from the viral LTR promoter. Previous mutagenesis studies have identified domains within Tat responsible for binding to its TAR RNA target and for transcriptional activation. The minimal Tat activation domain is composed of the N-terminal 48 residues, and mutational analyses identified a cluster of critical cysteines. The importance of four highly conserved aromatic amino acids within the activation domain has not been thoroughly investigated. We have systematically substituted these aromatic residues (Y26, F32, F38, Y47) of the HIV-1 LAI Tat protein with other aromatic residues (conservative mutation) or alanine (nonconservative mutation). The activity of the mutant Tat constructs was measured in different cell lines by transfection with a LTR-CAT reporter plasmid. The range of transcriptional activities measured for this set of Tat mutants allowed careful assessment of the level of Tat activity required for optimal viral replication. To test this, the mutant Tat genes were introduced into the pLAI infectious molecular clone and tested for their effect on virus replication in a T-cell line. We found that a twofold reduction in Tat activity already affects viral replication, and no virus replication was measured for Tat mutants with less than 15% activity. This strict correlation between Tat activity and viral replication demonstrates the importance of the Tat function to viral fitness. Interestingly, a less pronounced replication defect was observed in primary cell types. This finding may correlate with the frequent detection of proviruses with Tat-inactivating mutations in clinical samples.
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PMID:Determination of the minimal amount of Tat activity required for human immunodeficiency virus type 1 replication. 935 35

A series of human immunodeficiency virus type 1 (HIV-1) proviral gag gene mutants carrying bacterial CAT gene were constructed and monitored for the expression of reverse transcriptase and CAT in a highly sensitive single-round replication assay system to determine the defective replication phase in lymphocytic cells. All the mutants displayed no abnormality in the process of transcription and translation at late replication stage. In contrast, some matrix, capsid, and p6 mutants were defective at final phase, that is, assembly and virion release. Most of the mutants including nucleocapsid mutants, which showed normal phenotype at late stage, were defective at early replication phase. From the functional domain map thus obtained, it is evident that HIV-1 Gag proteins are required for both early and late replication phases.
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PMID:Functional domain mapping of HIV-1 Gag proteins. 942 69


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