UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein kinase inhibitor 2-aminopurine (2-AP) greatly stimulated expression in human promonocytes-macrophages of plasmid constructs carrying various reporter genes (chloramphenicol acetyltransferase, lacZ, firefly luciferase [luc], and Salmonella typhimurium histidinol dehydrogenase [his]) driven by the human immunodeficiency virus type 1 (HIV-1) long terminal repeat. Adenine, adenosine, and caffeine were also effective inducers, but other purine or pyrimidine derivatives were ineffective. Experiments with mutant derivatives of the HIV-1 long terminal repeat revealed no specific eukaryotic promoter elements necessary for 2-AP induction but indicated the need for some minimum combination of such elements. Induction of HIV-1-directed gene expression appeared not to require action of the transcription factor NF-kappa B. The mechanism of induction was investigated by using the luc and his genes linked to the HIV-1 long terminal repeat. 2-AP induced marked, steady rises in mRNA accumulation from both transfected and chromosomally integrated HIV-1 constructs but no increases from an endogenous gene encoding gamma-actin or glucose 6-phosphate dehydrogenase. Thus, induction is selective and not an artifact induced by transfecting DNA into cells. In run-on transcription experiments, the rates of transcription initiation of both transfected and integrated copies of the his gene increased about sixfold in cells treated with 2-AP. Thus, while increased initiation accounted for a portion of 2-AP induction, it could not cause the far greater increase in steady-state mRNA levels. 2-AP induction did not change mRNA decay rates and differed from the phorbol ester (phorbol myristate acetate)-induced activation of the protein kinase C-NF-kappa B pathway in its time course and in its requirement for new protein synthesis. Gel retardation assays showed that unlike phorbol myristate acetate induction, 2-AP induction is enhancer independent. Whereas many previous studies have implicated the activation of various protein kinases in gene induction, we here describe a mechanism of gene activation that appears to involve protein kinase inhibition as a component of the induction response.
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PMID:Inducible transcriptional activation of the human immunodeficiency virus long terminal repeat by protein kinase inhibitors. 835 80

Epidemiologic studies show an association between infection with human immunodeficiency virus type 1 (HIV-1) and human papillomavirus (HPV) associated anogenital disease. To investigate possible molecular mechanisms of HIV-1 modulation of HPV expression, we studied the effect of an HIV-1 regulatory protein, tat1, on gene expression directed by the upstream regulatory region (URR) of HPV type 16 (HPV 16). HPV 16 URR-directed chloramphenicol acetyltransferase (CAT) expression driven by the native HPV 16 promoter (P97) was increased in the presence of tat1 alone. Tat1 also reversed E2-mediated repression of P97-directed CAT expression. E2 mediated CAT expression with URR constructs containing the SV40 promoter was enhanced when tat1 and E2 were cotransfected. Using a cervical carcinoma cell line (SiHa), E2 enhancement of URR-directed gene expression was elevated in the presence of extracellular tat1 or during cocultivation with HIV-1-infected cells. These results show HIV can modulate HPV gene expression in cell culture and that the increased rate of HPV-associated cervical disease in asymptomatic HIV-seropositive women may result from HPV-HIV molecular interactions.
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PMID:The HIV-1 tat protein enhances E2-dependent human papillomavirus 16 transcription. 838 65

Human immunodeficiency virus type 1 (HIV-1)-infected subjects show a high incidence of Epstein-Barr virus (EBV) infection. This suggests that EBV may function as a cofactor that affects HIV-1 activation and may play a major role in the progression of AIDS. To test this hypothesis, we generated two EBV-negative human B-cell lines that stably express the EBNA2 gene of EBV. These EBNA2-positive cell lines were transiently transfected with plasmids that carry either the wild type or deletion mutants of the HIV-1 long terminal repeat (LTR) fused to the chloramphenicol acetyltransferase (CAT) gene. There was a consistently higher HIV-1 LTR activation in EBNA2-expressing cells than in control cells, which suggested that EBNA2 proteins could activate the HIV-1 promoter, possibly by inducing nuclear factors binding to HIV-1 cis-regulatory sequences. To test this possibility, we used CAT-based plasmids carrying deletions of the NF-kappa B (pNFA-CAT), Sp1 (pSpA-CAT), or TAR (pTAR-CAT) region of the HIV-1 LTR and retardation assays in which nuclear proteins from EBNA2-expressing cells were challenged with oligonucleotides encompassing the NF-kappa B or Sp1 region of the HIV-1 LTR. We found that both the NF-kappa B and the Sp1 sites of the HIV-1 LTR are necessary for EBNA2 transactivation and that increased expression resulted from the induction of NF-kappa B-like factors. Moreover, experiments with the TAR-deleted pTAR-CAT and with the tat-expressing pAR-TAT plasmids indicated that endogenous Tat-like proteins could participate in EBNA2-mediated activation of the HIV-1 LTR and that EBNA2 proteins can synergize with the viral tat transactivator. Transfection experiments with plasmids expressing the EBNA1, EBNA3, and EBNALP genes did not cause a significant HIV-1 LTR activation. Thus, it appears that among the latent EBV genes tested, EBNA2 was the only EBV gene active on the HIV-1 LTR. The transactivation function of EBNA2 was also observed in the HeLa epithelial cell line, which suggests that EBV and HIV-1 infection of non-B cells may result in HIV-1 promoter activation. Therefore, a specific gene product of EBV, EBNA2, can transactivate HIV-1 and possibly contribute to the clinical progression of AIDS.
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PMID:Epstein-Barr virus nuclear antigen 2 transactivates the long terminal repeat of human immunodeficiency virus type 1. 838 79

Nitrogen mustard (HN2) and quinacrine mustard (QM) both inhibited the binding of NF kappa B to the GC-rich consensus sequence in the HIV long terminal repeat (LTR), as assessed by gel-shift assays. QM also inhibited the binding of OTF-1 to the AT-rich octamer present in the H2B promoter whereas HN2 was inactive. Inhibition of the binding of transcription factors was due to the drug interaction with DNA, since it also occurred when transcription factors were added to DNA after removal of free drug. In Jurkat cells transfected with pI3CAT, where the chloramphenicol acetyltransferase (CAT) gene is under the control of the HIV LTR, both HN2 and QM inhibited CAT gene expression. However, in Jurkat cells transfected with plasmid -147, where the CAT gene is under the control of the H2B promoter, QM inhibited CAT expression but HN2 did not. These results were obtained at concentrations of HN2 or QM that inhibited total DNA and RNA synthesis to a similar extent. The present results suggest that the more selective pharmacological activity of HN2 (HN2 is an active antineoplastic agent whereas QM is inactive and very toxic) might be related to its preferential functional inhibition of GC-rich consensus sequence, possibly important in the regulation of genes involved in the malignant proliferation and behavior of some tumors.
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PMID:Differential inhibition of the DNA binding of transcription factors NF kappa B and OTF-1 by nitrogen mustard and quinacrine mustard: transcriptional implications. 840 25

The human immunodeficiency virus type 1 long terminal repeat, HIV-1-LTR, contains binding sites for several cellular transcription factors which contribute to HIV-1 gene expression. Our previous studies on the function of the HIV-1-encoded Nef protein suggested that Nef may be an inhibitor HIV-1 transcription. To determine whether Nef affects the binding of cellular factors implicated in HIV-1 regulation, 32P-labeled oligonucleotides corresponding to the binding sites were incubated with nuclear extracts prepared from Nef-expressing T-cell lines that were not stimulated or were stimulated with T-cell mitogens. We found that Nef inhibited the recruitment of AP-1 DNA-binding activity in mitogen-stimulated human T-cells. Additionally, Nef expressing cells were transiently transfected with a plasmid in which HIV-1 AP-1 DNA recognition sequences were cloned downstream of the chloramphenicol acetyltransferase (CAT) gene. Mitogen-mediated transcriptional activation of the CAT gene in this construct was inhibited in Nef-expressing cells but not in control cells. These studies suggest that, by inhibiting AP-1 activation, Nef may play a role in regulating HIV-1 gene expression in infected T-cells.
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PMID:HIV-1 Nef protein inhibits the recruitment of AP-1 DNA-binding activity in human T-cells. 848 Apr 25

Transcription from the HIV-1 long terminal repeat (LTR) was shown to be inhibited by DNA CpG methylation both in vivo and in vitro. Enzymatic methylation of CpG sites localized within the LTR decreased the transcription of the CAT reporter gene, chloramphenicol acetyltransferase, as assayed by the transient expression of this gene in tissue culture. The inhibitory effect could be initially overcome, in trans, by the transactivator tat. As a function of time, the presence of tat had no observable effect on transcription, within the limits of detection sensitivity, suggesting that the level of basal transcription was reduced to very low levels. This effect is suggestive of the involvement of cellular CpG methylation-dependent inhibitory factors which have been characterized by other laboratories. These data imply that transactivation is reduced to low levels after longer periods of time when the DNA template is sparsely methylated. The transcriptional inhibitory process may involve proteins such as MeCP which may interact with methylated DNA more slowly and/or weakly. Conversely, densely methylated DNA was transcriptionally repressed immediately which suggests the rapid/strong association of the cellular inhibitory factor(s). The transcriptional inhibitory effect was also observed in an in vitro transcription run-off system. These data suggest that the methylation-mediated inhibition of transcription is directly affected by CpG methylation density and may involve other factors.
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PMID:Transcription of the HIV-1 LTR is regulated by the density of DNA CpG methylation. 849 86

The drug pentoxifylline (PTX) (1-(5'-oxohexyl) 3,7-dimethylxanthine) down-regulates human immunodeficiency virus (HIV-1) long terminal repeat (LTR)-directed gene expression in the human monocytic cell line U38. This effect of PTX has been tested in clinical trials. In this investigation, a similar inhibitory effect of PTX on HIV-1 LTR-driven gene expression was observed (a) in a stable transfectant of the human embryo kidney cell line 293-27-2 carrying an expression plasmid construct with the HIV-1 LTR fused to the bacterial lac Z gene, and also (b) by transient transfection of human embryo kidney cells 293 S with fusion plasmid constructs with wild-type [pHIV-LTR-chloramphenicol acetyltransferase (CAT)] or mutated (pHIV-LTR-mut-CAT) nuclear factor kappa B (NF-kappa B) motifs. In both stable and transient transfection studies, 4-beta-phorbol-12-beta-myristate-acetate (PMA)-induced or tumor necrosis factor-alpha (TNF-alpha)-induced activation of the HIV-1 LTR was correlated with a concomitant elevated level of NF-kappa B interaction with its motifs. The inducibility of HIV-1 LTR-driven gene expression by PMA or TNF-alpha in transiently transfected cells was completely eliminated by point mutations in the NF-kappa B motifs, suggesting that NF-kappa B plays a major role in the activation of the HIV-1 LTR by these agents in this cell system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pentoxifylline inhibits HIV-1 LTR-driven gene expression by blocking NF-kappa B action. 850 80

CD8+ T lymphocytes of HIV-1-infected individuals can efficiently suppress HIV-1 replication in CD4+ T lymphocytes. To elucidate the molecular events underlying this suppression, we have used the HIV-1 LTR directing the chloramphenicol acetyltransferase gene (CAT) in transient transfection assays using human Jurkat T cells. In addition to supernatants of patient CD8+ T lymphocytes (CD4+ > 350/microliters), supernatant of a T cell clone derived by Herpesvirus saimiri (HVS)-mediated transformation of CD8+ T lymphocytes of a patient demonstrating inhibition of virus replication were examined. Similar levels of inhibition of LTR-mediated gene expression in response to Tat or mitogenic activation with phorbol ester and calcium ionophore were observed by supernatants of both sources. The inhibitory effect of CD8+ T lymphocytes was not exclusive to lentiviral LTRs since transcription of both the HTLV-I LTR and RSV LTR in response to mitogen was effectively inhibited. In examination of the influence of CD8+ T cell-derived supernatant on NF kappa B-mediated activation, a dimer of the HIV-1 NF kappa B elements directing CAT was markedly inhibited by supernatants of both patient CD8+ lymphocytes and the HVS-derived CD8+ clone. Thus the inhibitory nature of CD8+ T lymphocytes appears not to be specific to lentiviral promoters and may mediate an inhibitory effect via the NF kappa B element.
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PMID:Suppression of activation of the human immunodeficiency virus long terminal repeat by CD8+ T cells is not lentivirus specific. 857 88

Protein tyrosine kinase p59fyn (Fyn) associates with the TCR-CD3 complex, which suggests that Fyn plays a significant role in the signal transduction involving TCR complex. In addition to cellular genes, viral promoters such as the HIV long terminal repeat (LTR) are also activated upon T cell activation. To elucidate the functional significance of Fyn in the expression of viral promoters, we transfected a Fyn-expression vector together with a reporter plasmid containing the chloramphenicol acetyltransferase gene driven by HIV LTR into a human T cell line, Jurkat. In this assay, Fyn stimulated the promoter in HIV LTR when the transfected cells were treated with both concanavalin A and PMA as an antigen-mimic stimulation. This activation required the intact SH2 domain of Fyn. Mutational analysis of HIV LTR showed that the NF kappa B binding sites were responsible for this effect. Electrophoretic mobility shift assays and UV cross-linking experiments showed that activation of T cells by anti-CD3 antibody induced four kappa B-binding proteins (50, 60, 65 and 100 kDa) in Fyn-overexpressing cells more efficiently than in the parental cells. Our results suggested that Fyn was able to regulate expression of a subset of genes via kappa B-binding proteins upon T cell activation.
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PMID:The protein tyrosine kinase Fyn activates transcription from the HIV promoter via activation of NF kappa B-like DNA-binding proteins. 858 83

In addition to Gag, Pol, and Env, primate lentiviruses encode other virion-associated proteins, including Vpr, Vpx, and Vif. Vpr- and Vpx-staphylococcal nuclease and chloramphenicol acetyltransferase fusion proteins incorporate into human immunodeficiency virus (HIV) virions and retain enzyme activity when expressed in trans with HIV proviruses (Wu et al., J. Virol. 69, 3389, 1995). To explore whether the viral protease (PR) could be expressed as a proteolytically active fusion protein, the HIV PR coding region was fused in-frame with the HIV-2 vpx and HIV-1 vpr genes. Using a vaccinia virus-T7 expression system, the Vpx-PR fusion protein was expressed and formed homodimers. Coexpression with Pr55Gag demonstrated that Vpx-PR possessed Gag-specific proteolytic activity and inhibited the production of Gag virus-like particles. Trans-expression of a PR-Vpr fusion protein with HIV-1 provirus caused a profound reduction in viral protein expression and virion production. Importantly, the PR-Vpr fusion protein caused a similar level of inhibition and intracellular cleavage of Pr55Gag precursor protein when coexpressed with protease defective HIV-1 provirus. The inhibitory effect of PR-Vpr expression on virion production was markedly greater than that of PR alone. These results indicate that Vpr arguments the intracellular proteolytic activity of PR when expressed as a fusion protein and thus may be relevant for the expression of PR in intracellular immunization strategies against HIV infection. Moreover, the ability to express and package enzymatically active PR-Vpr fusion protein, independent of Gag/Pol, may provide a novel means to study enzyme function.
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PMID:Proteolytic activity of human immunodeficiency virus Vpr- and Vpx-protease fusion proteins. 862 47

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