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

The transactivator protein Tat stimulates transcriptional elongation from the HIV-1 LTR. One mechanism by which Tat increases HIV-1 transcription is by interacting with RNA polymerase II and TFIIH to increase phosphorylation of the polymerase C-terminal domain. Recent studies indicate that specific elongation factors may also be required to modulate Tat function. Here, we used biochemical analysis and in vitro transcription assays to identify cellular factors required for Tat activation. This analysis resulted in the purification of a cellular factor Tat-CT1 which is a human homolog of the yeast transcription factor SPT5. Immunodepletion of Tat-CTl from HeLa extract demonstrated that this factor was involved in transcriptional activation by Tat. However, the absence of this factor from HeLa extract did not prevent transcriptional activation by VP16. These findings are consistent with a model in which Tat-mediated effects on transcriptional elongation are mediated in part by the action of the human homolog of the yeast transcription factor SPT5.
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PMID:Role of the human homolog of the yeast transcription factor SPT5 in HIV-1 Tat-activation. 951 52

The HIV-1 Tat protein is an RNA-binding transcriptional transactivator. Recent findings suggest that Tat associates with a cellular kinase that phosphorylates the carboxyl-terminal domain of the largest subunit of RNA polymerase II. Here we review, in brief, the role of Tat-associated kinase in Tat-activated transcription. We discuss evidence that suggests involvement of TFIIH and/or P-TEFb.
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PMID:Tat, Tat-associated kinase, and transcription. 957 May 10

Tat stimulates human immunodeficiency virus type 1 (HIV-1) transcription elongation through recognition of the transactivation response (TAR) RNA stem-loop structure at the 5' end of nascent viral transcripts. Recently, a human transcription elongation factor P-TEFb, consisting of CDK9 kinase, cyclin T and other associated factors, has been shown to interact with Tat to restore Tat activation in HeLa nuclear extract depleted of P-TEFb. Here, we report the purification of a P-TEFb complex fraction containing epitope-tagged wild-type CDK9 or kinase-inactive CDK9 and five tightly associated polypeptides. Only wild-type P-TEFb complex with an active CDK9 kinase was able to hyperphosphorylate the C-terminal domain of RNA polymerase II and mediate Tat transactivation in P-TEFb-depleted HeLa nuclear extract. Tat also stimulated transcription elongation by recruitment of the P-TEFb complex to the HIV-1 promoter through a Tat-TAR interaction. A possible mechanism for P-TEFb to become associated with polymerase elongation complexes and function as a general elongation factor was demonstrated by an interaction of P-TEFb with double-stranded RNA molecules through an 87 kDa subunit. Finally, P-TEFb was found to interact with and phosphorylate Tat-SF1, a Tat cofactor required for Tat transactivation. Our data indicate that the various subunits of the human P-TEFb complex may play distinct roles at multiple stages to mediate Tat activation of HIV-1 transcription elongation.
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PMID:Transcription elongation factor P-TEFb mediates Tat activation of HIV-1 transcription at multiple stages. 964 38

A strong transcriptional pause delays human RNA polymerase II three nt after the last potentially paired base in HIV-1 TAR, the RNA structure that binds the transactivator protein Tat. We report here that the HIV-1 pause depends in part on an alternative RNA structure (the HIV-1 pause hairpin) that competes with formation of TAR. By probing the nascent RNA structure in halted transcription complexes, we found that the transcript folds as the pause hairpin before and at the pause, and rearranges to TAR concurrent with or just after escape from the pause. The pause signal triggers a 2 nt reverse translocation by RNA polymerase that may block the active site and be counteracted by formation of TAR. Thus, the HIV-1 pause site modulates nascent RNA rearrangement from a structure that favors pausing to one that both recruits Tat and promotes escape from the pause.
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PMID:Transcriptional pausing at +62 of the HIV-1 nascent RNA modulates formation of the TAR RNA structure. 965 86

HIV-1 gene expression requires the transactivator Tat, which stimulates viral transcript elongation. Recent results show that two cellular cyclin-dependent kinases, which phosphorylate the carboxy-terminal domain of the RNA polymerase II large subunit, contact Tat and contribute to the control of transcriptional elongation.
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PMID:Transcriptional control: Tat cofactors and transcriptional elongation. 965 70

During transcription of mRNA genes, there is a correlation between the phosphorylation state of the C-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAP II) and the ability of the RNAP II complex to processively transcribe the gene. To examine the involvement of CTD phosphorylation in modulation of RNAP II function, we have analyzed the ability of a known CTD kinase, human Cdk8, to modulate HIV-1 LTR-driven gene expression upon directed targeting to a promoter-proximal nascent RNA element. The results indicated that Cdk8, when localized to an RNA element, activates gene expression in a catalysis-dependent manner. Also, Cdk8 targeted to RNA was observed to act in a synergystic manner with DNA-targeted Sp1 but not with DNA-targeted HIV-1 Tat, suggesting that RNA-targeted Cdk8 acts on similar rate limiting post-initiation events as Tat. As recent observations suggest that Tat/TAR-mediated transcription of the proviral genome of HIV depends on specific phosphorylation of RNAP II in its CTD by the Tat-associated kinase (TAK/p-TEFb/Cdk9), our results indicate that Cdk8 shares with Cdk9 the ability to modulate transcription upon targeting to a nascent RNA element.
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PMID:Targeting of CDK8 to a promoter-proximal RNA element demonstrates catalysis-dependent activation of gene expression. 968 96

Interferon (IFN) treatment of lentivirus-infected cells substantially reduces virus replication in vitro. Although the replication of both HIV-1 and simian immunodeficiency virus (SIV) is inhibited, IFN blocks the replication of these viruses at different stages of the viral life cycle. We previously demonstrated that in HIV-1-infected cells, IFN blocks a late step in viral replication, leading to a decrease in viral protein stability and a deregulation of polyprotein processing. In contrast, in SIV-infected cells, IFN blocks an early step in viral replication, between virus binding and reverse transcription. Thus, the viral gene products targeted by IFN may be different for each of these viruses. To attempt to define which viral proteins are targeted by the IFN response, we examined the effects of IFN on the replication of two SIV/HIV-1 (SHIV) chimeric viruses, SHIV-4(vpu+) and SHIV-4(vpu-) in 174 x CEM cells. These viruses were grown from constructs in which the SIVmac239 env, tat, and rev genes have been replaced with those HIV-1. The use of SHIV-4(vpu+) allowed us to examine whether vpu, which is unique to HIV-1, might contribute to the differential effects of IFN on HIV-1 and SIV replication. Surprisingly, we found that IFN inhibited SHIV replication differently than the replication of either HIV-1 or SIV. IFN treatment of SHIV-infected cells resulted in a decrease in the level of viral RNA expression but had no apparent effect on the integration of proviral DNA. Nuclear runoff transcription assays indicated that the reduction of SHIV RNA expression in IFN-treated cells was not due to alterations in RNA polymerase II-mediated transcription, suggesting that IFN may block SHIV replication by promoting the increased degradation of viral RNA. The presence of absence of the vpu gene did not alter the effects of IFN on SHIV replication, indicating that Vpu is not responsible for the differential effect of IFN on HIV-1 and SIV replication. Thus the response of SHIVs to antiviral agents such as IFN may be unique from either HIV-1 or SIV. This may be an important consideration when using SHIVs to evaluate anti-HIV-1 therapies in animal models of AIDS.
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PMID:Interferon inhibits the replication of HIV-1, SIV, and SHIV chimeric viruses by distinct mechanisms. 970 19

Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disposition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curcumin) which favorably interact with an "accessory" region of IN. This region is supposed to be located adjacent to the binding site accommodating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of coplanarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain energy of the coplanar conformation.
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PMID:Geometrically and conformationally restrained cinnamoyl compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation, and molecular modeling. 976 32

Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-1, lymphoid-enhancer binding factor 1, and TATA-box binding protein. These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays. When used in combination, the polyamides inhibit virus replication by >99% in isolated human peripheral blood lymphocytes, with no detectable cell toxicity. The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II promoters suggests a general approach for regulation of gene expression, as well as a mechanism for the inhibition of viral replication.
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PMID:Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands. 978 80

Cyclin T1 has been identified recently as a regulatory subunit of CDK9 and as a component of the transcription elongation factor P-TEFb. Cyclin T1/CDK9 complexes phosphorylate the carboxy terminal domain (CTD) of RNA polymerase II (RNAP II) in vitro. Here we report that the levels of cyclin T1 are dramatically upregulated by two independent signaling pathways triggered respectively by PMA and PHA in primary human peripheral blood lymphocytes (PBLs). Activation of these two pathways in tandem is sufficient for PBLs to enter and progress through the cell cycle. However, the expression of cyclin T1 is not growth and/or cell cycle regulated in other cell types, indicating that regulation of cyclin T1 expression is dependent on tissue-specific signaling pathways. Upregulation of cyclin T1 in stimulated PBLs results in induction of the CTD kinase activity of the cyclin T1/CDK9 complex, which in turn correlates directly with phosphorylation of RNAP II in vivo, linking for the first time activation of the cyclin T1/ CDK9 pair with phosphorylation of RNAP II in vivo. In addition, we report here that endogenous CDK9 and cyclin T1 complexes associate with HIV-1 generated Tat in relevant cells and under physiological conditions (HIV-1 infected T cells). This, together with our results showing that HIV-1 replication in stimulated PBLs correlates with the levels of cyclin T1 protein and associated CTD kinase activity, suggests that the cyclin T1/CDK9 pair is one of the HIV-1 required host cellular cofactors generated during T cell activation.
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PMID:Upregulation of cyclin T1/CDK9 complexes during T cell activation. 987 25


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