The human immunodeficiency virus type I (HIV-1) nuclear protein Tat is a potent activator of viral gene transcription. Activation by Tat requires a cis-acting element, the transactivation response (TAR) site, located immediately downstream of the transcription start site. Several observations suggest that TAR functions as the nascent RNA product of the HIV long-terminal-repeat promoter (for a review, see ref. 6). Indeed, Tat protein and several cellular proteins bind directly to nascent TAR RNA in vitro. The significance of these in vitro interactions remains to be established. Here we report that Tat can activate transcription when bound to nascent RNA through the RNA-binding domain of another HIV-1 protein, Rev. Rev is a sequence-specific RNA-binding protein, which interacts with the viral RNA element RRE (refs 11-15). A Tat-Rev fusion protein efficiently activates transcription from an HIV-1 promoter derivative, in which TAR has been replaced by the RRE. We conclude that activation of transcription by Tat can occur by direct binding to nascent RNA, and that the sole function of TAR may be to provide a Tat-binding site. Our results further suggest that cellular proteins that bind specifically to TAR RNA or TAR DNA may not be essential for Tat-responsiveness.
"Studies of Cochrane and co-workers found that Rev could only export newly synthesized HIV RNA indicating that Rev acts on nascent transcripts rather than on downstream pathways engaged in splicing or RNA degradation . Another indirect demonstration of Rev acting co-transcriptionally comes from early studies on the transactivation potential of Tat-Rev hybrids tethered to TAR-less constructs through association with the RRE [112,113]. Therefore, rather than forming a nuclear storage compartment for viral pre-mRNA where Rev would act, as it has been previously proposed [51,53,114], HIV-1 pre-mRNA appears to be associated with Rev at the site of transcription from where it is further exported. However, direct evidence of Rev at the transcription site is still missing since most studies concerning Rev subcellular localization did not carefully investigate the nascent proviral RNA at the same time [114,115,116,117,118,119]. "
[Show abstract][Hide abstract] ABSTRACT: Gene expression of the human immunodeficiency virus type 1 (HIV-1) is a highly regulated process. Basal transcription of the integrated provirus generates early transcripts that encode for the viral products Tat and Rev. Tat promotes the elongation of RNA polymerase while Rev mediates the nuclear export of viral RNAs that contain the Rev-responsive RNA element (RRE). These RNAs are exported from the nucleus to allow expression of Gag-Pol and Env proteins and for the production of full-length genomic RNAs. A balance exists between completely processed mRNAs and RRE-containing RNAs. Rev functions as an adaptor that recruits cellular factors to re-direct singly spliced and unspliced viral RNAs to nuclear export. The aim of this review is to address the dynamic regulation of this post-transcriptional pathway in light of recent findings that implicate several novel cellular cofactors of Rev function.
"Despite the relatively small size of Tat protein, it strongly stimulates the gene expression of HIV provirus in multiple ways (reviewed in Okamoto, 1995; Jones, 1997; Jeang et al., 1999; Kahn, 1999): First, the formation of Tat–TAR complex was suggested to induce augmented transcription from the DNA template containing the TAR element, indicating that TAR might be the RNA equivalent of DNA enhancer element (thus called " RNA enhancer " ) (Sharp and Marciniak, 1989). The involvement of Tat in transcriptional initiation was supported by the fact that the fusion protein containing the GAL4 DNA-binding region and the Tat activation domain could support the transcriptional activation (Southgate et al., 1990). In fact, Tat has been shown to interact with RNA polymerase II holoenzyme (Mavankal et al., 1996) and histone acetylase (Hottiger and Nabel, 1998). "
[Show abstract][Hide abstract] ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) is unique in that it encodes its own transcriptional activator Tat, which specifically binds to the viral mRNA sequence TAR (transactivation response) element and activates viral transcription at the step of elongation as well as initiation. We recently reported that fluoroquinoline derivatives inhibited HIV-1 replication most likely by blocking viral transcription. In this report, we investigated the mechanism of action of one such compound 7-(3, 4-dehydro-4-phenyl-1-piperidinyl)-1, 4-dihydro-6-fluoro-1-methyl-8-trifluoromethyl-4-oxoquinoline-3-carbox ylic acid (K-37). We demonstrated that K-37 inhibited not only Tat but also other RNA-dependent transactivators. No effect was observed with DNA-dependent transactivators such as p65 (NF-kappaB) and Gal4VP16. Moreover, K-37 did not inhibit carboxyl-terminal domain (CTD)-kinase activities of CDK-activating kinase (CAK) and positive transcription elongation factor b (P-TEFb), which are known to be involved in Tat-mediated transactivation at the step of transcriptional elongation. It is suggested that RNA-mediated transactivation may involve a common unknown factor to which K-37 directly interacts. Since K-37 did not appear to block DNA-mediated transactivation and thus did not show strong nonspecific cytotoxicity as reported previously, K-37 and its derivative compounds are considered to be feasible candidates for a novel AIDS therapy.
"Tat might also play some role in the transcriptional initiation. For example, the GAL4-Tat fusion protein activates transcription from a promoter containing GAL4 binding sites (Southgate et al., 1990). Furthermore, Tat is also known to interact with RNAP II holoenzyme (Cujec et al., 1997b), TATA-binding protein (Kashanchi et al., 1994), and histone acetylase such as CBP (Benkirane et al., 1998; Hottiger et al., 1998). "
[Show abstract][Hide abstract] ABSTRACT: The activation of the HIV-1 long terminal repeat (LTR) by the viral transcriptional transactivator Tat is an essential step in the viral replication cycle. To increase the processivity of RNA polymerase II, Tat interacts with the positive transcription elongation factor b (P-TEFb) and cyclin-dependent kinase (CDK)-activating kinase (CAK). In this study, we demonstrate that a pseudo-substrate peptide for CDK7, mC2p, inhibits HIV-1 replication as well as Tat transactivation. Specifically, mC2p blocks only the activity of CAK and not that of P-TEFb. Moreover, mC2p inhibits Tat transactivation and HIV replication. Therefore, the activation of CDK7 by Tat is considered a critical step of Tat transactivation and mC2p and related compounds represent potential candidates for novel anti-HIV therapeutics.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.