Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017;23(28):4098-4102.
doi: 10.2174/1381612823666170704130635.

The HIV-1 Tat Protein: Mechanism of Action and Target for HIV-1 Cure Strategies

Andrew P Rice  1
Affiliations
Review

The HIV-1 Tat Protein: Mechanism of Action and Target for HIV-1 Cure Strategies

Andrew P Rice. Curr Pharm Des. 2017.

Abstract

The general mechanism involved in Tat activation of RNA Polymerase II (RNAP II) elongation of the integrated HIV-1 was elucidated over 20 years ago. This mechanism involves Tat binding to the TAR RNA element that forms at the 5' end of viral transcripts and recruiting a general RNAP II elongation factor termed as PTEFb. This elongation factor consists of CDK9 and Cyclin T1, and when recruited by Tat to TAR RNA, CDK9 was proposed to phosphorylate the carboxyl terminal domain of RNAP II and thereby activate elongation. Research in the past two decades has shown that the mechanism of Tat action is considerably more complicated than this simple model. In metabolically active cells, CDK9 and Cyclin T1 are now known to be largely sequestered in a RNA-protein complex termed the 7SK RNP. CDK9 and Cyclin T1 are released from the 7SK RNP by mechanisms not yet fully elucidated and along with Tat, bind to TAR RNA and orchestrate the assembly of a Super Elongation Complex (SEC) containing several additional proteins. CDK9 in the SEC then phosphorylates multiple substrates in the RNAP II complex to activate elongation. Importantly for therapeutic strategies, CDK9 and Cyclin T1 functions are down-regulated in resting CD4+ T cells that harbor latent HIV-1, and their up-regulation is required for reactivation of latent virus. Current strategies for a functional cure of HIV-1 infection therefore are likely to require development of latency reversal agents that up-regulate CDK9 and Cyclin T1 function in resting CD4+ T cells.

Keywords: CDK9; Cyclin T1; HIV latency; HIV-1; P-TEFb; Tat.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest

The author has no conflicts of interest.

Figures

Figure 1
Figure 1. Mechanism of action of Tat
Cis-regulatory elements (e.g., NF-κB, Sp1) in the HIV-1 LTR direct binding of RNAP II to the viral promoter, transcriptional initiation occures, and TAR RNA at the 5′ end of the nascent viral transcript is produced. Tat binds to TAR RNA along with Cyclin T1 and CDK9 and this orchestrates the assembly of the Super Elongation Complex consisting of ENL/AF9/ELL2/AFF4. CDK9 phosphorylates subunits of DSIF and NELF and thereby overcomes their inhibition of RNAP II elongation. The CTD of RNAP II is hyperphosphorylated by CDK9. Cyclin T1 and CDK9 can be extracted from the 7SK P-TEFb RNP by Tat as indicated.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Sodroski JG, Rosen CA, Wong-Staal F, Popovic M, Arya SK, Gallo RC, et al. Trans-Acting Transcriptional Regulation of Human T-Cell Leukemia Virus Type III Long Terminal Repeat. Science. 1985;227:171–3. - PubMed
    1. Sodroski JG, Patarca R, Rosen CA, Haseltine WA. Location of the trans-activating region on the genome of human T-cell lymphotropic virus III. Science. 1985;229:74–7. - PubMed
    1. Kao SY, Calman AF, Luciw PA, Peterlin BM. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature. 1987;330:489–93. - PubMed
    1. Feng S, Holland EC. HIV-1 tat trans-activation requires the loop sequence within tar. Nature. 1988;334:165–7. - PubMed
    1. Ernberg I, Gait MJ, Green SM, Heaphy S, Karn J, Lowe AD, et al. Human immunodeficiency virus 1 tat protein binds trans- activation-responsive region (TAR) RNA in vitro. Proc Natl Acad Sci USA. 1989;86:6925–9. - PMC - PubMed

Publication types

MeSH terms