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
. 2012:2012:123605.
doi: 10.1155/2012/123605. Epub 2012 Jul 30.

Impact of Tat Genetic Variation on HIV-1 Disease

Luna Li  1 , Satinder Dahiya, Sandhya Kortagere, Benjamas Aiamkitsumrit, David Cunningham, Vanessa Pirrone, Michael R Nonnemacher, Brian Wigdahl
Affiliations

Impact of Tat Genetic Variation on HIV-1 Disease

Luna Li et al. Adv Virol. 2012.

Abstract

The human immunodeficiency virus type 1 (HIV-1) promoter or long-terminal repeat (LTR) regulates viral gene expression by interacting with multiple viral and host factors. The viral transactivator protein Tat plays an important role in transcriptional activation of HIV-1 gene expression. Functional domains of Tat and its interaction with transactivation response element RNA and cellular transcription factors have been examined. Genetic variation within tat of different HIV-1 subtypes has been shown to affect the interaction of the viral transactivator with cellular and/or viral proteins, influencing the overall level of transcriptional activation as well as its action as a neurotoxic protein. Consequently, the genetic variability within tat may impact the molecular architecture of functional domains of the Tat protein that may impact HIV pathogenesis and disease. Tat as a therapeutic target for anti-HIV drugs has also been discussed.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Schematic representation of HIV-1 Tat with locations of the six main domains indicated. Within each domain, important amino acid residues are designated. In addition, known functions of the domains or interactions with the protein involved in transcription are also highlighted.
Figure 2
Figure 2
Molecular architecture of the HIV-1 long-terminal repeat. The viral promoter, the long-terminal repeat (LTR), can be divided into the U3, R, and U5 regions. Upon integration, the LTR presents stretches of DNase I hypersensitivity sites (shown as HS2, HS3, and HS4) as a result of the well-defined, conversed positioning of the two nucleosomes; nuc-0 and nuc-1. This architecture results in exposure of stretches of DNA extremely rich in transcription factor-binding sites that include different regulatory proteins in the process of HIV-1 transcription. These factors respond to various extracellular and intracellular stimuli, resulting in upregulation/downregulation of specific downstream transcription factors that act via binding to their respective binding sites in the LTR. Also, positioning of nuc-1 is crucial because it is present immediately downstream of the start site (+1); this nucleosome needs to be remodeled for active processive transcription to ensue from the LTR. Moreover, modifications like acetylation, phosphorylation, and methylation of histone tails regulate LTR-directed transcription. The HIV-1 Tat protein regulates the chromatin environment via interactions with several components including methyltransferases, acetyltransferases, and a number of transcription factors in addition to binding to the TAR element in nascent HIV-1 RNA.
Figure 3
Figure 3
Functions of Tat. Tat plays a crucial role in synthesis of full-length HIV-1 mRNA transcripts. In the absence of Tat, the viral promoter remains latent with NF-κB (p50 homodimers) and histone deacetylase complexes (HDACs) maintaining a repressive chromatin environment by deacetylating the histones (a). Thus, RNA polymerase-(RNAPII) driven transcription is not progressive- and full-length HIV-1 transcripts are not synthesized. (b) Under a cellular stimulation environment, the latent state is overcome by recruitment of CBP/p300 complex to the viral promoter, the LTR. The Tat protein translocates to the nucleus and triggers a release of P-TEFb (CDK9/CycT1) from an inactive complex with HEXIM1, LARP, and 7SK RNA (1). The active P-TEFb in complex with Tat then interacts with the stem-loop structure (TAR) in the nascent HIV-1 mRNA's 5′ end. This event triggers the phosphorylation of the C-terminal domain (CTD) of RNAPII by CDK9, resulting in productive transcription from the LTR (b). Tat also participates in formation of a “super elongation complex” with factors including ELL2, AFF1, EAF1, and others, which also aids in synthesis of full-length HIV-1 transcripts from the relieved template (2). Tat also recruits another kinase DNA-PK in a ternary complex with Sp1 transcription factor at the LTR (3). This results in phosphorylation of Sp1 and activation of Sp1-mediated LTR-directed transcription. Tat also interacts with C/EBPβ and triggers an increase in the nuclear levels of C/EBPβ, again indirectly regulating the transcription of the HIV-1 genome (4). Moreover, Tat also regulates transcription of other cellular promoters of phosphatases like PTEN and PP2A. These play crucial regulatory roles in apoptosis of HIV-1-infected CD4+ T cells (5).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Garcia JA, Harrich D, Soultanakis E, Wu F, Mitsuyasu R, Gaynor RB. Human immunodeficiency virus type 1 LTR TATA and TAR region sequences required for transcriptional regulation. EMBO Journal. 1989;8(3):765–778. - PMC - PubMed
    1. Rana TM, Jeang KT. Biochemical and functional interactions between HIV-1 Tat protein and TAR RNA. Archives of Biochemistry and Biophysics. 1999;365(2):175–185. - PubMed
    1. Fields BN, Knipe DM, Howley PM. Fields' Virology. 5th edition. Philadelphia, Pa, USA: Lippincott Williams & Wilkins; 2007.
    1. Jeang KT, Xiao H, Rich EA. Multifaceted activities of the HIV-1 transactivator of transcription, tat. Journal of Biological Chemistry. 1999;274(41):28837–28840. - PubMed
    1. Barre-Sinoussi F, Chermann JC, Rey F. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS) Science. 1983;220(4599):868–871. - PubMed

LinkOut - more resources