123605.fig.003a
(a)
123605.fig.003b
(b)
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- B (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).