Fig. 2.

HIV-1 Tat interactions and transcriptional regulation. (1) Tat interacts with P-TEFb and triggers its release from the inactive complex formed with 7SK, HEXIM-1 and La ribonucleoprotein domain family member (LARP). (2) The active P-TEFb is recruited to the LTR as a result of the interaction of Tat with the TAR element formed at the 5′ end of the nascent HIV-1 RNA. This event is followed by phosphorylation of the CTD of RNAP II by the CDK9 component of P-TEFb. These phosphorylation events help RNAP II to shift from an initiation mode to an elongation mode, resulting in production of full-length HIV-1 mRNA that exits to the cytosol to be used to make HIV-1 proteins. In addition, the full activity of Tat is associated with its post-translation modifications, namely acetylation and methylation. (3) Tat also regulates the activity of Sp1 in LTR-directed transcription by recruiting DNA-PK to phosphorylate Sp1. (4) Tat activates other cellular promoters such as PTEN and PP2A and is secreted into the extracellular milieu, which has been shown to play a crucial role in apoptosis of CD4⁺ T-cells and to mediate neuronal toxicity.