Human immunodeficiency virus trans-activator of transcription–trans-activation response element interaction (HIV Tat–TAR interaction) (HIV Tat–TAR interaction)

The HIV Tat–TAR interaction is a critical regulatory mechanism in the life cycle of the Human Immunodeficiency Virus (HIV) (UniProt P04608). The Trans-Activator of Transcription (Tat) is a viral protein that binds to the Trans-Activation Response (TAR) element, a stable RNA stem-loop structure located at the 5' end of all nascent HIV-1 transcripts (PubMed: 11527494). This binding event is essential for the recruitment of the host's positive transcription elongation factor b (P-TEFb) complex, which consists of Cyclin T1 and Cyclin-dependent kinase 9 (CDK9) (PubMed: 21884667). Once recruited, CDK9 phosphorylates the C-terminal domain of RNA polymerase II, dramatically increasing the efficiency of viral transcription elongation (PubMed: 10490611). Without this interaction, HIV-1 transcription is highly inefficient, resulting in short, non-functional transcripts. Because this interaction is vital for viral replication and is highly conserved, it represents an attractive therapeutic target for antiretroviral therapy (PubMed: 24333650). Drugs targeting this interaction typically aim to either sterically block the Tat-TAR binding site or inhibit the associated P-TEFb complex, such as Alvocidib (Flavopiridol) (ClinicalTrials.gov). However, challenges include the potential for off-target effects on host transcription and the rapid emergence of viral resistance (PubMed: 16111629).

Other names

Tat-TAR complexHIV-1 Tat-TAR interactionTrans-activator of transcription-Trans-activation response element

Inhibition of the binding between the HIV Tat protein and the TAR RNA stem-loop, preventing the recruitment of the P-TEFb complex and subsequent phosphorylation of RNA polymerase II, thereby blocking viral transcription elongation.