Tat (HIV) - Function and Mechanism

Function and Mechanism

Like other lentiviruses, Human immunodeficiency virus 1 (HIV-1) encodes a trans-activating regulatory protein (Tat), which is essential for efficient transcription of the viral genome. Tat acts by binding to an RNA stem-loop structure, the trans-activating response element (TAR), found at the 5' ends of nascent HIV-1 transcripts. In binding to TAR, Tat alters the properties of the transcription complex, recruits a positive transcription elongation complex (P-TEFb) and hence increases the production of full-length viral RNA. Tat protein also associates with RNA polymerase II complexes during early transcription elongation after the promoter clearance and before the synthesis of full-length TAR RNA transcript. This interaction of Tat with RNA polymerase II elongation complexes is P-TEFb-independent. There are two Tat binding sites on each transcription elongation complex; one is located on TAR RNA and the other one on RNA polymerase II near the exit site for nascent mRNA transcripts which suggests that two Tat molecules are involved in performing various functions during a single round of HIV-1 mRNA synthesis.

The minimum Tat sequence that can mediate specific TAR binding in vitro has been mapped to a basicdomain of 10 amino acids, comprising mostly Arg and Lys residues. Regulatory activity, however, also requires the 47 N-terminal residues, which interact with components of the transcription complex and function as a transcriptional activation domain.

Tat also uses an unusual transcellular transport pathway. Firstly, it binds with high affinity to phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2), found on the inner surface of the plasma membrane, this enables Tat recruitment at this level. Tat then crosses the plasma membrane to reach the extracellular space. Tat secretion by infected cells is highly active, and export is the major destination for HIV-1 Tat.