Recruitment of a protein complex containing Tat and cyclin T1 to TAR governs the species specificity of HIV-1 Tat

Abstract

Human cyclin T1 (hCycT1), a major subunit of the essential elongation factor P‐TEFb, has been proposed to act as a cofactor for human immunodeficiency virus type 1 (HIV‐1) Tat. Here, we show that murine cyclin T1 (mCycT1) binds the activation domain of HIV‐1 Tat but, unlike hCycT1, cannot mediate Tat function because it cannot be recruited efficiently to TAR. In fact, overexpression of mCycT1, but not hCycT1, specifically inhibits Tat–TAR function in human cells. This discordant phenotype results from a single amino acid difference between hCycT1 and mCycT1, a tyrosine in place of a cysteine at residue 261. These data indicate that the ability of Tat to recruit CycT1/P‐TEFb to TAR determines the species restriction of HIV‐1 Tat function in murine cells and therefore demonstrate that this recruitment is a critical function of the Tat protein.