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

Human cyclin T1 (hCycT1), a major subunit of the essential elongation facto r 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) bin ds the activation domain of HIV-1 Tat but, unlike hCycT1, cannot mediate Ta t function because it cannot be recruited efficiently to TAR. In fact, over expression of mCycT1, but not hCycT1, specifically inhibits Tat-TAR functio n in human cells. This discordant phenotype results from a single amino aci d difference between hCycT1 and mCycT1, a tyrosine in place of a cysteine a t 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.