Regulation of Human Immunodeficiency Virus Type 1 Gene Expression by Clade-Specific Tat Proteins

Abstract

The major group of human immunodeficiency virus type 1 (HIV-1) strains that comprise the current global pandemic have diversified during their worldwide spread into at least 10 distinct subtypes, or clades. Subtype C predominates in sub-Saharan Africa and is responsible for the majority of worldwide HIV-1 infections, subtype B predominates in North America and Europe, and subtype E is prevalent in Southeast Asia. Significant amino acid variations have been observed among the clade-specific Tat proteins. For the present study, we examined clade-specific interactions between Tat, transactivation-responsive (TAR) element, and P-TEFb proteins and how these interactions may modulate the efficiency of HIV-1 transcription. Clade-specific Tat proteins significantly modified viral gene expression. Tat proteins derived from HIV-1 clades C and E were strong transactivators of long terminal repeat (LTR) activity; Tat E also had a longer half-life than the other Tat proteins and interacted more efficiently with the stem-loop TAR element. Chimeric Tat proteins harboring the Tat E activation domain were strong transactivators of LTR expression. While Tat B, C, and E were able to rescue a Tat-defective HIV-1 proviral clone, Tat E was significantly more efficient at rescue than Tat C, possibly due to the relative stability of the Tat protein. Swapping the activation domains of Tat B, C, and E identified the cyclin T1 association domain as a critical determinant of the transactivation efficiency and of Tat-defective HIV-1 provirus rescue.