RNA-TARGETED ACTIVATORS, BUT NOT DNA-TARGETED ACTIVATORS, REPRESS THESYNTHESIS OF SHORT TRANSCRIPTS AT THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 LONG TERMINAL REPEAT

The human immunodeficiency virus type 1 (HIV-1) promoter directs the s ynthesis of two types of RNA molecules: full-length transcripts, whose synthesis is activated by the viral activator Tat, and short transcri pts, whose synthesis is dependent on the inducer of short transcripts (IST), a bipartite DNA element located in large part downstream of the HIV-1 transcriptional start site. In the absence of Tat, short transc ripts constitute the large majority of the RNA molecules synthesized f rom the HIV-1 promoter. In the presence of Tat, synthesis of the short transcripts is repressed and synthesis of the full-length transcripts is activated. Tat is unique among transcriptional activators in actin g through an RNA target, the TAR element. However, Tat has been shown to activate transcription from a DNA target when fused to the appropri ate DNA binding domain, raising the question of why Tat has been direc ted to the RNA. Here we have compared the abilities of Tat and other R NA- and DNA-bound activators to stimulate transcription from the HIV-1 promoter. We show that DNA-targeted activators, including DNA-targete d Tat, activate the synthesis of both short and long transcripts, whil e RNA targeted Tat and another RNA-targeted activator activate the syn thesis of full-length transcripts but specifically repress that of sho rt transcripts. The unique ability of RNA-targeted activators to down- regulate short transcript synthesis suggests that Tat is directed to t he RNA specifically for the purpose of repressing short transcripts.