A New Paradigm in Eukaryotic Biology: HIV Tat and the Control of Transcriptional Elongation

V iruses are intracellular pathogens that are subject to intense selective pressures during their ongoing battles within the host. To propagate successfully, they must exploit numerous machineries of the infected cell. Thus, studies of their replicative cycles have yielded fundamental insights into eukaryotic biology. A prime example is the human immunodefi ciency virus (HIV), which is a lentivirus that causes the acquired immunodefi ciency syndrome (AIDS). Unlike simpler oncoviruses that rely exclusively on host cell machinery, lentiviruses code for additional accessory and regulatory proteins that act as molecular switches at different stages of viral entry and exit from the infected cell. Studying the actions of these viral proteins has yielded understanding of diverse cellular functions such as the innate immunity against retroviruses, control of transcriptional elongation, export of macromolecules from the nucleus to the cytoplasm, and intracellular traffi cking of proteins (reviewed in [1]). The transcriptional transactivator (Tat) is a key regulatory protein of HIV. It is expressed early after the virus integrates into the cell, and stimulates the elongation of RNA polymerase II (RNAPII). This type of transcriptional control had not been previously appreciated; thus, work on Tat established a new paradigm in the fi eld of eukaryotic biology. Moreover, these fi ndings impacted greatly studies of cotranscriptional processing of nascent mRNA. To understand these processes better, we need to start with the basics of transcriptional control. RNAPII is the enzyme that transcribes protein-coding genes in eukaryotic cells. Elegant studies in vitro fi rst suggested that the simple recruitment of RNAPII to transcription units was not suffi cient for the copying of genes and cotranscriptional processing of their transcripts. Rather, distinct steps could be defi ned, which began with the assembly of the preinitiation complex (PIC), promoter clearance, pausing, and arrest, and ended with effi cient elongation of transcription (reviewed in [2]). The central component of PIC is the general transcription factor (GTF) TFIID, which contains the TATA-box-binding protein (TBP) and 12 to 15 TBP-associated factors (TAFs). TFIID acts as a " landing pad " for other GTFs and RNAPII to nucleate PIC assembly. Moreover, TAFs serve as coactivators to a diverse set of activators. Both an ordered stepwise assembly and the recruitment of the 100-plus-subunit " holoenzyme " have been proposed to be critical for the positioning of RNAPII at start sites of transcription. Next, the GTF TFIIH unwinds the DNA, opens the transcription bubble, and phosphorylates serines …