Fig. 3

Stimulation of efficient HIV-1 transcription elongation through Tat-dependent P-TEFb recruitment and remodeling of the chromatin barrier. The current understanding of the regulation of processive HIV-1 transcription, as portrayed here, is based mainly on studies conducted using cell line models. A Epigenetic repressive features at the proviral promoter prevent the recruitment of RNA polymerase II (RNAP II) and assembly of the preinitiation complex, thereby restricting the expression of Tat. Latent proviruses also characteristically possess elevated acetylated histone H4 (AcH4) levels that permit their occupancy by the short isoform of BRD4, which reinforces viral latency through direct recruitment of BAF SWI/SNF complexes. Without Tat expression, an accumulation of inefficiently transcribing promoter-proximally paused RNAP II complexes due to NELF and DSIF activity may lead to abortive transcription. B Chromatin remodeling and efficient assembly of preinitiation complexes may initially allow for the onset of Tat-independent transcription elongation likely occurring through the recruitment of P-TEFb by NF-κB, BRD4, TRIM28, or HSF1. Synthesized Tat efficiently trans-activates HIV-1 transcription elongation by outcompeting BRD4 for P-TEFb binding and recruiting P-TEFb with the super elongation complex (SEC) to the TAR hairpin. P-TEFb eventually phosphorylates the RNAP II C-terminal domain (CTD), its linker region between the polymerase core and CTD, the SPT5 subunit of DSIF, and the NELF-E subunit. Phosphorylated DSIF is transformed into a positive elongation factor, while NELF-E phosphorylation leads to the dissociation of the NELF complex from RNAP II. The phosphorylated RNAP II CTD and linker provide a scaffold to anchor the histone chaperone SPT6, which, along with FACT, is essential in enabling the elongating machinery to transcribe through nucleosomal barriers. These RNAP II phospho-modifications may also anchor elongation factors, co-transcriptional processing complexes, and chromatin-modifying enzymes