Viral–Host Interactions That Control HIV-1 Transcriptional Elongation

Abstract

1. Summary Regulation of the pause and elongation by RNA polymerase (Pol) II is used widely by metazoans to attain the pattern of gene expression that is essential for optimal cell growth/renewal, differentiation and stress response. Currently, much of what we know about Pol II elongation control comes from pioneering studies of the HIV-1-encoded Tat protein and its host cellular co-factors. The interaction between the two fuels a powerful feedback circuit that activates HIV transcription and prevents the virus from entering latency. One of the key Tat cofactors is the human positive transcription elongation factor b (P-TEFb), which exists in a family of complexes with distinct functions during Tat transactivation. This article reviews recent progresses in HIV transcription research with an emphasis on the intricate control of the various P-TEFb complexes, structural and functional insights into their interactions with Tat, the multifaceted roles of post-translational modifications of Tat and epigenetic control of HIV chromatin in modulating Tat activity and HIV latency. The knowledge from these studies will not only help design better strategies to fight HIV infection and transcriptional latency, but also advance the overall understanding of the mechanism controlling transcriptional elongation in general.

AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation

“…When an SEC is recruited to the HIV promoter by Tat and TAR, the contained P-TEFb and ELL1/2 components potentially can act on the same polymerase enzyme to activate transcription synergistically (10). However, direct biochemical evidence still is needed to confirm that P-TEFb alone is not sufficient for full Tat activity and that efficient HIV transactivation must rely on the complete SEC.In addition to residing in the SEC, P-TEFb also exists in several other complexes and shuttles between inactive and active states in response to different intracellular and extracellular signals (5,7,8). Under normal conditions, most nuclear P-TEFb Significance Transcriptional elongation by RNA polymerase II produces fulllength RNA transcripts and plays a general and prominent role in regulating gene expression.…”

“…It has long been known that in the absence of the HIVencoded transactivating protein (Tat), Pol II can initiate transcription from the viral promoter efficiently but pauses soon after the synthesis of a short RNA segment that folds into a stem-loop structure termed the "transactivation-response" (TAR) element. Tat overcomes Pol II pausing by recruiting the host positive transcription elongation factor b (P-TEFb) to the newly formed TAR RNA to stimulate the production of full-length HIV transcripts (7,8). Containing cyclin-dependent kinase 9 (CDK9) and cyclin T1 (CycT1), P-TEFb triggers the release of paused Pol II by phosphorylating and thereby antagonizing the inhibitory actions of two negative elongation factors, DSIF and NELF (5, 6).…”

“…In addition to residing in the SEC, P-TEFb also exists in several other complexes and shuttles between inactive and active states in response to different intracellular and extracellular signals (5,7,8). Under normal conditions, most nuclear P-TEFb Significance Transcriptional elongation by RNA polymerase II produces fulllength RNA transcripts and plays a general and prominent role in regulating gene expression.…”

“…Within the SEC, AFF1/4 are known to be structural scaffolds that use their interspersed short hydrophobic regions to attract and coordinate other SEC components (7,10,11). However, AFF1does not seem to have such a role in either 7SK snRNP or the Brd4-containing PAB.…”

Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription

“…2) (reviewed in [51, 65]). In vitro studies show that Tat and HEXIM1 can both compete to recruit P-TEFb through the same N-terminal CycT1-binding site, with Tat/CycT1 affinity measured to be 10-fold greater, thus giving an advantage to Tat over HEXIM1 [16, 39, 66].…”