The human immunodeficiency virus (HIV) is responsible for one of the biggest contemporary viral pandemics. 40 years after its discovery, one of the major barriers to cure people living with HIV lies in the persistence of reservoirs of latently infected cells. These cells escape the effect of current antiretroviral molecules and harbor within their genome silent viral copies that can be reactivated to produce new infectious viruses. Currently, one of the main goals of HIV research is to better understand the molecular mechanisms that govern the silencing of HIV in latently infected cells to effectively target these reservoirs.
In these cells, the expression of the virus is blocked at the stage of transcription of the integrated viral DNA (called provirus) which is ensured by the cellular machinery associated with RNA polymerase II (RNAPII). When not released efficiently, proximal pausing of ARNPII at the viral promoter can lead to premature termination of provirus transcription, thereby contributing to the silencing of its expression. It is in this context that the authors revealed the key role of a new termination complex in the transcriptional repression of HIV-1 within latently infected cells.
The objective of the study was to identify new molecular determinants involved in the premature termination of HIV-1 transcription. The scientists therefore analyzed the functions of more than ten termination factors in a cellular model allowing to measure the transcriptional activity of the viral promoter. From this initial screen, a single key protein, PCF11, was identified for its major role in transcriptional repression of the virus.
Then, the authors searched for the molecular partners of PCF11 and discovered its interaction with WDR82, a protein associated with RNAPII whose role as a non-canonical termination factor is beginning to be elucidated at the cellular transcriptome level. They therefore deciphered the role of this new protein complex in the transcriptional repression of HIV-1. The study of the interaction of PCF11 and WRD82 with chromatin shows that they are specifically recruited in an interdependent manner at a proximal region located downstream of the transcription start site. Furthermore, the analysis of the provirus expression at the RNA level reveals that PCF11 and WDR82 act together to force the premature termination of provirus transcription in latently infected cells.
This work identifies that the PCF11-WDR82 termination complex is at the heart of an unsuspected mechanism for silencing HIV-1. Targeting these termination factors in new therapeutic approaches could allow the reservoirs to be purged for treatment-free cure.
Figure legend: In latent cells, PCF11 represses the HIV-1 promoter transcription by cooperating with WDR82 at the proximal region of the viral promoter. The recruitment of PCF11-WDR82 by the RNA polymerase II (RNAPII) could stimulate its dissociation from DNA and promote premature transcription termination.
Reference
Ait Said M, Bejjani F, Abdouni A, Ségéral E, Emiliani S. Premature transcription termination complex proteins PCF11 and WDR82 silence HIV-1 expression in latently infected cells. Proc Natl Acad Sci U S A. 2023 Dec 5;120(49):e2313356120. doi: 10.1073/pnas.2313356120. PMID: 38015843; PMCID: PMC10710072.
