Nuclear RNA surveillance complexes silence HIV-1 transcription.

Xavier Contreras,Sylvie Rouquier,Rosemary Kiernan,Emilie Rousset,Stéphane Pelletier,Marion Helsmoortel,Emmanuelle Beyne,Kader Salifou,Lisa Bluy,Gabriel Sanchez

doi:10.1371/journal.ppat.1006950

Abstract

Expression from the HIV-1 LTR can be repressed in a small population of cells, which contributes to the latent reservoir. The factors mediating this repression have not been clearly elucidated. We have identified a network of nuclear RNA surveillance factors that act as effectors of HIV-1 silencing. RRP6, MTR4, ZCCHC8 and ZFC3H1 physically associate with the HIV-1 TAR region and repress transcriptional output and recruitment of RNAPII to the LTR. Knock-down of these factors in J-Lat cells increased the number of GFP-positive cells, with a concomitant increase in histone marks associated with transcriptional activation. Loss of these factors increased HIV-1 expression from infected PBMCs and led to reactivation of HIV-1 from latently infected PBMCs. These findings identify a network of novel transcriptional repressors that control HIV-1 expression and which could open new avenues for therapeutic intervention.

Highlights

The human immunodeficiency virus-1 (HIV-1) remains one of the world’s leading health threats with over 36 million people infected worldwide (UNAIDS, Global Report, 2016)
Following integration into the host genome, HIV-1 expression is silenced in a small population of cells, largely via epigenetic mechanisms that repress long terminal repeat region (LTR)-mediated transcription
We identify a network of nuclear RNA surveillance factors that repress HIV transcription and whose loss increases virus expression in latently infected J-Lat and peripheral blood mononuclear cells (PBMCs)

Summary

Introduction

The human immunodeficiency virus-1 (HIV-1) remains one of the world’s leading health threats with over 36 million people infected worldwide (UNAIDS, Global Report, 2016). Despite significant advances in antiretroviral therapy, it is not currently possible to eradicate HIV-1 infection due to the presence of a small but highly persistent reservoir of infected cells that host transcriptionally repressed proviruses. Transcriptional activation of these proviruses occurs rapidly following cessation of therapy leading to renewed high viral burden.

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Discussion

Conclusion