CBF-1 Promotes the Establishment and Maintenance of HIV Latency by Recruiting Polycomb Repressive Complexes, PRC1 and PRC2, at HIV LTR.

Adhikarimayum Lakhikumar Sharma,Ashok Chauhan,Michael Bukrinsky,Lin Sun,Joseph Hokello,Mudit Tyagi,Sonia Zicari,Rene Daniel,Aseel Alqatawni,Shilpa Sonti,Gary Simon

doi:10.3390/v12091040

Abstract

The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the human immunodeficiency virus (HIV)-1 LTR promoter. Here, we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in the reactivation of latent HIV proviruses. Chromatin immunoprecipitation (ChIP) assays using latently infected primary T cells and Jurkat T-cell lines demonstrated that CBF-1 induces the establishment and maintenance of HIV latency by recruiting polycomb group (PcG/PRC) corepressor complexes or polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Knockdown of CBF-1 resulted in the dissociation of PRCs corepressor complexes enhancing the recruitment of RNA polymerase II (RNAP II) at HIV LTR. Knockdown of certain components of PRC1 and PRC2 also led to the reactivation of latent proviruses. Similarly, the treatment of latently infected primary CD4+ T cells with the PRC2/EZH2 inhibitor, 3-deazaneplanocin A (DZNep), led to their reactivation.

Highlights

The anti-human immunodeficiency virus (HIV) therapy, ART, has been highly successful in controlling human immunodeficiency virus (HIV) replication and maintaining the level of circulatingHIV below the limit of detection
We have demonstrated that C-promoter binding factor-1 (CBF-1), after binding to specific sites in HIV LTR, recruits corepressor complexes containing histone deacetylases (HDACs) (HDAC1 and HDAC3)
The polycomb group (PcG) proteins are divided in the form of two main corepressor complexes, PRC1 and PRC2 [80], that we showed to be present at the HIV LTR

Summary

Introduction

The anti-human immunodeficiency virus (HIV) therapy, ART, has been highly successful in controlling human immunodeficiency virus (HIV) replication and maintaining the level of circulatingHIV below the limit of detection. The failure of ART to eradicate HIV is due to the creation of stable reservoirs of latently infected cells harboring slowly or non-replicating viruses. Viruses 2020, 12, 1040 a stable pool of latently infected cells with half-life roughly around 44 months [4–6]. These latent reservoirs are frequently replenished due to both the homeostatic proliferation of latently infected cells and the ectopic reactivation of latent proviruses followed by new rounds of infection, presumably owing to locally sub-optimal ART concentrations [7–10]. Developing therapeutic interventions with a focus on HIV eradication will require the precise definition of the molecular mechanisms responsible for both the establishment and maintenance of HIV latency, in order to either reactivate latent proviruses, so that they can be destroyed, or fossilize them forever like human endogenous retroviruses (HERVs)

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Conclusion