HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin.

Bizhan Romani,Seyed Bahman Momen,Mojtaba Hamidi-Fard,Mohammad Reza Aghasadeghi,Pooneh Rahimi,Elham Allahbakhshi,Razieh Kamali Jamil

doi:10.1038/srep31924

Abstract

HIV-1 Vpr is an accessory protein that induces proteasomal degradation of multiple proteins. We recently showed that Vpr targets class I HDACs on chromatin for proteasomal degradation. Here we show that Vpr induces degradation of HDAC1 and HDAC3 in HIV-1 latently infected J-Lat cells. Degradation of HDAC1 and HDAC3 was also observed on the HIV-1 LTR and as a result, markers of active transcription were recruited to the viral promoter and induced viral activation. Knockdown of HDAC1 and HDAC3 activated the latent HIV-1 provirus and complementation with HDAC3 inhibited Vpr-induced HIV-1 reactivation. Viral reactivation and degradation of HDAC1 and HDAC3 was conserved among Vpr proteins of HV-1 group M. Serum Vpr isolated from patients or the release of virion-incorporated Vpr from viral lysates also activated HIV-1 in latently infected cell lines and PBMCs from HIV-1 infected patients. Our results indicate that Vpr counteracts HIV-1 latency by inducing proteasomal degradation of HDAC1 and 3 leading to reactivation of the viral promoter.

Highlights

HIV-1 infection establishes latent viral reservoirs early during primary infection that constitute a major challenge to eradication[1]
We have recently reported that HIV-1 Vpr induces proteasomal degradation of class I histone deacetylases (HDACs) in a localized manner which is more focused on the chromatin
We showed that Vpr was able to induce depletion of all the four members of class I HDACs, including HDAC1, HDAC2, HDAC3, and HDAC8 in J-Lat cells when transduced at an MOI of 5.0 (Supplementary Fig. S1A)

Summary

Introduction

HIV-1 infection establishes latent viral reservoirs early during primary infection that constitute a major challenge to eradication[1]. One of the current strategies to purge the viral reservoirs is reactivating the latent viral reservoirs using HDAC inhibitors, or other small molecules that activate the latent provirus, so that the infected cells could be removed by immune system[20]. We have recently reported that HIV-1 Vpr induces proteasomal degradation of class I HDACs in a localized manner which is more focused on the chromatin. This effect of Vpr was found to counteract silent infection of macrophages by maintaining an active LTR during infection[28]. We examined whether Vpr has an effect on class I HDACs and reactivation of the HIV-1 provirus in latently infected cells. Using HIV-1 latently infected cell lines and unstimulated PBMCs from patients, we found that expression of Vpr in infected cells or treatment with extracellular Vpr reactivate the latent HIV-1 provirus which was related to depletion of class I HDACs, especially HDAC1 and HDAC3

Methods

Results

Conclusion