# DNA damage induced by HIV-1 Vpr triggers epigenetic remodeling and transcriptional programs to enhance virus transcription and latency reactivation

## TL;DR

This study shows that HIV-1 uses a protein called Vpr to cause DNA damage, which helps the virus become more active and escape dormancy, offering new treatment possibilities.

## Contribution

The study reveals that Vpr-induced DNA damage promotes epigenetic changes and transcriptional programs that enhance HIV-1 transcription and latency reactivation.

## Key findings

- Vpr induces DNA damage responses that trigger epigenetic remodeling and enhance HIV-1 promoter activity.
- Vpr exists in two pools: one in the nucleus associated with chromatin and one in the cytoplasm linked to an E3-ubiquitin ligase.
- Vpr-induced DDR and epigenetic activities are present in global HIV-1 subtypes and patient isolates.

## Abstract

Hijacking of host DNA damage repair (DDR) pathways to facilitate virus replication is broadly conserved amongst diverse viral families. It has been well established that the HIV-1 accessory protein Vpr induces constitutive DDR signaling and G2/M cell cycle arrest, but the virologic function of this activity remains unclear. Here, we use a combination of functional, pharmacologic, biochemical, and genetic approaches to establish that virion-associated and de novo Vpr proteins induce DDR responses that trigger global epigenetic remodeling and activation of transcription programs to enhance HIV-1 promoter activity during acute infection and reactivation from latency. Functional, genetic, and bimolecular fluorescence complementation experiments reveal that Vpr segregates into two functionally discrete pools—a multimeric pool in the nucleus associated with chromatin and a monomeric pool in the cytoplasm associated with a host E3-ubiquitin ligase. Vpr-induced DDR and epigenetic remodeling activities are present in common HIV-1 subtypes circulating globally and in patient-derived isolates.

HIV-1 induces a persistent DNA damage response through Vpr, but whether this affects the viral cycle has remained unclear. This study shows that Vpr-driven DNA damage promotes epigenetic remodeling and transcriptional programs that enhance HIV-1 transcription and latency reactivation, identifying a possible target for new treatment strategies.