HIV-1 Vpr drives epigenetic remodeling to enhance virus transcription and latency reactivation

Abstract

Despite decades of research, the primary proviral function of the HIV-1 Vpr accessory protein remains enigmatic. Vpr is essential for pathogenesis in vivo and for virus replication in myeloid cells, but the underlying cause-and-effect mechanism(s) driving these phenomena are poorly understood. Canonically, Vpr hijacks a cellular ubiquitin ligase complex to target several dozen host proteins for proteasomal degradation. Many of these substrates were recently revealed to be involved in DNA damage repair (DDR), which rationalizes the longstanding observation that Vpr induces constitutive activation of DDR signaling. Here, we use a combination of functional, biochemical, and genetic approaches establish a clear mechanistic link between Vpr-induced DDR signaling and remodeling of the epigenetic landscape to enhance HIV-1 promoter activity during acute infection and virus reactivation from latency. Functional, genetic, and bimolecular fluorescence complementation experiments reveal that Vpr utilizes degradation-dependent and -independent mechanisms to induce epigenetic remodeling and that Vpr segregates into two discrete pools with dedicated activities--A multimeric pool in the nucleus that is associated with chromatin and a monomeric pool associated with DCAF1 in the cytoplasm. Vpr function in remodeling the nuclear environment is present in common HIV-1 subtypes worldwide and provides a mechanistic rationale for its essentiality in virus replication. Author summaryWhile HIV-1 Vpr plays an essential role in virus replication, the molecular mechanisms underlying its essentiality remain enigmatic. Vprs best characterized function is the ability to induce the depletion of several dozen host proteins by hijacking a cellular E3-ubiquitin ligase complex. Here, we establish that Vpr promotes global epigenetic remodeling to enhance HIV-1 promoter activity during acute infection and virus reactivation from latency. We demonstrate that epigenetic remodeling activity is linked to Vprs ability to induce constitutive DNA damage repair signaling, and that it occurs through both degradation-dependent and -independent mechanisms. Moreover, this Vpr function is present in common HIV-1 subtypes circulating globally. This study provides novel mechanistic insights into how HIV-1 exploits host DNA repair pathways and sheds light on Vprs proviral function.