Induction of DNA Damage-Repair-Linked Phenotypes Is Conserved Amongst a Panel of Diverse SIV Vpr Proteins

Human immunodeficiency virus (HIV) encodes four accessory proteins that contribute to virus replication primarily through the counteraction of host innate immune defense mechanisms. One of these proteins, Vpr, induces constitutive DNA damage responses (DDRs) to drive global epigenetic remodeling and activation of transcription programs that enhance HIV-1 promoter activity during acute infection and virus reactivation from latency. Vpr is conserved amongst diverse simian immunodeficiency virus (SIV) strains; however, the evolutionary breadth of Vpr’s ability to remodel the nuclear environment has yet to be thoroughly characterized. Here, we investigate a diverse panel of 16 SIV Vpr proteins and demonstrate that 13 out of 16 are capable of increasing activation of the DDR marker γH2AX compared to control infected cells. Moreover, cells infected with these variants also exhibit increased abundance of two histone marks associated with transcription and euchromatin formation, as well as increased activation of two transcription factors known to be critical for HIV-1 promoter activity. Furthermore, site-directed mutagenesis of a highly homologous SIV Vpr protein that failed to engage DDR revealed a set of previously uncharacterized amino acid residues required for HIV-1 Vpr DDR engagement. Finally, structural modeling and functional analyses revealed that phylogenetically diverse Vpr proteins from SIV African green monkey strains induce remodeling of the nuclear environment through an evolutionarily distinct set of amino acid residues. Together, these findings demonstrate that hijacking of DNA damage repair responses to promote remodeling of the nuclear environment is a broadly conserved Vpr function.