RPRD2 (regulation of nuclear pre-mRNA domain containing 2) is a multifunctional protein involved in transcriptional regulation and innate antiviral immunity. As a CTD-interaction domain-containing protein, RPRD2 associates with RNA polymerase II and participates in dephosphorylation of the CTD, contributing to transcription regulation 1. RPRD2 localizes primarily to the nucleus where it binds RNA, DNA, and DNA:RNA hybrids 2. Beyond transcription, RPRD2 functions as a potent innate immune restriction factor (also called REAF—RNA-associated early-stage antiviral factor) that restricts HIV-1 replication by impeding reverse transcription 3. HIV-1 Vpr protein counteracts RPRD2's antiviral activity through proteasomal degradation in a process dependent on Vpr's nuclear localization and interaction with cullin 4A-DCAF1 E3 ligase 3. RPRD2 is upregulated upon T cell activation and highly expressed in myeloid cells 2. Beyond HIV restriction, RPRD2 interacts with HUSH and PAF1 complexes to negatively regulate genome-wide transcription and maintain HIV latency 2. Dysregulation of RPRD2 methylation has been associated with renal aging and functional decline 4, and mutations in RPRD2 were identified in Burkitt lymphoma 5.