Evolutionary interplay between viruses and R-loops

Abstract

Viruses frequently interact with host transcriptional and epigenetic regulatory networks. A commonly overlooked element of these interactions is the formation of R-loops, three-stranded nucleic acid structures comprising an RNA–DNA hybrid and a displaced single DNA strand. Accumulating evidence implicates R-loops in viral integration site preferences, the regulation of latent viral genomes, epigenetic silencing, and even the genesis of small interfering RNAs (siRNAs) that modulate mobile viral elements. This perspective presents the potential connections among viral genes, transposons, and R-loops; examines the roles of R-loops in viral pathogenesis, latency, and reactivation; explores how viruses harness or evade R-loop–associated responses; and highlights future research directions—from mapping R-loop hotspots to exploiting R-loop modulation for antiviral therapy.