A team led by Esther González-Almela at Guangdong Academy of Medical Sciences revealed that herpes simplex virus type 1 (HSV-1) hijacks host enzymes RNA polymerase II and topoisomerase 1 (TOP1) during its lytic cycle for viral gene transcription and replication. Inhibiting TOP1 halted viral activity, suggesting a promising therapeutic target to stop HSV-1 before it enters latency, a state shielding it from antivirals. Super-resolution microscopy unveiled physical interactions between viral and host DNA in transcriptionally active regions, providing mechanistic insights into viral genome compaction and replication compartments, as reported in Nature Communications.