A cytomegalovirus-encoded lncRNA blocks cell-cycle progression

During infection with human cytomegalovirus (HCMV), the viral long non-coding RNA RNA2.7 becomes the most abundant polyadenylated transcript in the cell, yet its function has remained enigmatic. By combining RNA sequencing, metabolic labeling of newly synthesized RNA, and ribosome profiling, we define how RNA2.7 modulates host gene expression and promotes viral propagation. We show that RNA2.7 stabilizes numerous host mRNAs by sequestering a broad array of RNA-binding proteins, reshaping the cellular transcriptome. Accordingly, RNA2.7 is essential for HCMV-induced cell-cycle arrest at the G1-S transition specifically when infection occurs in G1, thereby enhancing viral replication in actively cycling cells. Notably, RNA2.7 expression alone is sufficient to block cell-cycle progression, and screening RNA2.7 fragments identifies a region containing an extended polyadenosine stretch that is required for this activity. Our findings reveal how RNA2.7 promotes viral replication by modulating host mRNA stability and enforcing cell-cycle arrest, creating favorable conditions for infection.