Human cytomegalovirus hijacks L1 retrotransposon to fuel its heterogeneity

Human Cytomegalovirus (HCMV) causes severe morbidity and mortality in an immune-compromised or immune-naïve host. Among DNA viruses, the genetic diversity of HCMV is unexpectedly high and comparable to those of RNA viruses, which hinders the development of effective vaccines and causes the emergence of antiviral resistance. However, little is known about how HCMV acquires genetic variation. Here, we propose an evolution strategy of HCMV, that exploits host “jumping DNA” L1 retrotransposon as a mutagen. We found that HCMV infection switches on L1 expression by upregulating transcription factors YY1 and RUNX3. Furthermore, HCMV DNA processivity factor, UL44 recruits L1 ribonucleoproteins to viral replication compartments and induces DNA damage to its genome. Deep-sequencing analysis of cultured HCMV genome revealed that L1 retrotransposon facilitates mutation burden on the viral genome. Indeed, laboratory adaptation of HCMV to fibroblasts is only observed upon active L1 expression. These findings demonstrate the evolution mechanism and molecular insights of how HCMV acquires genetic fitness by the hijacking of host L1 retrotransposon.