Something old, something new? Herpesvirus genome packaging examined in light of lessons from the tailed bacteriophages

What are viruses, if not nucleic acids surrounded by proteinaceous shells? While the energy-dependent viral packaging motors of tailed bacteriophages have been studied in great depth, our understanding of how eukaryotic double-stranded DNA (dsDNA) viruses package their genomes into nascent capsids remains incomplete. Herpesviruses are ubiquitous human pathogens that drive diverse clinical symptoms. The success of letermovir, a first-in-class human cytomegalovirus genome packaging inhibitor, suggests that this critical step in the virus life cycle can be targeted in other herpesvirus infections. Here, we integrate recent structural, biophysical, and genetic information from representative dsDNA viruses to define the overarching principles of viral genome packaging and highlight evolutionary distinctions. What lessons can we learn from bacteriophages to further our understanding of herpesvirus packaging, and can these insights generate new opportunities for antiherpesvirus therapeutics?