Human cytomegalovirus (HCMV) is responsible for life-threatening infections in 
immunocompromised individuals and can cause serious congenital malformations. 
Available antivirals target the viral polymerase but are subject to 
cross-resistance and toxicity. New antivirals targeting other replication steps 
and inducing fewer adverse effects are therefore needed. During HCMV 
replication, DNA maturation and packaging are performed by the terminase 
complex, which cleaves DNA to package the genome into the capsid. Identified in 
herpesviruses and bacteriophages, and with no counterpart in mammalian cells, 
these terminase proteins are ideal targets for highly specific antivirals. A new 
terminase inhibitor, letermovir, recently proved effective against HCMV in phase 
III clinical trials, but the mechanism of action is unclear. Letermovir has no 
significant activity against other herpesvirus or non-human CMV. This review 
focuses on the highly conserved mechanism of HCMV DNA-packaging and the 
potential of the terminase complex to serve as an antiviral target. We describe 
the intrinsic mechanism of DNA-packaging, highlighting the structure-function 
relationship of HCMV terminase complex components.