Several viral proteins have now been reported to regulate the APC in overexpression, and evidence correlating the role of these factors and viral replication is emerging. Deletion of the parapoxvirus PACR or CAV protein apoptin markedly attenuated virus growth in tissue culture even though their ability and role in inhibiting the APC during infection has not been clarified [23, 39] . Recently, the UL97 kinase of HCMV has been shown to phosphorylate Cdh1 and partially inhibit the APC during infection but with unknown consequences for viral replication [24] . Our study elucidates the mechanism by which pUL21a regulates APC in the context of virus infection and indicates a role of this pUL21a activity in viral replication. Mutation abolishing the APC binding activity of pUL21a had no impact on viral growth in tissue culture, but the loss of both pUL21a-APC binding and pUL97 markedly attenuated viral replication relative to the loss of pUL97 alone. Our data suggest that HCMV has evolved a sophisticated strategy by encoding both pUL97 and pUL21a to overcome APC activity. However, further experiments are needed to unequivocally demonstrate the vital role of APC regulation in HCMV replication and provide mechanistic insight into how this regulation impacts its biology.