What would be the benefit for the virus to alter APC activity? The APC may restrict HCMV replication via several mechanisms. The APC not only promotes cell cycle progression through M phase, it also prevents cells from prematurely entering S phase. Thus virus-mediated APC regulation may help HCMV maintain an S phase-like cellular environment for viral replication. The APC targets more than 40 proteins for degradation, so it may deplete host factors critical to viral replication. Consequently, viruses may need to alter the substrate specificity of the APC or allow accumulation of APC substrates critical for viral replication. Interestingly, the only viruses within the poxvirus and herpesvirus families that are known to modulate the APC (e.g. parapoxviruses and HCMV) are those that do not encode viral thymidine kinase (TK) and ribonucleotide reductase subunit M2 (RRM2). Both enzymes are APC substrates and critical for the production of deoxyribonucleotides. It is tempting to speculate that this viral regulation of the APC may provide viruses a means to produce sufficient nucleotides to replicate their genome [23, 27] . Nonetheless, the APC also targets proteins involved in cellular DNA synthesis, glycolysis and glutaminolysis, and cell cycle progression, all of which could impact viral replication [41] . Moreover, the APC may also promote ubiquitination and degradation of viral proteins to restrict infection [42] . Several HCMV proteins contain a putative destruction Box (D-box) motif, an APC recognition signal commonly found in its substrates [24] . Future work is needed to differentiate these possibilities and unravel the APC substrates that may be critical for viral replication.