Human cytomegalovirus (HCMV) is a β-herpesvirus and a ubiquitous pathogen that infects over 60% of the adult population. HCMV is a significant cause of morbidity and mortality in immuno-compromised people and newborn infants, and can cause permanent disabilities such as hearing loss, vision impairment, and mental retardation. We recently reported that the 7 host cell sirtuin (SIRT) proteins are viral restriction factors1. Knock-down of each SIRT elevates HCMV viral titre following infection. Similarly, SIRTs can modulate viral progeny of herpes simplex virus 1, adenovirus, and influenza A. Given all SIRTs contain a deacetylase domain, it was assumed their host cell defence was dependent upon their ability to remove acetyl-modifications from protein substrates. However, we have recently discovered that mitochondrial SIRT4 can hydrolyze lipoyl-modifications far more efficiently than acetyl, and established it as the first cellular lipoamidase2. Importantly, a biological target of SIRT4 is pyruvate dehydrogenase (PDH), a fundamental regulator of cellular metabolism. We now show that PDH activity is inhibited during early stages of HCMV infection (HPI), SIRT4 expression is elevated, and PDH-lipoyl levels are diminished. Critically, lipoamidase activity of SIRT4 induced by the host most likely limits metabolic flux used to generate fatty acids for the virion envelope. Heightened PDH activity during later stages of infection suggest a viral HCMV protein may inhibit SIRT4 lipoamidase function.