Antiviral Inhibition Targeting the HCMV Kinase pUL97 Requires pUL27-Dependent Degradation of Tip60 Acetyltransferase and Cell-Cycle Arrest

SummaryInfection with the β-herpesvirus human cytomegalovirus (HCMV) is lifelong, causing limited disease in healthy adults, but life threatening in immunocompromised individuals. The viral kinase pUL97, a functional ortholog of cellular cyclin-dependent kinases (CDKs), is critical for HCMV replication and a target for antiviral drug development. Upon kinase inhibition, drug-resistant strains emerge with mutations in UL27, an HCMV gene of unknown function. Using a proteomics approach, we discovered that pUL27 is necessary and sufficient to degrade Tip60, a host acetyltransferase and interacting partner of HIV Tat. Consistent with this, the expression of Tat restored antiviral inhibition of an otherwise resistant HCMV strain. The functional consequence of Tip60 degradation was the induction of the CDK inhibitor p21Waf1/Cip1 and cell-cycle arrest, representing changes necessary for the antiviral effects of pUL97 inhibition. Consequently, either increasing p21Waf1/Cip1 expression or decreasing Tip60 levels improved the antiviral activity of the HCMV kinase inhibitor maribavir.

Graphical AbstractFigure optionsDownload high-quality image (121 K)Download as PowerPoint slideHighlights
► HCMV pUL27 is necessary and sufficient to degrade Tip60 acetyltransferase
► Disruption of Tip60 levels resulted in increased p21 and a cell-cycle arrest
► HIV Tat complements the function of HCMV pUL27
► Inhibition of HCMV by maribavir requires disruption of Tip60 levels