Fig 9. Proposed model for US28-mediated regulation of quiescence during HCMV infection.

During infection of monocytes with WT HCMV, US28 limits HCMV-induced EGFR phosphorylation. Downstream of EGFR, PI3K phosphorylates PI(4,5)P₂ to PIP₃. Additionally, HCMV infection results in increased SHIP1 activity, which dephosphorylates PIP₃ to PIP₂. Recruitment of Akt to PIP₂ leads to preferential phosphorylation at Ser⁴⁷³ and establishment of a quiescent infection during infection with WT HCMV. In monocytes infected with US28Δ HCMV, EGFR is robustly phosphorylated without changes in SHIP1 activity. Thus, in the absence of US28, an accumulation of PIP₃ leads to Akt phosphorylation at both Ser⁴⁷³ and Thr³⁰⁸, which is required for IE1 induction and lytic HCMV replication. Created with Biorender (biorender.com).