In the canonical STAT3 signaling pathway, binding of agonist to receptors 
activates Janus kinases that phosphorylate cytoplasmic STAT3 at tyrosine 705 
(Y705). Phosphorylated STAT3 dimers accumulate in the nucleus and drive the 
expression of genes involved in inflammation, angiogenesis, invasion, and 
proliferation. Here, we demonstrate that human cytomegalovirus (HCMV) infection 
rapidly promotes nuclear localization of STAT3 in the absence of robust 
phosphorylation at Y705. Furthermore, infection disrupts interleukin-6 
(IL-6)-induced phosphorylation of STAT3 and expression of a subset of 
IL-6-induced STAT3-regulated genes, including SOCS3. We show that the HCMV 
72-kDa immediate-early 1 (IE1) protein associates with STAT3 and is necessary to 
localize STAT3 to the nucleus during infection. Furthermore, expression of IE1 
is sufficient to disrupt IL-6-induced phosphorylation of STAT3, binding of STAT3 
to the SOCS3 promoter, and SOCS3 gene expression. Finally, inhibition of STAT3 
nuclear localization or STAT3 expression during infection is linked to 
diminished HCMV genome replication. Viral gene expression is also disrupted, 
with the greatest impact seen following viral DNA synthesis. Our study 
identifies IE1 as a new regulator of STAT3 intracellular localization and IL-6 
signaling and points to an unanticipated role of STAT3 in HCMV infection.