STAT1 and herpesviruses: Making lemonade from lemons

Signal transducer and activator of transcription 1 (STAT1) is engaged downstream of interferon and other cytokine receptors and has traditionally been defined as an antiviral effector of the host. Consistent with the antiviral role, genetic deficiency of STAT1 leads to increased replication of diverse viruses and severe disease that can lead to host's mortality, including in rare human cases of STAT1 insufficiency. Surprisingly, excessive STAT1 activation recently identified in patients with heterozygous gain-of-function STAT1 mutations and subsequently modeled in laboratory mice, also leads to poor control of select virus infections, including herpesviruses. Thus, the function of STAT1 in viral infections might be more nuanced and extend beyond the canonical antiviral role of this host factor. This review will compare the findings in the animal models and human cases to discuss the role of STAT1 in herpesvirus infection of the intact host, including the emerging cell type-specific proviral roles of STAT1.