BACKGROUND: There have been several reports that have linked human cytomegalovirus (CMV) to gliomas. Although clinical trials of immunotherapy against CMV antigens found in gliomas have commenced in multiple institutions, the data linking these tumors to this virus remains controversial. METHODS: To study the controversial role of cytomegalovirus (CMV) in glioblastoma, we assessed the effects of murine CMV (MCMV) perinatal infection in a GFAP-cre; Nf1loxP/+ ; Trp53-/+ genetic mouse model of glioma (Mut3 mice). RESULTS: Early on after infection, MCMV antigen was predominantly localized in CD45+ lymphocytes in the brain with active viral replication and local areas of inflammation, but by 7 weeks there was a generalized loss of MCMV in brain, confirmed by bioluminescent imaging. MCMV-infected Mut3 mice exhibited a shorter survival time from their gliomas, when compared to control Mut3 mice, perinatally infected with mock or with a different neurotropic virus. Animal survival was also significantly shortened when orthotopic gliomas were implanted in mice perinatally infected with MCMV vs. controls. MCMV infection increased phosphorylated STAT3 (P-STAT3) levels in neural stem cells (NSCs) harvested from Mut3 mice SVZ and in vivo there was increased P-STAT3 in NSCs in MCMV-infected compared to control mice. Of relevance, human CMV (HCMV) also increased P-STAT3 and proliferation of patient-derived glioblastoma neurospheres, while a STAT3 inhibitor reversed this effect in vitro and in vivo. CONCLUSIONS: These findings thus associate CMV infection to a STAT3-dependent modulatory role in glioma formation/progression in the context of tumor suppressor mutations in mice and possibly in humans. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.