The most common adult
primary brain tumor,
glioblastoma (GBM), is characterized by fifteen months median patient survival and has no clear etiology. We and others have identified the presence of human cytomegalovirus (HCMV) gene products endogenously expressed in GBM tissue and primary cells, with a subset of viral genes being consistently expressed in most samples. Among these viral genes, several have important oncomodulatory properties, regulating
tumor stemness, proliferation, immune evasion, invasion and angiogenesis. These findings lead us to hypothesize that a specific HCMV gene signature may be associated with GBM pathogenesis. To investigate this hypothesis, we used
glioma cell lines and primary
glioma stem-like cells (GSC) infected with clinical and laboratory HCMV strains and measured relative viral gene expression levels along several time points up to 15 weeks post-
infection. While HCMV gene expression was detected in several infected
glioma lines through week 5 post-
infection, only HCMV-infected GSC expressed
viral gene products 15 weeks post-
infection. Efficiency of
infection across time was higher in GSC compared to cell lines. Importantly, HCMV-infected GSC outlived their uninfected counterparts, and this extended survival was paralleled by increased tumorsphere frequency and upregulation of stemness regulators, such as SOX2, p-STAT3, and BMX (a novel HCMV target identified in this study).
Interleukin 6 (IL-6) treatment significantly upregulated HCMV gene expression in long-term infected
glioma cultures, suggesting that pro-inflammatory signaling in the
tumor milieu may further augment HCMV gene expression and subsequent
tumor progression driven by viral-induced cellular signaling. Together, our data support a critical role for long-term, low-level HCMV
infection in promoting survival, stemness, and proliferation of GSC that could significantly contribute to GBM pathogenesis.