Investigating the effects of human cytomegalovirus infection in the adult brain

The relationship between human cytomegalovirus (HCMV) and glioblastoma (GBM) remains highly controversial. Consensus regarding both detection of HCMV and any potential oncogenic role within tumours has yet to be reached. Nevertheless, HCMV-directed immunotherapy can lead to GBM clearance, supporting a direct link.
Detection of HCMV in GBM is predominantly within CD133+ stem-like cells, although infectious virus is seemingly absent. Adult neural progenitor cells (NP) are a likely cell of origin for GBM, yet unlike foetal and iPSC-derived neural progenitors, the behaviour of HCMV within genuine adult NP is unknown.
Here I have shown that HCMV can infect adult NP cells in vitro, with virus detected up to 100 days post infection. Initial infection of adult NP’s in vitro results in lytic gene expression without infectious virion production. However, application of an in vitro differentiation protocol leads to detectable secreted infectivity. HCMV infection perturbs the differentiation seen in uninfected controls with cells retaining progenitor morphology rather than developing neuronal features. Additionally, infection post-differentiation appears to de-differentiate these cells as they lose their neuronal processes and regain PCNA and Ki67 expression.
This work shows that several pathways associated with gliomagenesis are dysregulated during HCMV infection of NP including modulation of cell cycle, MAPK and PI3K-Akt, with TERT expression increased in HCMV+ NP post-differentiation compared to a non-infected control. HCMV induces a stem cell phenotype in NP, including inducing expression of GBM stem cell marker CD133 and stem cell factor KLF4. This is significant as these changes are all known to occur in GBM.
HCMV appears to unlock phenotypic plasticity as it both impairs and seemingly reverses NP differentiation, consistent with a potential direct oncogenic role during GBM pathogenesis. This may be important in understanding the role of HCMV in GBM, specifically during gliomagenesis.