Persistent HCMV infection of a glioblastoma cell line contributes to the development of resistance to temozolomide.

Glioblastoma multiforme (GBM) is the most aggressive form of primary human gliomas. While chemotherapy using the DNA alkylating agent temozolomide (TMZ) is a first line treatment for GBMs, the development of resistance to TMZ is a common limitation to successful treatment. Human Cytomegalovirus (HCMV) is a ubiquitous β-herpesvirus that establishes a lifelong infection latent infection in host haematopoetic cells, where lytic replication of the virus is silenced. HCMV can also establish a persistent infection in hosts, where low levels of virus are lytically produced. Furthermore, multiple studies have identified HCMV DNA and/or proteins in human GBM samples, and have shown that acute infection with HCMV confers a glioblastoma stem cell (GSC) phenotype, further supporting an oncomodulatory role for HCMV in GBM progression and severity. In this current study, we examined the long-term effects of HCMV persistence to cell viability, cell proliferation, and the development of TMZ resistance over time using a glioblastoma cell line known as LN-229. Persistent HCMV infections were established and maintained in this cell line for 30 weeks without the addition of new virus. Here, we report that HCMV persistence in this cell line resulted in increased cell viability, increased cell proliferation, and a marked resistance to the DNA alkylating agent, TMZ, over time, suggesting that low levels of lytically replicating HCMV could contribute to tumor progression in GBM.