Genetic Analysis of Cytomegalovirus in Malignant Gliomas

Bhattacharjee, Bornali; Renzette, Nicholas; Kowalik, Timothy F.

doi:10.1128/jvi.00015-12

Cited by 92 publications

(86 citation statements)

References 59 publications

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“…26 Other studies have suggested that halted differentiation of neuroprogenitor cells is an early step in gliomagenesis. 27 Since HCMV proteins and nucleotide sequences seem to be present in most GBMs 16,[28][29][30] and that HCMV-IE expression is a prognostic marker for poor patient survival irrespective of the GBM subtype, 18 our present model of HCMV infection of primary GBM cells appears to recapitulate early events during glioma development.…”

Section: Discussionmentioning

confidence: 90%

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

et al. 2015

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Glioblastoma (GBM) is associated with poor prognosis despite aggressive surgical resection, chemotherapy, and radiation therapy. Unfortunately, this standard therapy does not target glioma cancer stem cells (GCSCs), a subpopulation of GBM cells that can give rise to recurrent tumors. GBMs express human cytomegalovirus (HCMV) proteins, and previously we found that the level of expression of HCMV immediate-early (IE) protein in GBMs is a prognostic factor for poor patient survival. In this study, we investigated the relation between HCMV infection of GBM cells and the presence of GCSCs. Primary GBMs were characterized by their expression of HCMV-IE and GCSCs marker CD133 and by patient survival. The extent to which HCMV infection of primary GBM cells induced a GCSC phenotype was evaluated in vitro. In primary GBMs, a large fraction of CD133-positive cells expressed HCMV-IE, and higher co-expression of these two proteins predicted poor patient survival. Infection of GBM cells with HCMV led to upregulation of CD133 and other GSCS markers (Notch1, Sox2, Oct4, Nestin). HCMV infection also promoted the growth of GBM cells as neurospheres, a behavior typically displayed by GCSCs, and this phenotype was prevented by either chemical inhibition of the Notch1 pathway or by treatment with the anti-viral drug ganciclovir. GBM cells that maintained expression of HCMV-IE failed to differentiate into neuronal or astrocytic phenotypes. Our findings imply that HCMV infection induces phenotypic plasticity of GBM cells to promote GCSC features and may thereby increase the aggressiveness of this tumor. GBM is the most prevalent and the most aggressive primary malignancy of the central nervous system in adults. It is a highly vascularized and infiltrating tumor, rarely cured and prone to recurrence. The median duration of survival after diagnosis is less than 15 months, despite aggressive therapy consisting of surgical resection and concomitant radiotherapy and chemotherapy. 1 Surgical resection of GBMs is typically incomplete, as they are located in the brain and are highly infiltrative. Postoperative radiotherapy and chemotherapy fail to eradicate all remaining GBM cells. Thus, a breakthrough in identifying a new treatment option leading to a cure of this disease is still lacking.GBMs contain a subpopulation of highly tumorigenic cells with unlimited capacity for self-renewal that are commonly resistant to standard therapy. Phenotypically and functionally, these cells resemble neural stem cells and, when implanted in immunodeficient mice, can generate new tumors. As a result, they are referred to as glioma cancer initiating cells or glioma cancer stem cells (GCSCs) (reviewed in Lima et al. 2 ).Because of their apparent pivotal role in gliomagenesis and tumor recurrence after therapy, GCSCs are a major focus of research whose ultimate goal is to identify more effective therapies for GBM patients.GCSCs were first identified by their surface expression of CD133, based on the findings that these cells grow as neurospheres under nonadher...

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Section: Discussionmentioning

confidence: 90%

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

et al. 2015

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“…Forty-seven of the 48 samples were collected from infants with congenital CMV infection, and 1 sample was collected from an adult with glioblastoma multiforme (GBM). The GBM sample has been described previously (16) and was included to serve as an outlier to compare with the remaining samples. The dataset encompasses over 41 gigabases of HCMV sequence (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Subjects B101, B103, M103, MS1, and MS2 were described previously (11) as were U01, U04, and U33 (10) and G1 (16). The use of specimens from subjects PL2 and U45 was approved by the University of The samples H5478/H5529 and H1109/H1861/H1875 were derived from the Epidemiologische Untersuchung zur Erhebung der lnzidenz der kongenitalen Cytomegalvirus Infektion study, which was approved by the EthikKommission der Medizinischen Fakultät at the Universitätsklinikum Tübingen.…”

Section: Methodsmentioning

confidence: 99%

“…The viral interhost diversity was first described through restriction fragment length polymorphism analysis (12) and was subsequently confirmed with targeted gene and genome-wide sequencing (7,8,13). In a similar manner, HCMV intrahost diversity has been described using genetic and genomic sequencing (10,11,(14)(15)(16)(17) and has been shown to be comparable with diversity observed in RNA viruses, the benchmark of variable populations (10). HCMV thus exists within hosts as a heterogeneous collection of diverse but related genomes, herein termed a population, rather than a single sequence.…”

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Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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112

129

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Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.human cytomegalovirus | HCMV | congenital CMV | virology | evolution

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“…11 This phenomenon has been reported by other groups as well. 18,19 Studies using PCR techniques to detect 20 different regions of the CMV genome found CMV positivity was much more likely in GBM samples compared to epilepsy samples. 20 They also found that CMV detection was higher in more recent samples compared to older samples.…”

Section: Detection In Gliomasmentioning

confidence: 99%

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

et al. 2018

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Controversy surrounds the role of cytomegalovirus (CMV) in glioblastoma (GBM). However, several studies have shown that CMV nucleic acids and proteins are present within GBM tumor tissue. CMV has been implicated in GBM pathogenesis by affecting tumor stem cell factors, angiogenesis and immune pathways. Anti-viral therapy has not been found to definitively improve outcomes for patients with GBM. Several studies have leveraged CMV by targeting CMV antigens using ex-vivo expanded T cells or dendritic cell vaccines. The initial results from these studies are promising and larger studies are underway.

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Genetic Analysis of Cytomegalovirus in Malignant Gliomas

Cited by 92 publications

References 59 publications

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

Limits and patterns of cytomegalovirus genomic diversity in humans

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

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