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Hochhalter et al. Association between HCMV and GBM

the data presented at the symposium and discussions US28 regulates several cellular pathways including
with experts at that time, it was concluded that HCMV STAT3, VEGF, and e-NOS signaling which promotes
sequences and viral gene expression exist in many GBM pathogenesis by regulating angiogenesis,
high-grade gliomas and that in vitro studies suggest invasion, and immune evasion. [28,29] While these
that HCMV can modulate key signaling cellular experiments show that these viral genes have the
pathways in glioblastomas. [17] potential to be oncogenic, the question as to whether
HCMV is association with GBM remains unclear.
Currently, HCMV is not considered to be a classic
oncogenic virus because it has not been demonstrated The current line of thinking in the association between
to possess acute transforming activity. Instead, it is HCMV and GBM revolves around four potential
[18]
believed that HCMV contributes to GBM pathogenesis hypotheses. The first is that HCMV is causal;
[30]
through oncomodulation of host cellular pathways. however, there is no evidence to date to support this
This notion of HCMV modulating host cellular concept in humans. The best evidence we have at this
pathways stems from evidence generated in other time for HCMV causing GBMs is in a mouse model.
[31]
model systems. Specifically, studies performed in a Researchers at Brigham and Women’s Hospital
mouse model have shown that persistent infection of developed a mouse CMV-infected GBM mouse model
endothelial cells by CMV, defined as the expression of using mut3 mice, which spontaneously develop grade
viral genes without evidence of cytopathogenic effect III and IV astrocytomas. They demonstrated that
on host cells, resulted in the production of inflammatory MCMV-infected mut3 mice had decreased overall
cytokines and renin, which led to the development survival compared to naive mut3 mice. The second
[31]
of hypertension. Applying this evidence to GBM, hypothesis is that HCMV may be oncomodulatory,
[19]
one hypothesis proposes that persistent infection thereby enhancing tumor progression by a specific
with HCMV could lead to production of inflammatory mechanism or a combination of mechanisms, which
cytokines that may contribute to pathogenesis through were detailed in the previous section. [17,18,20,22-24,26-29,32,33]
disruption of the cell cycle. [17] The third hypothesis is that HCMV may be a
bystander with little effect on tumor growth, and
Of the estimated 173 open reading frames present in the HCMV antigens are expressed because of the
the HCMV genome, only a few of the gene products, highly immunosuppressive tumor microenvironment
[20]
such as IE1, pp71, glycoprotein B, and US28, have observed in GBM. There is no direct evidence to
been detected in GBMs. Forced expression of HCMV date to support this concept. The last hypothesis is
IE1 was shown to increase stemness properties that these observations are merely an experimental
(e.g. self-renewal) and proliferation of glioma stem- artifact. Several recent publications have outlined
like cells in vivo. Follow-up studies demonstrated possible scenarios where detection of HCMV may be
[21]
that IE1 promotes the tumor phenotype in these due to experimental artifact including cross-reactivity
settings through inactivation of the p53 and Rb tumor of antibodies, the concentration of antibodies,
[35]
[34]
suppressor proteins and through activation of the or presence of expression vector genetic material in
PI3-K/AKT signaling pathway. Long-term HCMV sequencing datasets. [36]
[22]
infected glioma cultures demonstrated upregulation
of key signaling mediators such as SOX2, STAT3, HCMV DETECTION IN GBM
BMX and IL-6. In addition, infection of GBM cells
[23]
with HCMV led to upregulation of CD133 and other Several studies have investigated the association
stem cell-like factors such as Notch1, Sox2, Oct4, between HCMV and GBM in an attempt to resolve
and Nestin. HCMV infection of GBM cells has also this controversial issue. Various detection approaches
[24]
led to tumor proliferation through an upregulation of have been utilized by several investigators including
a proteoglycan, endocan, which has been shown to traditional techniques (e.g. PCR, ISH, and IHC) and
be involved in several cellular processes including next generation sequencing (NGS) technology in an
angiogenesis. [25] Previously, overexpression of attempt to detect the presence of HCMV in GBM cells
HCMV pp71 was shown to induce a pro-inflammatory [Table 1].
response via activation of NFKB signaling in adult
neural precursor cells. HCMV glycoprotein B has The most recent studies that have reported a positive
[26]
been shown to mediate viral cellular entry via the association utilized traditional detection methods. One
receptor tyrosine kinase PDGFR-alpha resulting in study looked for the presence of HCMV antigens pp65
activation of the PI3-K/AKT signaling pathway. or IE1-72 in 25 pediatric GBM patients. The study
[27]
Another key HCMV product that is implicated in GBM showed a 66.7% detection rate in the samples for
development is the chemokine receptor US28. HCMV either pp65 or IE1-72. The authors of this study also
[58]
98 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ June 16, 2017