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Hochhalter et al. Association between HCMV and GBM

to be diagnosed in the United States in 2017. Nearly genesis. To determine whether HCMV was actually
[14]
[1]
everyone diagnosed with GBM succumbs to the associated with GBM, they developed a standardized
disease, which has a median survival of 12-15 months viral detection protocol. However, in a recent paper,
even with aggressive treatment. Despite years of Baumgarten et al. demonstrated negative results
[2]
[10]
research, there has been minimal improvement in the for HCMV in their GBM cohort despite demonstrating
overall survival rate. Reports of human cytomegalovirus positive staining in their control samples. In a
(HCMV) in GBM 15 years ago by Cobbs et al. raised paper addressing this, Cobbs et al. stated that
[3]
[11]
hopes for potential viral targeted therapeutic options Baumgarten et al. [10] did not use the carefully
for this disease. Recently, anti-HCMV immunotherapy optimized protocol established in his lab, which is
[15]
based clinical trials have been established to crucial to detect low level HCMV infection in GBM.
assess efficacy in treating this disease. At the basic In response, Cinatl et al. stated that in observing
[12]
research level, efforts are being made to investigate similar staining in their glioma samples from HCMV
the oncogenic potential of individual HCMV genes seropositive and seronegative patients, they reached
to understand how HCMV might contribute to GBM. out to the 3 groups reporting positive results. In one
Despite these continuing efforts and the time lapsed group, the data could not be reproduced. The other
since the discovery of HCMV in GBM, the association two groups agreed to stain samples from Cinatl’s lab,
remains controversial. This review serves to highlight however, found no difference in staining in the glioma
the latest developments in this association and its samples observed between the HCMV seropositive
clinical validity as a therapeutic target for primary and seronegative patients. Despite demonstrating
brain tumors. negative results, this data was not available to publish.
Moving forward, both groups agree that a standard
ENVIRONMENTAL ETIOLOGIES OF GBM protocol for detecting HCMV in GBM samples needs
to be established and agreed upon.
Although several studies have investigated risk factors
for brain tumors, our knowledge of their etiology is Several hypotheses have been proposed to help
limited. The only clear environmental risk factor that explain discrepancies reported in the literature including
has been identified for glial neoplasms is ionizing geographic differences, differences in seropositivity,
radiation. The relationship between viruses and the use of different cohorts, and differences in
[4]
the development of primary brain tumors is complex protocols and experimental conditions used for
and unclear. While the majority of efforts have been traditional detection methods, such as polymerase
focused on studying HCMV, other viruses such as chain reaction (PCR), in situ hybridization (ISH), and
polyomaviruses JC and BK have been implicated immunohistochemistry (IHC) assays, which can lead
in brain tumors. [5,6] JC and BK viruses typically are to differences in sensitivities for detecting low levels of
asymptomatic infections that predominately present viral gene expression.
in immune suppressed individuals. Disease states
from polyomavirus infections are broad and range Although differences in HCMV seropositivity have been
from BK virus-related nephropathy to JC virus- investigated, there is currently no clear association
[7]
related progressive multifocal leukoencephalopathy. between HCMV seropositivity and incidence of GBM.
[8]
The propensity for the CNS characteristic of these HCMV seroprevalance is lower in Whites than in
viruses has led to attempts to develop better screening Blacks and Hispanics; however, GBM incidence is
methods to clarify this relationship. [9] higher. Additionally, HCMV seroprevalance is higher
[16]
in women than men, while the incidence of GBM is
HCMV AND GBM ASSOCIATION higher in men. [16]

Although an association between HCMV and GBM As a way to consolidate the data regarding the
was first reported in 2002, there is still a high detection of HCMV in CNS tumors, a symposium
[3]
degree of inconsistency in the literature regarding was convened in Washington, DC on April 17, 2011.
the detection of viral agents in CNS tumors. Further, At this symposium, oncologists and virologists
the recent debate between Cinatl and Cobbs labs as studying this very relationship had the opportunity to
to the presence of HCMV in GBM continues to fuel discuss data addressing this topic. At the conclusion
this ongoing controversy. [10-13] The initial concept of of this symposium, a summary paper was published
oncomodulation was developed by Cinatl et al. in reporting the consensus position in 4 major areas
[14]
1996. In their study, they proposed that HCMV could including the existence of HCMV in gliomas, the role
increase tumor malignancy by infecting tumor cells and of HCMV in gliomas, HCMV as a therapeutic target,
affecting either directly or indirectly cofactors for tumor and key future investigative directions. Based on
[17]
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ June 16, 2017 97