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. 2012 Mar;14(3):246-55.
doi: 10.1093/neuonc/nor227. Epub 2012 Feb 8.

Consensus on the role of human cytomegalovirus in glioblastoma

Affiliations

Consensus on the role of human cytomegalovirus in glioblastoma

Kristine Dziurzynski et al. Neuro Oncol. 2012 Mar.

Abstract

The human cytomegalovirus (HCMV) and glioma symposium was convened on April 17, 2011 in Washington, DC, and was attended by oncologists and virologists involved in studying the relationship between HCMV and gliomas. The purpose of the meeting was to reach a consensus on the role of HCMV in the pathology of gliomas and to clarify directions for future research. First, the group summarized data that describe how HCMV biology overlaps with the key pathways of cancer. Then, on the basis of published data and ongoing research, a consensus was reached that there is sufficient evidence to conclude that HCMV sequences and viral gene expression exist in most, if not all, malignant gliomas, that HCMV could modulate the malignant phenotype in glioblastomas by interacting with key signaling pathways; and that HCMV could serve as a novel target for a variety of therapeutic strategies. In summary, existing evidence supports an oncomodulatory role for HCMV in malignant gliomas, but future studies need to focus on determining the role of HCMV as a glioma-initiating event.

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Figures

Fig. 1.
Fig. 1.
Correlation of patterns of immunohistochemical localization of human cytomegalovirus (HCMV) immediate early 1 (IE1) protein with in situ hybridization for HCMV DNA in a glioblastoma (GBM) that invades normal brain. (A) Low-power view of anti-IE1 immunostain demonstrates GBM invading normal brain cortex (cortical surface at far right; bar, 200 µm). (B–D) Boxed areas in (A) at higher power demonstrate IE1 immunoreactivity moving from an area of frank tumor (B) to an area of invading tumor (C) to an area of normal brain (D). Detection of HCMV DNA by in situ hybridization using an HCMV total genome probe (in an adjacent section and similar regions of the same tumor in B–D) reveals a similar pattern, moving from malignant (E) to invasive (F) to normal (G) brain. Bar, 10 µm.
Fig. 2.
Fig. 2.
Selected immune subversive human cytomegalovirus (HCMV) proteins blocking CTL and NK cell recognition and antigen presentation pathways. HCMV gene nomenclature designates genes as UL for unique long and US for unique short to reflect regions of the genome from which the gene originates. UL83 (pp65) inhibits presentation of the immunodominant CMV protein immediate early 1 (IE1); US2 mediates degradation of HLA class I and II a chains; US3 causes retention of class I molecules within the ER; US6 inhibits TAP-mediated peptide transportation into the ER; US11 (like US2) causes destruction of class I a chains; UL16 inhibits NK cell recognition via the activating receptor NKG2D by binding to its ligands (ULBPs); UL18 activates LIR-1, an inhibitory receptor found on NK cells, lymphocytes, and most other immune cells; and UL40 activates the inhibitory NKG2A/B receptor by upregulating HLA-E expression. HCMV produces a functional IL-10 homolog (UL111A) and induces expression of cellular PGE-2 and TGF-β, which further inhibit NK cell response.

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