title: γ₁34.5-deleted HSV-1-expressing human cytomegalovirus IRS1 gene kills human glioblastoma cells as efficiently as wild-type HSV-1 in normoxia or hypoxia.
abstract: Pathophysiological hypoxia, which fosters the glioma stem-like cell (GSC) phenotype, is present in high-grade gliomas and has been linked to tumor development, invasiveness and resistance to chemotherapy and radiation. Oncolytic virotherapy with engineered herpes simplex virus-1 (HSV-1) is a promising therapy for glioblastoma; however, the efficacy of γ(1)34.5-deleted HSVs, which have been used in clinical trials, was diminished in hypoxia. We investigated the ability of a chimeric human cytolomegalovirus (HCMV)/HSV-1 virus, which expresses the human CMV protein kinase R evasion gene IRS1 and is in preparation for clinical trials, to infect and kill adult and pediatric patient-derived glioblastoma xenografts in hypoxia and normoxia. Infectivity, cytotoxicity and viral recovery were significantly greater with the chimeric virus compared with the γ(1)34.5-deleted virus, regardless of oxygen tension. The chimeric virus infected and killed CD133+ GSCs similarly to wild-type HSV-1. Increased activation of mitogen-activated protein kinase p38 and its substrate heat-shock protein 27 (Hsp27) was seen after viral infection in normoxia compared with hypoxia. Hsp27 knockdown or p38 inhibition reduced virus recovery, indicating that the p38 pathway has a role in the reduced efficacy of the γ(1)34.5-deleted virus in hypoxia. Taken together, these findings demonstrate that chimeric HCMV/HSV-1 efficiently targets both CD133+ GSCs and glioma cells in hypoxia.
authors.affiliation: Brain Tumor Research Program, Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: G K
authors.initials: GK
authors.lastname: Friedman
authors.affiliation: Brain Tumor Research Program, Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Nan
authors.affiliation: Brain Tumor Research Program, Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Haas
authors.affiliation: Brain Tumor Research Program, Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Kelly
authors.affiliation: Brain Tumor Research Program, Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Moore
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Langford
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Beierle
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Markert
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Cassady
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: G Y
authors.initials: GY
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D030781:Organisms, Genetically Modified; D011494:Protein Kinases / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; D014764:Viral Proteins; D011494:Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases