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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

Gene Therapy volume 22, pages 348–355 (2015)Cite this article

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An Erratum to this article was published on 02 April 2015

This article has been updated

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 γ134.5-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 γ134.5-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 γ134.5-deleted virus in hypoxia. Taken together, these findings demonstrate that chimeric HCMV/HSV-1 efficiently targets both CD133+ GSCs and glioma cells in hypoxia.

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  • 02 April 2015

    This article has been corrected since advance online publication and an erratum is also printed in this issue

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Acknowledgements

Funding was provided by the St Baldrick’s Foundation, The Rally Foundation, Hyundai Hope on Wheels and Kaul Pediatric Research Institute to GKF, as well as the National Institutes of Health (NIH) (CA071933, CA097247 and CA151129). We thank Enid Keyser and the Analytic and Preparative Core Facility (supported by P30 AR048311 and P30 AI027767) for assistance with FACS analysis and Drs Darell Bigner, Jann Sarkaria and C David James for sharing the human xenograft lines with us for these studies.

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Authors and Affiliations

  1. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Brain Tumor Research Program, University of Alabama at Birmingham, Birmingham, AL, USA

    G K Friedman, L Nan, M C Haas, V M Kelly & B P Moore

  2. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA

    C P Langford, J M Markert & G Y Gillespie

  3. Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA

    H Xu

  4. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA

    X Han

  5. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA

    E A Beierle

  6. Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    K A Cassady

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  1. G K Friedman
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  3. M C Haas
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  4. V M Kelly
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Correspondence to G K Friedman.

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Competing interests

Dr Markert and Dr Gillespie are founders of and own stock and stock options (<7% interest) in Catherex Inc. and in Aettis Inc., biotechnology companies that are developing other oncolytic HSV that are not the subject of this current investigation. They serve as consultants for Catherex Inc. as well. Dr Gillespie currently serves as one of five unpaid members of the Board of Directors for Catherex Inc. The virus used in this study is not licensed by either company or the subject of any company plans for clinical use. Dr Gillespie has served as a paid advisor to the Program Project at the Ohio State University that seeks to find improved methods for the application of oncolytic HSV to treat localized and metastatic cancers. This is generally, but not specifically, related to the subject matter of this investigation.

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Friedman, G., Nan, L., Haas, M. et al. 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. Gene Ther 22, 348–355 (2015). https://doi.org/10.1038/gt.2014.107

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  • DOI: https://doi.org/10.1038/gt.2014.107

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