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Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV

Gene Therapy volume 20, pages 761–769 (2013)Cite this article

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Abstract

Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disease (LPD) after hematopoietic stem cell or solid organ transplantation remains a life-threatening complication. Expression of the virus-encoded gene product, EBER, has been shown to prevent apoptosis via blockade of PKR activation. As PKR is a major cellular defense against Herpes simplex virus (HSV), and oncolytic HSV-1 (oHSV) mutants have shown promising antitumor efficacy in preclinical models, we sought to determine whether EBV-LPD cells are susceptible to infection by oHSVs. We tested three primary EBV-infected lymphocyte cell cultures from neuroblastoma (NB) patients as models of naturally acquired EBV-LPD. NB12 was the most susceptible, NB122R was intermediate and NB88R2 was essentially resistant. Despite EBER expression, PKR was activated by oHSV infection. Susceptibility to oHSV correlated with the expression of the HSV receptor, nectin-1. The resistance of NB88R2 was reversed by exogenous nectin-1 expression, whereas downregulation of nectin-1 on NB12 decreased viral entry. Xenografts derived from the EBV-LPDs exhibited only mild (NB12) or no (NB88R2) response to oHSV injection, compared with a NB cell line that showed a significant response. We conclude that EBV-LPDs are relatively resistant to oHSV virotherapy, in some cases, due to low virus receptor expression but also due to intact antiviral PKR signaling.

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Acknowledgements

We thank Patria G Spear (Northwestern University, IL, USA) for providing the nectin-1 expression vector pBG38, and CHO-K1, CHO-N1 and CHO-N2 cells. This work was supported by Cincinnati Children’s Hospital Medical Center Division of Hematology/Oncology, CancerFree Kids, teeoffagainstcancer.org, the Katie Linz Foundation, Alex’s Lemonade Stand Foundation for Childhood Cancer, the Ohio State University Comprehensive Cancer Center Pelotonia Team Science Award, the Research Institute at Nationwide Children’s Hospital, Canadian Cancer Society Research Institute, and NIH grants R21-CA133663-01A1 (TPC), R01-CA114004 (TPC), R01-CA119298 (JCG) and P01-NS040923 (JCG).

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Authors and Affiliations

  1. Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    P-Y Wang, M A Currier & T P Cripe

  2. The Research Institute at Nationwide Children’s Hospital and the Division of Hematology/Oncology/BMT, Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, USA

    P-Y Wang, M A Currier & T P Cripe

  3. The Hospital for Sick Children and the Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    L Hansford & D Kaplan

  4. Department of Neurosurgery and James Comprehensive Cancer Center, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Medical Center, Columbus, OH, USA

    E A Chiocca

  5. Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

    H Uchida, W F Goins, J B Cohen & J C Glorioso

  6. Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    H Uchida

  7. Department of Matrix Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands

    T H van Kuppevelt

  8. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    X Mo

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Correspondence to T P Cripe.

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Wang, PY., Currier, M., Hansford, L. et al. Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV. Gene Ther 20, 761–769 (2013). https://doi.org/10.1038/gt.2012.93

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