Abstract
Oncolytic herpes simplex virus (HSV)-1 γ134.5-deletion mutants (Δγ134.5 HSV) are promising agents for tumor therapy. The attenuating mutation renders the virus aneurovirulent but also limits late viral protein synthesis and efficient replication in many tumors. We tested whether one function of γ134.5 gene, which mediates late viral protein synthesis through host protein kinase R (PKR) antiviral response evasion, could be restored, without restoring the neurovirulence. We have previously reported the construction of two chimeric Δγ134.5 HSV vectors (chimeric HSV), C130 and C134, which express the human cytomegalovirus (HCMV) PKR-evasion genes TRS1 and IRS1, respectively. We now demonstrate the following. The HCMV/HSV-1 chimeric viruses (i) maintain late viral protein synthesis in the human malignant glioma cells tested (D54-MG, U87-MG and U251-MG); (ii) replicate to higher titers than Δγ134.5 HSV in malignant glioma cells in vitro and in vivo; (iii) are aneurovirulent; and (iv) are superior to other Δγ134.5 HSV with both improved reduction of tumor volumes in vivo, and improved survival in two experimental murine brain tumor models. These findings demonstrate that transfer of HCMV IRS1 or TRS1 gene into Δγ134.5 HSV significantly improves replication in malignant gliomas without restoring wild-type neurovirulence, resulting in enhanced tumor reduction and prolonged survival.
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Acknowledgements
We thank Huey Nguyen and Der Wei Venable for expert technical assistance, Dr M Shimamura and Ms Spira Steyn for editing. We thank Dr Wenquan Wang for reading the manuscript and providing his expert statistical advice, Dr Kurt Zinn for his assistance through the multi-modality imaging center, Dr B Roizman for providing HSV-1(F), R3616, and discussions, and Dr T Shenk for providing the pHCMV215 plasmid. We acknowledge the support of the Ruth L Kirschstein NRSA Fellowship 1 F31 NS050924–01 and Medical Scientist Training Program (ACS), NCI P50 CA 097247 (GYG, KAC) and NCI P01 CA 71933 (JMM, JNP, GYG).
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Shah, A., Parker, J., Gillespie, G. et al. Enhanced antiglioma activity of chimeric HCMV/HSV-1 oncolytic viruses. Gene Ther 14, 1045–1054 (2007). https://doi.org/10.1038/sj.gt.3302942
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DOI: https://doi.org/10.1038/sj.gt.3302942
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