1. ¹Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA
2. ²Department of Pediatrics, Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
3. ³Department of Surgery, Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
4. ⁴Department of Medicine- Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: Dr KA Cassady, Department of Pediatrics, University of Alabama at Birmingham, 1600 6th Avenue South, CHB-118C, Birmingham, AL 35233, USA. E-mail: kcassady@peds.uab.edu

⁵Current address: UAB, 1600 6th Avenue South, CHB-118B, Birmingham, AL 35233, USA.

⁶Current address: UAB, 1530 3rd Avenue South, THT 1052, Birmingham, AL 35294-0006, USA.

⁷Current address: UAB, 1600 6th Avenue South, TCH-700, Birmingham, AL 35233, USA.

⁸Current address: UAB, 1530 3rd Avenue South, NP 2540, Birmingham, AL 35294-3300, USA.

⁹Current address: UAB, 510 20th Street South, FOT 1050, Birmingham, AL 35294-3410, USA.

Received 7 September 2006; Revised 18 December 2006; Accepted 15 January 2007; Published online 12 April 2007.

Abstract

Oncolytic herpes simplex virus (HSV)-1 ₁34.5-deletion mutants (₁34.5 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 ₁34.5 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 ₁34.5 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 ₁34.5 HSV in malignant glioma cells in vitro and in vivo; (iii) are aneurovirulent; and (iv) are superior to other ₁34.5 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 ₁34.5 HSV significantly improves replication in malignant gliomas without restoring wild-type neurovirulence, resulting in enhanced tumor reduction and prolonged survival.