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Updated: Jul 15, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Enhanced antiglioma activity of chimeric HCMV/HSV-1 oncolytic viruses
A C Shah1, J N Parker, G Y Gillespie
1Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Abstract:
Oncolytic herpes simplex virus (HSV)-1 gamma(1)34.5-deletion mutants (Deltagamma(1)34.5 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 gamma(1)34.5 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 Deltagamma(1)34.5 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 Deltagamma(1)34.5 HSV in malignant glioma cells in vitro and in vivo; (iii) are aneurovirulent; and (iv) are superior to other Deltagamma(1)34.5 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 Deltagamma(1)34.5 HSV significantly improves replication in malignant gliomas without restoring wild-type neurovirulence, resulting in enhanced tumor reduction and prolonged survival.
Insights
Engineered oncolytic herpes simplex virus (HSV) vectors expressing human cytomegalovirus (HCMV) genes demonstrate enhanced replication in malignant gliomas. These chimeric viruses improve tumor reduction and survival without regaining neurovirulence, offering a promising cancer therapy.
Area of Science:
- Oncolytic virology
- Gene therapy
- Neuro-oncology
Background:
- Oncolytic herpes simplex virus (HSV)-1 gamma(1)34.5-deletion mutants (Deltagamma(1)34.5 HSV) show promise for tumor therapy but have limited replication.
- The gamma(1)34.5 gene facilitates late viral protein synthesis by evading the host's protein kinase R (PKR) antiviral response.
Purpose of the Study:
- To engineer Deltagamma(1)34.5 HSV vectors that restore late viral protein synthesis and replication in tumors.
- To assess if restoring this function can be achieved without reintroducing neurovirulence.
Main Methods:
- Construction of chimeric Deltagamma(1)34.5 HSV vectors (C130 and C134) expressing human cytomegalovirus (HCMV) PKR-evasion genes TRS1 and IRS1.
- Evaluation of viral replication, protein synthesis, neurovirulence, tumor volume reduction, and survival in malignant glioma models (in vitro and in vivo).
Main Results:
- HCMV/HSV-1 chimeric viruses maintained late viral protein synthesis in human malignant glioma cells.
- These chimeric viruses replicated to higher titers than Deltagamma(1)34.5 HSV in vitro and in vivo.
- The engineered viruses remained aneurovirulent and demonstrated superior tumor volume reduction and improved survival in murine brain tumor models.
Conclusions:
- Transferring HCMV IRS1 or TRS1 genes into Deltagamma(1)34.5 HSV significantly enhances replication in malignant gliomas.
- This enhancement occurs without restoring wild-type neurovirulence, leading to improved tumor reduction and prolonged survival.
- These findings support the potential of these chimeric viruses as effective oncolytic agents for glioma treatment.
