Abstract
A virulent recombinant HSV lacking the diploid γ134.5 gene (Δγ134.5) have been investigated over the last two decades both for anti-tumor therapy and as vaccine vectors. The first generation vectors, while safe, are incapable of sustained replication in the majority of treated patients. An interferon inducible host antiviral kinase, protein kinase R (PKR), limits late viral protein synthesis and replication of Δγ134.5 viruses. This review describes the development of new Δγ134.5 vectors, through serial passage selection and direct viral genome engineering, which demonstrate selective PKR evasion in targeted cells and improved viral replication without restoring neurovirulence.
Highlights
Serial passage is a time-honored viral laboratory method that has been used to select progeny with attenuating mutations (e.g. OKA vaccine strain from varicella zoster virus)
A different method hypothesized that transfer of the human cytomegalovirus (HCMV) protein kinase R (PKR) evasion genes TRS1 or IRS1 gene to a 134.5 virus would improve viral replication and anti-glioma activity
A similar greater anti-tumor benefit was seen comparing the viruses against a murine neuroblastoma model [23]. These studies suggest that replication of oncolytic HSV-1 vectors in partially restrictive tumor cells due to anti-viral PKR responses can be significantly improved by encoding PKR-evasion genes from a related herpesvirus
Summary
Serial passage is a time-honored viral laboratory method that has been used to select progeny with attenuating mutations (e.g. OKA vaccine strain from varicella zoster virus). In addition to discussing the protein product encoded by the HSV 134.5 gene that counters this host antiviral response, the review describes how mutant viruses lacking the 134.5 gene ( 134.5) have been studied as vaccine and anti-tumor therapies because of their safety in humans. While these vectors are safe, their limited late viral protein synthesis and diminished replication limit their efficacy. Serial passage of 134.5 recombinants has been used to identify whether compensatory mutations improve viral replication or the anti-tumor properties of the 134.5 mutants. Current efforts to improve these vectors’ replication are focused upon engineering a new generation of HSV recombinants based on the earlier serial passage experiments
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