Genetic metamorphosis of herpes simplex virus-1 into a biological therapeutic for human cancer

Abstract

Over the past decade, rapid progress has been made in engineering safe, replicating herpes simplex virus-1 (HSV-1) mutants for use as biological oncolytic agents in the treatment of human cancer. While initial efforts demonstrated the potential of HSV-1 mutants as antitumour agents, they relied on viruses that were not sufficiently attenuated. Following its identification as the major viral neurovirulence determinant, mutations in the γ34.5 gene were subsequently incorporated into oncolytic strains. Despite the fact that γ34.5 mutant derivatives can be safely administered to mice, non-human primates and humans, their efficacy is limited because, like many weakened viral strains, they replicate poorly in a number of cell types, including cancer cells. Strategies to improve the oncolytic properties of γ34.5 mutant derivatives through further genetic manipulation are reviewed. In addition, traditional treatment modalities that incorporate viral inoculation, along with efforts to elicit an antitumour immune response following treatment with γ34.5 derivatives, are discussed.

• oncolytic
• replication-competent virus
• herpes simplex virus-1 γ34.5 mutants