Selective Editing of Herpes Simplex Virus 1 Enables Interferon Induction and Viral Replication That Destroy Malignant Cells.

Affiliation

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA [Email]

Abstract

Oncolytic herpes simplex virus 1 (HSV-1), devoid of the γ134.5 gene, exerts antitumor activities. However, the oncolytic effects differ, ranging from pronounced to little responses. Although viral and host factors are involved, much remains to be deciphered. Here we report that engineered HSV-1 ΔN146, bearing amino acids 147 to 263 of γ134.5, replicates competently in and lyses malignant cells refractory to the γ134.5 null mutant. Upon infection, ΔN146 precludes phosphorylation of translation initiation factor eIF2α (α subunit of eukaryotic initiation factor 2), ensuring viral protein synthesis. On the other hand, ΔN146 activates interferon (IFN) regulatory factor 3 (IRF3) and IFN expression, known to prime immunity against virus and tumor. Nevertheless, ΔN146 exhibits sustained replication even exposed to exogenous IFN-α. In a 4T1 tumor model, ΔN146 markedly reduces tumor growth and metastasis formation. This coincides with viral replication or T cell infiltration in primary tumors. ΔN146 is undetectable in normal tissues in vivo Targeted HSV-1 editing results in a unique antineoplastic agent that enables inflammation without major interference of viral growth within tumor cells.IMPORTANCE Oncolytic herpes simplex virus 1 is a promising agent for cancer immunotherapy. Due to a complex virus-host interaction, less is clear about what viral signature(s) constitutes a potent oncolytic backbone. Through molecular or genetic dissection, we showed that selective editing of the γ134.5 gene enables viral replication in malignant cells, activation of transcription factor IRF3, and subsequent induction of type I IFN. This translates into profoundly reduced primary tumor growth and metastasis burden in an aggressive breast carcinoma model in vivo Our work reveals a distinct oncolytic platform that is amendable for further development.

Keywords

herpes simplex virus,oncolytic viruses,viral replication,virus-host interactions,