Infected cell protein 34.5 (ICP34.5) mRNA regulated by microRNA-124 and microRNA-143 binding sites (ICP34.5-miR-124/143-BS)

Infected cell protein 34.5 (ICP34.5), encoded by the γ134.5 gene, is a critical neurovirulence factor of Herpes Simplex Virus type 1 (HSV-1) that enables viral replication by antagonizing the host cell's protein kinase R (PKR) response (He et al., 1997, PNAS). In the context of oncolytic virotherapy, the ICP34.5 mRNA is engineered to include binding sites for microRNAs such as miR-124 and miR-143 to enhance the safety profile of the virus. miR-124 is highly expressed in normal neurons but significantly downregulated in glioblastoma cells, while miR-143 is often downregulated in various cancers (Grandi et al., 2010, Gene Therapy). By incorporating these binding sites into the 3' untranslated region (UTR) of the ICP34.5 mRNA, the expression of the protein is post-transcriptionally silenced in healthy neural tissues, thereby preventing viral replication and associated neurotoxicity (Mazzacurati et al., 2015, Molecular Therapy). Conversely, in tumor cells where these microRNAs are absent, ICP34.5 is expressed, allowing the oncolytic virus to replicate selectively and lyse the cancer cells. This strategy represents a sophisticated approach to achieving tumor-specific replication while maintaining the potent oncolytic activity of the virus.

Other names

γ134.5 mRNARL1 mRNANeurovirulence factor ICP34.5 mRNAICP34.5-miR-BSMicroRNA-targeted ICP34.5

MicroRNA-mediated post-transcriptional gene silencing to restrict viral neurovirulence factor expression to microRNA-deficient tumor cells.