Neurovirulence factor ICP34.5 (ICP34.5)

Neurovirulence factor ICP34.5 is a multifunctional protein encoded by the RL1 gene of Herpes Simplex Virus (HSV-1 and HSV-2) that is essential for viral pathogenesis and neurovirulence [1, 6]. Its primary biological function is to prevent the host cell from shutting down protein synthesis in response to infection; it achieves this by recruiting host protein phosphatase 1 (PP1) to dephosphorylate the translation initiation factor eIF2-alpha, thereby neutralizing the antiviral activity of double-stranded RNA-dependent protein kinase (PKR) [4, 8]. Beyond translation regulation, ICP34.5 also inhibits autophagy by binding to Beclin 1 and suppresses innate immune responses by interfering with the interferon (IFN) signaling pathway and STING-mediated DNA sensing [3, 9, 10]. In therapeutic development, ICP34.5 is a critical target for genetic deletion in oncolytic virotherapy, as seen in the FDA-approved drug Talimogene laherparepvec (T-VEC) [13, 15]. Deleting this factor ensures that the virus cannot replicate in healthy neurons but can still proliferate in tumor cells with impaired antiviral pathways, providing a mechanism for tumor-selective lysis and safety [15, 19]. Additionally, small molecules that inhibit the ICP34.5-PP1 interaction, such as Salubrinal, are being explored as potential antiviral agents to block HSV replication [1, 6].

Other names

Infected cell protein 34.5Protein gamma(1)34.5RL1gamma-1 34.5

Genetic deletion to achieve tumor-selective replication and attenuation of neurovirulence in oncolytic viruses [13, 15]. Inhibition of the ICP34.5-PP1 phosphatase complex to prevent viral protein synthesis and replication [1, 6].