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The γ1 34.5 protein of herpes simplex viruses (HSV) is essential for viral pathogenesis, where it precludes translational arrest mediated by double-stranded-RNA-dependent protein kinase (PKR). Paradoxically, inhibition of PKR alone is not sufficient for HSV to exhibit viral virulence. Here we report that γ1 34.5 inhibits TANK binding kinase 1 (TBK1) through its amino-terminal sequences, which facilitates viral replication and neuroinvasion. Compared to wild-type virus, the γ1 34.5 mutant lacking the amino terminus induces stronger antiviral immunity. This parallels a defect of γ1 34.5 for interacting with TBK1 and reducing phosphorylation of interferon (IFN) regulatory factor 3. This activity is independent of PKR. Although resistant to IFN treatment, the γ1 34.5 amino-terminal deletion mutant replicates at an intermediate level between replication of wild-type virus and that of the γ1 34.5 null mutant in TBK1+/+ cells. However, such impaired viral growth is not observed in TBK1−/− cells, indicating that the interaction of γ1 34.5 with TBK1 dictates HSV infection. Upon corneal infection, this mutant replicates transiently but barely invades the trigeminal ganglia or brain, which is a difference from wild-type virus and the γ1 34.5 null mutant. Therefore, in addition to PKR, γ1 34.5 negatively regulates TBK1, which contributes viral replication and spreadin vivo .

Inhibition of TANK Binding Kinase 1 by Herpes Simplex Virus 1 Facilitates Productive Infection