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

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Abstract
The γ 1 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 γ 1 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 γ 1 34.5 mutant lacking the amino terminus induces stronger antiviral immunity. This parallels a defect of γ 1 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 γ 1 34.5 amino-terminal deletion mutant replicates at an intermediate level between replication of wild-type virus and that of the γ 1 34.5 null mutant in TBK1 +/+ cells. However, such impaired viral growth is not observed in TBK1 −/− cells, indicating that the interaction of γ 1 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 γ 1 34.5 null mutant. Therefore, in addition to PKR, γ 1 34.5 negatively regulates TBK1, which contributes viral replication and spread in vivo .