Abstract
Herpes simplex viruses (HSV) are human pathogens that switch between lytic and latent infection. While attenuated HSV is explored for vaccine, the underlying event remains poorly defined. Here we report that recombinant HSV-1 with a mutation in the γ134.5 protein, a virulence factor, stimulates dendritic cell (DC) maturation which is dependent on TANK-binding kinase 1 (TBK1). When exposed to CD11+ DCs, the mutant virus that lacks the amino terminus of γ134.5 undergoes temporal replication without production of infectious virus. Mechanistically, this leads to sequential phosphorylation of interferon regulatory factor 3 (IRF3) and p65/RelA. In correlation, DCs up-regulate the expression of co-stimulatory molecules and cytokines. However, selective inhibition of TBK1 precludes phosphorylation of IRF3 and subsequent DC activation by the γ134.5 mutant. Herein, the γ134.5 mutant is immune-stimulatory and non-destructive to DCs. Remarkably, upon immunization the γ134.5 mutant induces protection against lethal challenge by the wild type virus, indicative of its vaccine potential. Furthermore, CD11+ DCs primed by the γ134.5 mutant in vivo mediate protection upon adoptive transfer. These results suggest that activation of TBK1 by engineered HSV is crucial for DC maturation, which may contribute to protective immunity.
Highlights
Herpes simplex viruses (HSV) are human pathogens that switch between lytic and latent infection
To characterize an HSV-1 mutant that lacks the amino-terminal domain of γ134.5, we evaluated virus infection of dendritic cell (DC)
We show that an HSV-1 mutant that harbors an N-terminal truncation in the γ134.5 protein is able to infect DCs and induce phosphorylation of interferon regulatory factor 3 (IRF3) and RelA/p65
Summary
Herpes simplex viruses (HSV) are human pathogens that switch between lytic and latent infection. CD11+ DCs primed by the γ134.5 mutant in vivo mediate protection upon adoptive transfer These results suggest that activation of TBK1 by engineered HSV is crucial for DC maturation, which may contribute to protective immunity. HSV typically infects the mucosal tissues where it undergoes viral entry, gene expression, DNA replication, assembly and egress. In this process, the virus sequentially expresses an array of viral proteins that work coordinately, resulting in a productive cycle. Alternative mechanisms exist in DCs to detect HSV These include cyclic GAMP synthase and DDX41 that sense intracellular viral DNA and induce cytokine expression[11,12]. The γ134.5 protein redirects protein phosphatase 1 to dephosphorylate eIF-2α21
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