An Engineered Herpesvirus Activates Dendritic Cells and Induces Protective Immunity.
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.
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Yijie
Y
Ma
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.|Institute of Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Min
M
Chen
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Huali
H
Jin
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Bellur S
BS
Prabhakar
Department of Pathology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Tibor
T
Valyi-Nagy
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Bin
B
He
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005818:Genetic Engineering; D006564:Herpesviridae / Q000502:physiology*; D006566:Herpesviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D007109:Immunity; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction; D014611:Vaccination
D000998:Antiviral Agents; D016207:Cytokines; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human