An Engineered Herpesvirus Activates Dendritic Cells and Induces Protective Immunity

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• Herpes simplex viruses (HSV) are human pathogens known for their ability to establish both lytic and latent infections.
• Attenuated strains of HSV are being investigated for vaccine development, but the precise mechanisms driving their immune-stimulatory effects are not fully understood.

Purpose of the Study:

• To investigate the immune-stimulatory properties of a recombinant HSV-1 mutant lacking the amino terminus of the γ134.5 protein.
• To elucidate the role of TANK-binding kinase 1 (TBK1) in the maturation of dendritic cells (DCs) induced by this engineered HSV-1.

Main Methods:

• Utilized a recombinant HSV-1 mutant with a deletion in the γ134.5 gene, a known viral virulence factor.
• Exposed CD11+ DCs to the mutant virus and assessed viral replication, DC maturation markers, cytokine production, and signaling pathways.
• Investigated the role of TBK1 by using selective inhibitors and examining downstream signaling molecules like IRF3 and p65/RelA.

Main Results:

• The γ134.5 mutant HSV-1 replicated temporally in DCs without producing infectious virions, leading to IRF3 and p65/RelA phosphorylation.
• DC maturation, evidenced by up-regulated co-stimulatory molecules and cytokines, was dependent on TBK1 activation.
• Inhibition of TBK1 blocked IRF3 phosphorylation and subsequent DC activation.
• Immunization with the γ134.5 mutant conferred protection against lethal wild-type HSV-1 challenge, and adoptively transferred, primed DCs also mediated protection.

Conclusions:

• Engineered HSV-1, specifically the γ134.5 mutant, acts as an immune-stimulatory agent that promotes DC maturation in a TBK1-dependent manner.
• This TBK1-mediated DC activation by engineered HSV-1 is crucial for inducing protective immunity, highlighting its potential as a vaccine vector.