Alphaherpesviruses have developed a finetuned balance with the immune system of the host,

allowing (lifelong) infection of the host and efficient transmission but at the same time leading to

relatively benign symptoms, such as cold sores with herpes simplex virus 1 (HSV-1).

Disturbance of the balance with the immune system can have severe consequences. Deficiencies in

Natural Killer (NK) cells severely affect the balance, and can lead to life-threatening disease, such as

HSV-1 encephalitis (1, 2).

NK cells have an array of activating and inhibitory receptors on their cell surface. When an NK cell

encounters a potential target cell, it is the balance of activating and inhibitory signals elicited via

these receptors that determines whether the NK cell will kill the cell. Despite the obvious critical

role of NK cells in alphaherpesvirus pathogenesis, very little is known on the activating and

inhibitory signals received by NK cells when encountering an alphaherpesvirus-infected cell.

Recent, exciting data of the promoters show that particular alphaherpesvirus proteins elicit

inhibitory (gD, US3) or activating (gB) signals to NK cells. The general aim of the current project is to

unravel the mechanism how these viral proteins affect NK cell activity. The fundamental knowledge

generated can have important consequences for the design of alphaherpesvirus-based vaccines and

therapeutic vectors.