The aim of this project is to examine how the local skin microenvironment influences the generation of antiviral immune responses following herpes simplex virus type 2 (HSV-2) infection. Genital herpes, caused primarily by HSV-2, has a worldwide prevalence and is the leading cause of genital ulcers. An increasing number of clinical and epidemiological studies indicate that a recent genital HSV-2 infection increases the risk of HIV acquisition and transmission by up to 3-fold. Therefore, further studies that examine the local immune responses to HSV-2 infection are necessary to elucidate the mechanisms of enhanced risk of HIV-1 acquisition and reveal possible strategies for the development of an effective HSV vaccine. Our project will focus in particular on the responses of human natural killer T (NKT) cells, which are poised to respond within hours of activation and can rapidly modulate cellular immune responses. We will examine the ability of NKT cells to respond directly to virus infection and how the virus can affect their function. In addition, we will investigate how cutaneous immune cell types influence NKT cells and their ability to modulate appropriate cellular responses against HSV-2 infection. A three-dimensional organotypic culture model of skin will be utilised to examine these interactions in a physiologically relevant setting, obviating the need for the use of animal models. This study will provide critical information on how the immunomodulatory activities of NKT cells could be utilised as a viable strategy for the enhancement of local virus-specific immunity and thereby develop better genital herpes vaccines.