Innate and adaptive immunity in genital HSV-2 infection: Implications for vaccine development

Abstract

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen that infects the genital tract mucosa and is the most common case of genital ulcers in humans. Despite numerous studies, little is known about the mechanisms involved in immune protection and no anti-herpes vaccine has been developed to date. Thus, a better understanding of the immune mechanisms deployed against HSV-2 could facilitate the development of an effective vaccine against human genital herpes infection. The aims of the present thesis were to elucidate the roles of different immunological components in both innate and acquired immunity against genital HSV-2 infection. In addition the ability of HSV-2-pulsed dendritic cell vaccination to induce protective immunity in mice, was assessed. A well-established mouse model of genital HSV-2 infection was employed. In this model, vaginal inoculation of mice with HSV-2 provokes a severe genital infection leading to a lethal neurological illness, whereas primary genital infection/vaccination with the attenuated strain HSV-2 (TK-) gives rise to the development of protective immunity against later infection by wild type HSV-2. Using this model, it was shown in gene-targeted mice that B cells secreting natural antibodies, IFN-g, IL-12 and IL-18 are implicated in the innate control of primary genital infection, whereas CD4+ T cells and IFN-g are crucial for the development of acquired protective immunity against challenge one month later. The protective immunity in vaccinated mice was shown to be associated with HSV-2-specific IFN-g responses in vitro and delayed type hypersensitivity responses in vivo. However, CD8+ T cells, B-cells, IL-12 and IL-18 can be circumvented during the development of adaptive immune protection. Protective immunity appeared to be associated with a rapid induction of IFN-g-dependent RANTES production in the vaginal mucosa following a vaginal HSV-2 challenge. Finally, it was demonstrated that intravenous or subcutaneous vaccination of mice with HSV-2-antigen-pulsed bone marrow-derived dendritic cells confers protective immunity against genital herpes infection. These data have implications for our understanding of the immune mechanisms involved in protective immunity against HSV-2 infection and may facilitate development of an effective vaccine against genital herpes infections.