Herpes simplex virus type 2 (HSV-2) now infects the genital tracts of approximately one in five Americans. Protection against HSV-2 infection is very dependent on the development of vigorous antigen-specific T cell responses. Given the ability of HSV-2 to spread to the sensory ganglia soon after infection, vaccine-elicited T cells will need to be activated, express effector function, and be present at the appropriate sites of infection very rapidly after initial infection if vaccines are to prevent or greatly reduce the establishment of latent virus infection in the sensory ganglia. Therefore, immunization with an effective HSV vaccine should result in the deployment of effector memory T cells to the genital epithelium and perhaps to the sensory ganglia as well. In the proposed studies we will focus on the induction of protective T cell immunity by HSV vaccines. Specifically we will examine the requirements for deployment of HSV-specific memory T cells to the genital epithelium and sensory ganglia.
In Aim 1 we will use ELISPOT analysis to detect HSV-specific memory T cells in the sensory ganglia following immunization and test the requirement for HSV-specific T cell memory in the sensory ganglia to protect this tissue against HSV-2 infection. Most HSV vaccines currently being developed are expected to elicit humoral immune responses and predominantly CD4+ T cells.
In Aim 2 we will specifically deplete T cell subsets from HSV-immune mice to determine if CD4+ T cells are sufficient to provide the rapid T cell mediated component involved in protection of the vagina epithelium and sensory ganglia. Using a clonotype-specific monoclonal antibody to detect antigen-specific T cells in vivo, we will test in Aim 3 if vaccination strategies modeled after those used in current HSV vaccine clinical trials will result in deployment of memory cells to the genital epithelium and sensory ganglia. We will also test if deployment of memory T cells to these tissues can be improved by 1) immunization at mucosal or cutaneous sites near the genital tract and 2) increasing the magnitude of the vaccine elicited T cell response.
In Aim 4 we will use conventional plaque assays and quantitative PCR assays to detect virus in the genital epithelia and sensory ganglia to test if targeting an HSV vaccine to the genital tract results in greater T cell mediated protection of the genital epithelia and sensory ganglia compared to the protection resulting from systemic delivery of the same vaccine. ? ? ?
| Nelson, Michelle H; Bird, Melanie D; Chu, Chin-Fun et al. (2011) Rapid clearance of herpes simplex virus type 2 by CD8+ T cells requires high level expression of effector T cell functions. J Reprod Immunol 89:10-7 |
| Johnson, Alison J; Nelson, Michelle H; Bird, Melanie D et al. (2010) Herpes simplex virus (HSV)-specific T cells activated in the absence of IFN-gamma express alternative effector functions but are not protective against genital HSV-2 infection. J Reprod Immunol 84:8-15 |
| Chu, Chin-Fun; Meador, Michael G; Young, Christal G et al. (2008) Antibody-mediated protection against genital herpes simplex virus type 2 disease in mice by Fc gamma receptor-dependent and -independent mechanisms. J Reprod Immunol 78:58-67 |
