Large investments have been made in the design of a vaccine that induces a cellular immune response against HIV. However, the failed Merck STEP trial showed that a lot of work still needs to be done to establish the basic immunobiology pertaining to the relationship between T cell quality, quantity, and mucosal location and viral infection. CD4 T cells are the main target for HIV pathogenesis while cytotoxic CD8 T cells are thought to be the ideal effectors to mediate viral clearance. The goal of this proposal is to determine the relationship between CD4 and CD8 T cell quantity, quality, and location and viral infection, not in a HIV model system but in a well-established mouse model of acute and chronic viral infection. Defining the behavior of these cells in mucosal tissues will be pertinant to studies in HIV/SIV infection.
Aim I will focus on determining the relationships between antigen exposure, anatomic location, phenotype, and function among virus-specific CD4 T cells after lymphocytic choriomengingitis virus (LCMV) infection. I hypothesize that variables in duration and strength of stimulation influence the quality and anatomic distribution of CD4 T cells. Being that T cells are both targets for and effectors against HIV pathogenesis, the information gleaned from this aim will help us better understand the interactions between virus and target in mucosal tissues. The production of a HIV vaccine that induces broadly reactive neutralizing antibodies has proved difficult, therefore, one solution would be to develop a CD8 T cell vaccine. However, very little is known about the ability of CD8 T cells to clear a viral infection.
Aim I seeks to address the relationship between memory CD8 T cell quantity, quality and location and protection from infection. I hypothesize that in order to clear a viral infection, one must a have a threshold number of CD8 T cells at the location of primary infection. Determination of the quality, quality, and location of memory LCMV-specific CD8 T cells required for protection against infection will be determined by quantitative rtPCR.
Discovering the basic mechanisms by which effector and memory CD8 and CD4 T cell function in mucosal tissues following vaccination and infection is essential for the future development of a successful vaccine. This information is extremely necessary for the future development of a HIV vaccine that targets the cellular immune system.
| Fraser, Kathryn A; Schenkel, Jason M; Jameson, Stephen C et al. (2013) Preexisting high frequencies of memory CD8+ T cells favor rapid memory differentiation and preservation of proliferative potential upon boosting. Immunity 39:171-83 |
| Casey, Kerry A; Fraser, Kathryn A; Schenkel, Jason M et al. (2012) Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J Immunol 188:4866-75 |
