A rational approach to long-term containment of HIV infection is the combination of HAART with DNA vaccination aimed at stimulating virus-specific cytotoxic T lymphocytes (CTL) and T helper responses. Moreover, addition of novel adjuvants such as cholera-like toxins to DNA vaccines is likely to augment immune responses, and induce both systemic and mucosal immunity. The adjuvant effect of cholera-like toxins is apparent even when delivered to the skin, suggesting a novel mechanism of immune stimulation. Dendritic cells (DC) are an essential target for DNA-based vaccines and are likely to play a key role in the adjuvant effect of cholera-like toxins. The investigators hypothesize that cholera-like toxins alter the function of DC through the processes of maturation of trafficking, or both, such that systemic and mucosal T cell responses are generated. This could potentially occur through the stimulation of DC trafficking not only to peripheral lymph nodes but also to mucosal microenvironments. The overall goal of Project 4 is to elucidate the mechanism whereby adjuvanted DNA vaccines elicit augmented T cell responses. The investigators will address this goal in four specific aims: (1) To determine the capacity for cholera-line toxins to alter DC maturation and trafficking function in vivo: Murine studies, (3) To determine the capacity for cholera-like toxins to alter DC maturation and trafficking.
The aims are closely related to the overall program goal of designing and evaluating a therapeutic DNA vaccine for HIV. The studiers in Project 4 are highly interactive with other projects, including Project 1 (provision of DNA, studies of adjuvants in mice, monkey vaccination and immunotherapy studies), project 2 (monkey vaccination and immunotherapy studioes), and Project 3 (chemokine studies).
