The longterm goal of this research is to develop a live oral Shigella-HIV-1 vaccine vector that induces HIV-1 specific CD4+ and CD8+ T cell responses. Shigella spp. are fully virulent in humans and to a lesser extend in Rhesus macaques. There is a well defined rodent and non-human primate model available to evaluate safety, immunogenicity and efficacy of candidate live oral attenuated Shigella-vaccines. Analogous to L. monocytogenes, Shigella- escapes the endosomal compartment and replicates with the cytoplasm of epithelial cells, dendritic cells, and macrophages associated with colonic lymphoid tissue. The central hypothesis of this grant then is that a live oral attenuated Shigella-SIV and Shigella-HIV-1 vaccine vector will induce MHC class I and class II restricted mucosal T cell responses. To address this hypothesis, the investigator proposes to construct attenuated Shigella-SIV and Shigella-HIV-1 vectors that stably express a high level of a Gag-Nef fusion protein and identify the immunogenic constructs using the murine model. The constructs that are immunogenic in mice will be evaluated for immunogenicity and anti viral efficacy in Rhesus macaques.
