Development of a safe and effective HIV vaccine is the most viable strategy for stopping the spread of HIV infection, which has already affected 1% of the world's population. An effective HIV vaccine will likely require the induction of both protective cellular and humoral immune responses. Our overall goal in this project is to develop mechanisms by which effective CD8+ cytotoxic TG lymphocyte (CTL) and CD4+ T helper responses can be elicited against highly conserved viral proteins of HIV-1 and SIV such as Gag/Pol and to determine whether these cellular immune responses can offer protection against SIV or SHIV infection in primate models. Toward, a novel development is the construction of DNA expression vectors, which enable us to enhance Gag protein expression by several hundred fold in a Rev and RRE- independent and species independent fashion. A major focus of this application is to evaluate whether antigen targeting to selective intracellular and extracellular pathways can enhance the induction of immune responses for both DNA vaccine and recombinant viral vector such MVA and VEE based vaccines. We will also make use of the recombinant Venezuelan equine encephalitis virus (VEE) replicon system to evaluate promising priming booster regimens for the induction of CTL and T-helper responses in mice and monkeys. Finally, we will combine strategies that induce protective cellular immune responses against conserved viral Gag proteins with strategies that could induce broad and potent neutralizing antibody responses against viral system. Env molecules and evaluate this combined regimen in the SHIV/monkey challenge system. These studies are conceptualized as the necessary groundwork for the development and subsequent evaluation of HIV vaccines.
