My goal is to evaluate the immune responses induced by a novel HIV vaccine. There are unprecedented challenges to the development of an effective HIV vaccine, such as the extraordinary viral diversity of HIV-1 and the lack of clear immune correlates of protection. Two vaccine strategies tested in efficacy trials to date have failed to induce protection. The vaccine strategy developed in our laboratory focuses on directly exploiting dendritic cells'potential to improve the magnitude and quality of immune responses, either alone or in combination with other strategies. HIV antigens are delivered within fusion monoclonal antibodies directly to maturing dendritic cells via DEC-205, an endocytic dendritic cell receptor. We have shown that prime-boost immunization with anti-DEC-205 HIV Gag p24 fusion mAb with poly IC, as an adjuvant, induces protective immunity in mice. In addition, we have preliminary data showing that targeting of HIV antigens via DEC-205 receptor, in PBMCs from HIV-infeced individuals, induces both HIV-specific CD4+ and CD8+ T cell recall responses. The studies I propose to perform will investigate the primary immune responses generated by DEC-targeted HIV vaccines in healthy volunteers. The proposed immuno assays may prove useful for the evaluation of future HIV vaccine candidates. Our studies will also investigate optimal choices of HIV immunogens to achieve broader viral coverage without compromise of antigen processing and presentation. If successful, our vaccine approach will add to the current arsenal of HIV vaccine strategies. The educational plan of this K23 application includes training in the conduct of early phase clinical trials and laboratory experience in immunological assays along with extensive didactic teaching through coursework, seminars and conferences. Under the guidance of Dr. Steinman, Dr. Schlesinger and Dr. Markowitz, and with the research environment and support provided at the Rockefeller University, I will be able to perform the proposed sutdies and develop both clinical and laboratory research skills with the long term goal of becoming an independet researcher in HIV vaccine translational research.
Several HIV vaccines tested to date failed to induce protection against acquisition of HIV infection. New strategies are needed to address this global problem. Dendritic cells (DCs) are cells of the immune system that recognize and present foreign proteins to other immune cell types leading to a cascade of immune responses. DEC205 HIV vaccine delivers HIV proteins to DCs and induces immune responses against HIV.
|Trumpfheller, C; Longhi, M P; Caskey, M et al. (2012) Dendritic cell-targeted protein vaccines: a novel approach to induce T-cell immunity. J Intern Med 271:183-92|
|Caskey, Marina; Lefebvre, Francois; Filali-Mouhim, Abdelali et al. (2011) Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J Exp Med 208:2357-66|