The SIV-macaque model is a useful system to develop and test new anti-HIV vaccine strategies. Using this system, this proposal will investigate the capacity of a novel chemically-inactivated preparation of SIV to induce specific T cell responses when presented by a specialized white blood cell, the dendritic cell [DC]. DCs are the strongest antigen [Ag] presenting cells of the immune system and can induce Ag-specific naive and memory T cell as well as B cell immune responses. Typically, immature DCs ingest and process Ags very efficiently and as they mature acquire increased Ag-presenting capabilities. Therefore, specifically loading DCs with an array of viral Ags should result in the induction of strong anti-viral immune responses. A recently described chemically-inactivated form of SIV represents an excellent vaccine candidate. It is non-infectious, yet the proteins are conformationally intact. Hence, this Ag form provides all determinants normally encountered during infection, but in the absence of infectious virus. This inactivated virus has also been found to induce immune responses in vitro and in vivo. Therefore, combining this broadly immunogenic Ag preparation with potent Ag presenting DCs, should result in the activation of potent SIV-specific immunity. Specifically, this project will identify conditions for the optimal presentation of this Ag form by DCs first for virus-specific T cell responses in vitro and then in vivo. The hypothesis is that DCs, because of their capacity to process and present Ags, will present this non-infectious Ag efficiently to CD4 and CD8 T cells and induce potent anti-viral immunity. Specifically: 1. Can DCs efficiently present whole, inactivated virus to T cells in vitro? 2. Do liposome and antibody modifications of this Ag preparation enhance uptake and presentation by DCs? 3. Can DCs loaded with non-infectious virus induce immunity in vivo following subcutaneous re-injection of the cells into immunologically naive animals? These studies will reveal whether this noninfectious form of virus can be presented by DCs and induce efficacious anti-viral responses. Induction of virus-specific T cell immunity by DCs presenting this Ag preparation will provide the basis for development of DC-based vaccine and therapeutic strategies.
