This program is designed to exploit very recent advances in genetic engineering, cell biology, and a humanized animal model to develop cell- based immunotherapy for clinical use in HIV infected patients. The scientific resources of three laboratories that have previously successfully collaborated will be coordinated to achieve this goal. Accumulating data support the importance of cytotoxic T-lymphocytes (CTLs) in the host response to HIV, the etiologic agent of AIDS. Project I aims to create populations of functional CTLs against HIV that may be given to patients without MHC restriction, e.g., """"""""universal donor"""""""" effector cells. The chimeric antigenic recognition elements of these universal donor cells will be constructed utilizing reagents and insights derived from Project II. This second project aims to identify important effector elements by studying cloned CTLs and human monoclonal antibodies derived from HIV infected patients. The in vitro effector properties of universal donor chimeric CTLs will be assessed in Project II as well. The in vivo activities of primary and universal donor CTLs in HIV infected humanized SCID mice will be studied in Project III. Parallel work using these approaches in the CMV infection model will be pursued to analyze similarities and differences with HIV. This strategy provides the opportunity to create genetically altered immune effector cells that could be clinically provided to patients with HIV independent of the usual transplantation barriers, thereby improving host immune function.
