Animals models for AIDS are critical for understanding both the mechanisms of pathogenesis of human immunodeficiency virus-1 (HIV-1) and the evolution of immunity to HIV-1 (Gardner & Luciw, 1989). FIV is one of the most promising lentiviral models because it uses a small animal, poses no risk to humans, and is an important viral pathogen, causing a clinically relevant disease in cats that is remarkably similar to AIDS in humans. Not only does FIV share common lentiviral properties with HIV, it is also recognized as a common pathogen of cats, causing severe immunodeficiency that closely resembles HIV-1 related AIDS. The inadequacy of the antibody response to inhibit the progression of lentiviral pathogenesis suggests that cell-mediated immunity may be especially vital in controlling human AIDS. The presence of cytotoxic T lymphocytes (CTL's) have been directly associated with HIV-1 infection in the absence of clinical disease. Therefore, rational strategies for developing a protective vaccine should consider antigens which induce protective cell mediated immunity. Our long-term objective is to use the FIV model for developing a subunit vaccine which induces protective cell mediated immunity against lentiviral associated AIDS. The specific goal of this proposal is to identify immunodominant peptides or epitopic regions of the gag proteins that induce feline T lymphocyte responses. We will concentrate on identifying T cell responses to gag proteins, because they are highly conserved, and because the core proteins or other lentiviruses have been shown to induce CTL's. Retroviral vectors will be used to express the FIV nucleotide sequences in target T cells, which serve as natural host cells for FIV. Retroviral vectors will be used because they are non-invasive with a high efficacy of gene transfer, result in viable transgenic cell lines, will be capable of expressing the FIV peptides in the absence of viral vector proteins, and finally, should more closely simulate the endogenous expression and processing of lentiviral antigen in the natural host T cell. Therefore, transgenic target cells will be established that express the gag polyprotein, the individual gag proteins, p17, p24, & p10, overlapping peptides of the immunodominant protein(s). Autologous cells will be used as the source of target and effector cells for the characterization of the responses to gag polypeptides and the individual proteins. However, in order to establish a system that can, in the future, evaluate host protection through the adoptive transfer of effector and target cells, cloned T cells recognizing epitopes and target cells expressing peptides will be performed with syngeneic cats. Genetically identical cats will be produced using nuclear transplantation and embryo cloning techniques.
