The applicant has designed a Listeria monocytogenes-based vector system that expresses heterologous proteins. Unlike other bacterial vaccine systems, Listeria replicates in the cytoplasm of infected cells. This aspect of its life cycle, combined with the organism's ability to induce IL-12 secretion by macrophages leads to the induction of a strong CTL response. The applicant has used this system to elicit protective immunity in three animal models of viral disease, lymphocytic choriomeningitis virus infection of mice as well as HTLV-1 and cottontail rabbit papilloma virus infection of rabbits. Through a collaborative effort composed of researchers at the UCLA School of Medicine, the UC Davis Regional Primate Center, and Duke University, the applicant now proposes to apply insights gained from these preliminary studies to an evaluation of the rhesus macaque immune response to recombinant attenuated strains of Listeria that express a cocktail of SIV proteins. Despite the almost uniformly fatal course of HIV infection, animal models and studies of infected humans suggest that immune responses are capable of altering the tempo of viral replication. However, demonstration of an effective response has been largely limited to early, acute infection and in small trials of immune modulating therapies. Therefore, an understanding of the immune response to retroviral proteins is critical in attempts to design vaccines and anti-retroviral immune based interventions. The generation of CTL plays an important role in controlling retroviral infection: the ability to elicit a cell mediated immune response is an important component of any vaccine strategy. The applicant will focus on optimizing immunization protocols, both in terms of attenuation strategy and route of delivery, with the goal of inducing a mucosal immune response that limits viral replication following vaginal challenge. Specifically, the applicant will : (1) optimize attenuated L. Monocytogenes vectors expressing SIV proteins; (2) evaluate the immune response of rhesus macaques infected with the recombinant Listeria vectors; and (3) assess the ability of immunization strategies to alter virus replication.
