How a majority of those infected with Mycobacterium tuberculosis (Mtb) control the infection in a state referred to as latent TB infection (LTBI), is not completely understood. LTBI can reactivate to clinical TB in some individuals. Antigen-specific T cell responses, particularly CD4+ responses, are crucial to the control of Mtb infection in patients as well as in primate experimentally infected with Mtb. However, the identity of specific T cell responses that direct the control of Mtb in the LTBI state, or are responsible for reactivation, is not yet understood. In this project, we propose to identify the immune signatures associated with control of Mtb infection as LTBI either spontaneously or upon therapy, in rhesus macaques, a model in which LTBI can reproducibly be induced. The objectives of project 3 are highly complementary to those of the other two projects within this TBRU application, but will pave the way for testing novel therapeutic avenues in the future. The project will generate detailed data to demonstrate that Mtb-specific T cell responses associated with chemotherapy-mediated bacterial clearance are distinct from persistent Mtb infection in terms of phenotype, function and activation, both ex vivo and in vivo. In addition, clearance of Mtb or its failure will be tested via reactivation with co-infection with simian immunodeficiency virus (SIV), as a model of HIV/Mtb a common clinical occurrence in many parts of the developing world. T cell responses noted in the same monkey before and after chemotherapy induced latency will also be compared and these profiles will then be compared with human profiles from untreated and chemotherapy treated humans derived from projects 1 and 2. Finally, the impact of reexposure of LTBI monkeys to a heterologous Mtb will be modeled to monitor the evolution of specific T cell signatures in monkeys maintaining LTBI status vs those who develop clinical Tb, in efforts to validate the T cell signatures associated with LTBI status. Project 3 will be a collaboration between the Tulane and Yerkes National primate Research Centers. The studies will also markedly improve the definition of Mtb antigens, epitopes and their restricting MHCs in the Indian rhesus macaque, a critical model to address future experimental vaccines and therapies for which this project will provide correlates.