Perturbation of antigen-specific T cell responses in latent TB/SIV co-infection

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 DESCRIPTION (provided by applicant): Tuberculosis (TB) is the leading cause of death in Human Immunodeficiency Virus (HIV)-infected individuals globally. The majority of HIV-negative individuals infected with Mycobacterium tuberculosis (Mtb) are asymptomatic, and are considered to have latent TB infection (LTBI), providing compelling evidence for host immune control of infection. However, a subset of individuals with LTBI progress to clinically active TB disease when co-infected with HIV. This results from the reactivation of LTBI, potentially due to a loss of control of Mtb within pulmonary granulomatous lesions. Antigen-specific T cells are crucial for controlling Mtb infection in humans and in experimental animal models and lowering of CD4 T cell counts after HIV infection greatly increases the risk of developing TB. However, the mechanisms by which Mtb-specific T cell responses maintain LTBI, confer protective immunity or result in HIV-induced reactivation of LTBI, remain unclear. To develop an effective TB vaccine for populations with high HIV prevalence and to effectively treat Mtb/HIV co- infection, we urgently need to understand how HIV perturbs the latent control of Mtb infection in a chronic state by the primate immune system. We hypothesize that co-infection with HIV depletes and/or impairs in the functional capacities of Mtb-specific CD4 and CD8 T cells to drive reactivation of LTBI and that antiretroviral therapy (ART) only partially restores these functions. We propose to test this hypothesis using mechanistic experiments in the highly human-like nonhuman primate model of inhalation TB. Towards this goal we will i) Define the nature of Mtb-specific CD4 and CD8 T cell responses associated with immune control of Mtb infection in the lungs, BAL and peripheral blood of Indian rhesus macaques with LTBI; ii) Test the hypothesis that co-infection with SIVmac239 progressively impairs Mtb-specific CD4 and CD8 T cell functions, leading to reactivation of LTBI; and iii) Examine the effect of antiretroviral therapy on reconstitution of Mt-specific CD4 and CD8 T cell responses in Mtb/SIV co-infected NHPs.