Abstract Mycobacterium tuberculosis (Mtb) infection can lead to tuberculosis (TB) disease, causing ~9 million new infections and ~1.8 million deaths globally, every year. A quarter of these are deaths due to the TB/AIDS comorbidity, caused by Mtb/HIV co-infection and the resulting reactivation of LTBI. The resurgence of TB in the last two decades can be attributed to the failure of the anti-TB vaccine, Bacille Calmette-Guerin (BCG) in containing adult, pulmonary TB as well, the emergence of drug-resistance and the AIDS pandemic. The failure to control TB stems from the lack of complete understanding of the virulence and pathogenesis programs utilized by this highly specialized and successful pathogen in order to persist in the lungs of its hosts. As part of its virulence cycle, Mtb modulates host immunity. We have developed a robust macaque model Mtb/HIV co-infection, by using natural routes of Mtb infection and by using Simian Immunodeficiency Virus (SIV) as a surrogate for HIV. This model can be leveraged to study the physiology of Mtb in a true in-vivo setting. Using our model, we show that the expression of IDO (INDO, IDO1), a powerful immunosuppressant of activated CD4+ T cells, is dramatically enhanced in the lung granulomata of macaques. Levels of IDO are induced in a bacterial burden specific manner in myeloid cells. Thus, macaques that control inhaled Mtb infection as LTBI, do not express high levels of IDO in lung lesions, but those that progress to ATB do. IDO levels decline when animals with ATB are chemotherapeutically treated. Upon co-infection with SIV, 2/3rds of the macaques with LTBI reactivate disease - only these animals exhibited lung IDO induction. Finally, nonpathogenic infection with avirulent mutants of Mtb failed to elicit the induction of IDO. Amelioration of IDO enzymatic activity by an FDA, approved, safe compound in-vivo resulted in significant reduction in clinical signs of TB, pathology and bacterial burden, and increased survival. This was accompanied by increased lung T cell proliferation and induction of bronchus associated lymphoid tissue (iBALT). These events reshaped the granuloma is two different ways: i) functionally granulomas from treated (IDO blockaded) animals exhibited no signatures of T cell exhaustion but instead higher expression of T cell differentiation, apoptosis, bacterial killing and lung tissue remodeling pathways; ii) morphologically, greater relocation of T cells was observed to the center of the granulomata. The profoundly better killing of Mtb in macrophages by CD4+ T cells could be modeled in-vitro, in a novel macaque macrophage:CD4+ T cell co- culture system. Our results strongly suggest that IDO modulates a complex immune/metabolic signaling network that promotes bacterial survival, immune dysfunction and disease. Thus, inhibition of IDO is a prime target for adjunctive HDT against the multidrug resistant TB epidemic. Based on these data, we postulate that IDO1-signaling is key to modul...