The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4 + T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4 + T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8 + memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV-and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.Nonhuman primate | B cells | tuberculosis | CD4 T cells | CD8 T cells

SignificanceMycobacterium tuberculosis induces the expression of the indoleamine 2,3-dioxygenase (IDO) enzyme, which catabolizes tryptophan. Tryptophan metabolites potently suppress host immunity. The present study demonstrates that blockade of IDO activity reduces both clinical manifestations of tuberculosis (TB) as well as microbial and pathological correlates of the human TB syndrome in macaques. In granulomas, T cells localize in the periphery, and are unable to access the core, where bacilli persist. Inhibiting IDO activity altered granuloma organization such that more T cells translocated to the lesion core and exhibited highly proliferative signatures. Our results identify a highly efficient immunosuppressive mechanism at play in the granuloma environment that aids in M. tuberculosis persistence. The ability to modulate this pathway with safe and approved compounds could, however, facilitate chemotherapy-adjunctive host-directed therapy approaches for the control of TB.

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While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus-coinfected (M. tuberculosis/SIV-coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4 + T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4 + T cells were poorly restored specifically in the lung interstitium, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction in myeloid cells in the inducible bronchus-associated lymphoid tissue (iBALT) likely contributed to dysregulated T cell homing and impaired lung immunity. Thus, although ART was indispensable for controlling viral replication, restoring CD4 + T cells, and preventing opportunistic infection, it appeared inadequate in reversing the clinical signs of TB reactivation during the relatively short duration of ART administered in this study. This finding warrants the modeling of concurrent treatment of TB and HIV to potentially reduce the risk of reactivation of TB due to HIV to inform treatment strategies in patients with M. tuberculosis/HIV coinfection.

SUMMARYLung interstitial CD4+ T cells are critical for protection against pulmonary infections, but the fate of this population during HIV-1 infection is not well described. We studied CD4+ T cells in the setting of HIV-1 infection in human lung tissue, humanized mice, and a Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) nonhuman primate co-infection model. Infection with a CCR5-tropic strain of HIV-1 or SIV results in severe and rapid loss of lung interstitial CD4+ T cells but not blood or lung alveolar CD4+ T cells. This is accompanied by high HIV-1 production in these cells in vitro and in vivo. Importantly, during early SIV infection, loss of lung interstitial CD4+ T cells is associated with increased dissemination of pulmonary Mtb infection. We show that lung interstitial CD4+ T cells serve as an efficient target for HIV-1 and SIV infection that leads to their early depletion and an increased risk of disseminated tuberculosis.

Antigen-specific T cell responses are critical for immune control of M. tuberculosis infection. In response to M. tuberculosis infection, the majority of infected people mount robust CD4 + T cell responses involving Th1 cytokines, such as IFN-γ and TNF-α, which are important for activating macrophages and curtailing M. tuberculosis replication in the lung (6, 7). In addition, IL-17 and Th17 responses have emerged as important for protective immunity against TB (8,9). Animal studies have shown a role for IL-17 in induction of chemokines, recruitment of CD4 + T cells to the site of infection, formation of granulomas, and protection during M. tuberculosis infection and Bacille Calmette-Guérin (BCG) vaccination (10)(11)(12)(13)(14)(15)(16)(17)(18). The role of IL-17 and Th17 responses in human TB is less clear and has been mainly studied by comparing individuals with active TB and healthy controls. Reports from humans vary widely, with studies showing no difference in the levels of IL-17 between the groups (19), while others have seen low levels of IL-17 in patients with TB compared with healthy controls (20,21). Human genetic mutations and polymorphisms in IL-17 have been associated with TB susceptibility (12,22), whereas other studies have shown the association of Th17/IL-17 responses with TB pathogenesis and disease progression (23)(24)(25)(26). Overall, how IL-17, and in particular, M. tuberculosis antigen-specific Th17 cells, function to control M. tuberculosis infection during asymptomatic LTBI in humans remains poorly understood. We have limited knowledge of the onset and maintenance of M. tuberculosis antigen-specific Th1 and Th17 cell responses in the blood and lung compartments during LTBI and of the phenotypes and functions associated with the LTBI state. This is in part because small-animal models do not reproduce key aspects of human LTBI. Moreover, accurately documenting M. tuberculosis exposure, initial infection, and early events following infection in humans is almost impossible. Thus, studies of M. tuberculosis antigen-specific T cells in humans have been largely confined to cross-sectional characterization of peripheral responses in the blood (27)(28)(29)(30)(31). While some studies have examined responses in bronchoalveolar lavage (BAL) (32-34), longitudinal studies in humans comparing M. tuberculosis antigen-specific T cell responses in blood and lung compartments have been lacking. Thus, detailed characterization of the nature and kinetics of M. tuberculosis antigen-specific T cells associated with human-like asymptomatic LTBI is important for identifying correlates of immune control and protection.Nonhuman primate (NHP) macaque models of M. tuberculosis infection recapitulate multiple features of human M. tuberculosis infection, including clinically asymptomatic infection and symptomatic active TB disease (35-42), and are attractive for studying immune parameters associated with control of M. tuberculosis infection in peripheral blood and lung compartments. We have previously established a mode...