Tuberculosis owes its resurgence as a major global health threat mostly to the emergence of drug resistance and coinfection with HIV. The synergy between HIV and Mycobacterium tuberculosis (Mtb) modifies the host immune environment to enhance both viral and bacterial replication and spread. In the lung immune context, both pathogens infect macrophages, establishing favorable intracellular niches. Both manipulate the endocytic pathway in order to avoid destruction. Relevant players of the endocytic pathway to control pathogens include endolysosomal proteases, cathepsins, and their natural inhibitors, cystatins. Here, a mapping of the human macrophage transcriptome for type I and II cystatins during Mtb, HIV, or Mtb-HIV infection displayed different profiles of gene expression, revealing cystatin C as a potential target to control mycobacterial infection as well as HIV coinfection. We found that cystatin C silencing in macrophages significantly improves the intracellular killing of Mtb, which was concomitant with an increased general proteolytic activity of cathepsins. In addition, downmodulation of cystatin C led to an improved expression of the human leukocyte antigen (HLA) class II in macrophages and an increased CD4+ T-lymphocyte proliferation along with enhanced IFN-γ secretion. Overall, our results suggest that the targeting of cystatin C in human macrophages represents a promising approach to improve the control of mycobacterial infections including multidrug-resistant (MDR) TB.

While tuberculosis (TB) is a risk factor in HIV‐1‐infected individuals, the mechanisms by which Mycobacterium tuberculosis (Mtb), the agent of TB in humans, worsens HIV‐1 pathogenesis still need to be fully elucidated. Recently, we showed that HIV‐1 infection and spread are exacerbated in macrophages exposed to TB‐associated microenvironments. Transcriptomic analysis of macrophages conditioned with medium of Mtb‐infected human macrophages (cmMTB) revealed an up‐regulation of the typeI interferon (IFN‐I) pathway, characterized by the overexpression of IFN‐inducible genes. Historically, IFN‐I are well known for their antiviral functions, but our previous work showed that this is not the case in the context of coinfection with HIV‐1. Here, we show that the IFN‐I response signature in cmMTB‐treated macrophages matches the one observed in the blood of active TB patients, and depends on the timing of incubation with cmMTB. This suggests that the timing of macrophage's exposure to IFN‐I can impact their capacity to control HIV‐1 infection. Strikingly, we found that cmMTB‐treated macrophages are hyporesponsive to extrastimulation with exogenous IFN‐I, used to mimic HIV‐1 infection. Yet, depleting STAT1 by gene silencing to block the IFN‐I signaling pathway reduced TB‐induced exacerbation of HIV‐1 infection. Altogether, by aiming to understand why TB‐derived IFN‐I preexposure of macrophages did not induce antiviral immunity against HIV‐1, we demonstrated that these cells are hyporesponsive to exogenous IFN‐I, a phenomenon that prevents macrophage activation against HIV‐1.