Dysregulation of the IFN-I signaling pathway byMycobacterium tuberculosisleads to exacerbation of HIV-1 infection of macrophages

Abstract

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.

The immunosuppressive Tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4+ T cells

“…Here, we show that TB-PE decreases HIV-1 replication in CD4+ T cells by inhibiting the reverse transcription of the viral genome, one of the early steps in the HIV-1 replication cycle. These results contrast with previous publications showing that TB-associated microenvironments or mycobacterial components increase HIV-1 replication and spread (19, 21, 24, 26, 64, 65). However, these studies have investigated HIV-1 replication in macrophages, indicating that the effect of Mtb infection and the TB-associated microenvironment varies between cell types (19, 21, 24, 26, 64, 65).…”

Productive HIV-1 infection of tissue macrophages by fusion with infected CD4+ T cells

“…In the two conditions, MDM infection by cell fusion with infected T cells was significantly increased. Finally, silencing of myosin IIA in MDMs using an efficient siRNA approach ( Dupont et al, 2022 ; Dupont et al, 2020 ; Troegeler et al, 2017 ) led to a decrease in MLC phosphorylation ( Fig. S7, A and B ) along with a significant increase in the number of infected multinucleated MDMs ( Fig.…”

Tunneling nanotubes and tumor microtubes—Emerging data on their roles in intercellular communication and pathophysiology: Summary of an International FASEB Catalyst Conference October 2023

“…This physiological process is also essential for bone regulation and the formation of osteoclasts, which are multinucleated myeloid cells resulting from the fusion of mononuclear precursors and specialized in bone degradation. 1,19 In a pathological context, macrophage fusion occurs frequently, such as in response to foreign bodies or chronic inflammation such as granulomas, cancer or viral infection such as HIV-1. [20][21][22][23] The Verollet lab in Toulouse, France studies how phagocytes (e.g., macrophages and osteoclasts) interact with their environment, in physiological and pathological contexts.…”

“…Christel Verollet from INSERM, CNRS‐University of Toulouse, France focused on the role of TNTs in myeloid cell fusion and applications for tuberculosis and HIV‐related infections in a presentation entitled “Tunneling Nanotubes for Myeloid Cell Fusion.” Cell–cell fusion is an essential and evolutionarily conserved process in eukaryotes in which the two cells fuse to form syncytia (or multinucleated cells) involved in fertilization or in the formation of the placenta and muscles. This physiological process is also essential for bone regulation and the formation of osteoclasts, which are multinucleated myeloid cells resulting from the fusion of mononuclear precursors and specialized in bone degradation 1,19 . In a pathological context, macrophage fusion occurs frequently, such as in response to foreign bodies or chronic inflammation such as granulomas, cancer or viral infection such as HIV‐1 20–23 .…”

“…They are expert in the study of actin dynamics in cell–cell fusion processes in physiological (osteoclasts) and pathological contexts (HIV‐1 and HIV‐1/tuberculosis co‐infection). In this context, the laboratory was a pioneer in the field of TNTs in macrophages in the context of HIV/tuberculosis (TB) co‐infection 19,24–26 . Previous work from the Verollet lab, in collaboration with O. Neyrolles, IPBS, Toulouse, France, demonstrated that TNTs facilitate the transfer of HIV‐1 between macrophages, a phenomenon that is favored in TB‐derived microenvironments, and trigger macrophage fusion and the formation of highly virus‐productive multinucleated giant cells (MGCs) 27,28 .…”