Chronic HIV infection induces transcriptional and functional reprogramming of innate immune cells

Abstract

Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLHIV). We enrolled a cross-sectional cohort study of PLHIV on stable antiretroviral therapy and healthy controls. We assessed ex vivo cytokine production capacity and transcriptomics of monocytes and T-cells upon bacterial, fungal and viral stimulation. PLHIV exhibited an exacerbated pro-inflammatory profile in monocytederived cytokines, but not in lymphocyte-derived cytokines. Particularly, the production of the IL-1β to imiquimod, E. coli LPS and Mycobacterium tuberculosis was increased, and this production correlated with plasma concentrations of hsCRP and sCD14. This increase in monocyte responsiveness remained stable over time in subsequent blood sampling after >1year. Transcriptome analyses confirmed priming of the monocyte IL-1β pathway, consistent with a monocyte trained immunity phenotype. Increased plasma concentrations of β-glucan, a well-known inducer of trained immunity, were associated with increased innate cytokine responses. Monocytes of PLHIV exhibit a sustained pro-inflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLHIV likely plays a role in long-term HIV complications and provides a promising therapeutic target for inflammation-related comorbidities.

The Architecture of Circulating Immune Cells Is Dysregulated in People Living With HIV on Long Term Antiretroviral Treatment and Relates With Markers of the HIV-1 Reservoir, Cytomegalovirus, and Microbial Translocation

“…As discussed above, naïve T cells are able to differentiate into different Th subsets depending on the cytokine environment (42). We previously showed that PLHIV in our cohort exhibited a pro-inflammatory profile with increased levels of hsCRP (p=0.00022) and sCD14 (a marker of monocyte activation, p=0.0025; Figure 5A) as well as markedly elevated monocyte-derived cytokine responses, particularly IL-1b (20). Such a pro-inflammatory cytokine environment may push the differentiation of naive CD4+ cells into Th17 cells (42).…”

“…Prior studies have shown that untreated HIV infection results in a massive depletion of Th17 cells from the peripheral blood and the mucosa ( 9), a process that may partially be reversed by cART (46)(47)(48). We recently showed that PLHIV from the same cohort exhibited a pro-inflammatory profile with increased monocytederived cytokines, particularly IL-1b (20). IL-1b and IL-6 are among the critical cytokines driving differentiation of Th17 ( 42), and we postulate that these cytokines may have contributed to the higher circulating Th17 numbers.…”

“…As part of this project, we previously identified relevant environmental and host factors for circulating white blood cell (WBC) populations in healthy individuals (19). Embedded within the HFGP, we established a cohort of 211 virally suppressed PLHIV (200HIV) and showed that these individuals exhibited a sustained pro-inflammatory immune phenotype with priming of the interleukin (IL)-1b pathway (20). In the present study, we used the same cohort to comprehensively assess the peripheral WBC composition during treated HIV infection with a special focus on the adaptive immune system.…”

Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan

“…BDG assays are now widely used as diagnostic tools for identifying mycosis in clinical settings ( 3 – 5 ). Recent studies have shown that circulating BDG levels are linked to immune activation and inflammation in people living with chronic conditions that induce epithelial gut damage and subsequent microbial translocation such as CMV and HIV infections ( 6 – 9 ). A growing body of literature has highlighted the capacity of BDG to induce long-term epigenetic reprogramming in innate immune cells, termed trained immunity, which leads to an adjusted response to a subsequent challenge and to some metabolic changes, including a switch from oxidative phosphorylation to aerobic glycolysis ( 10 , 11 ).…”

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“…BDG assays are now widely used as diagnostic tools for identifying mycosis in clinical settings (3)(4)(5). Recent studies have shown that circulating BDG levels are linked to immune activation and inflammation in people living with chronic conditions that induce epithelial gut damage and subsequent microbial translocation such as CMV and HIV infections (6)(7)(8)(9). A growing body of literature has highlighted the capacity of BDG to induce long-term epigenetic reprogramming in innate immune cells, termed trained immunity, which leads to an adjusted response to a subsequent challenge and to some metabolic changes, including a switch from oxidative phosphorylation to aerobic glycolysis (10,11).…”