Abstract

Persons living with HIV (PLWH) are at higher risk of developing secondary illnesses than their uninfected counterparts, suggestive of a dysfunctional immune system in these individuals. Upon exposure to pathogens, monocytes undergo epigenetic remodeling that results in either a trained or a tolerant phenotype, characterized by hyper-responsiveness or hypo-responsiveness to secondary stimuli, respectively. We utilized CD14+ monocytes from virally suppressed PLWH and healthy controls for in vitro analysis following polarization of these cells toward a pro-inflammatory monocyte-derived macrophage (MDM) phenotype. We found that in PLWH-derived MDMs, pro-inflammatory signals (TNFA, IL6, IL1B, miR-155-5p, and IDO1) dominate over negative feedback signals (NCOR2, GSN, MSC, BIN1, and miR-146a-5p), favoring an abnormally trained phenotype. The mechanism of this reduction in negative feedback involves the attenuated expression of IKZF1, a transcription factor required for de novo synthesis of RELA during LPS-induced inflammatory responses. Furthermore, restoring IKZF1 expression in PLWH-MDMs partially reinstated expression of negative regulators of inflammation and lowered the expression of pro-inflammatory cytokines. Overall, this mechanism may provide a link between dysfunctional immune responses and susceptibility to co-morbidities in PLWH with low or undetectable viral load.

Highlights

  • Proper adherence to combined antiretroviral therapy can efficiently suppress viral replication and increase life expectancy of Persons living with HIV (PLWH)

  • We evaluated the expression of SOCS1 and SOCS3 throughout the four stages (T0, GM-CSF, M1, and LPS challenge) and found that SOCS1 mRNA was highly but almost induced in both control- and PLWH-monocyte-derived macrophage (MDM) at both M1 and LPS challenge conditions, while SOCS3 expression was significantly lower in PLWH-MDMs compared to controls in the same experimental conditions (Figure 1D)

  • IKAROS is required for the new synthesis of RELA following LPS stimulation, and we found expression of IKZF1, the gene encoding IKAROS, significantly decreased in PLWH-MDMs compared to controls (Figure 4C)

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Summary

Introduction

Proper adherence to combined antiretroviral therapy (cART) can efficiently suppress viral replication and increase life expectancy of PLWH. Among the mechanisms contributing to chronic inflammation, microbial product translocation from the gut lumen to the blood leads to increased plasma levels of lipopolysaccharide (LPS) [1,2,3,4,5,6,7,8], which can persist even in virally suppressed PLWH. This suggests that LPS could chronically affect innate immune cell function. An imbalance in the immune response can lead to long-term hyper-activation that underlies atherosclerosis and other inflammatory disorders [17, 18] or contributes to cancer [19]

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