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Comparative analysis of chromatin state in monocytes from HIV+ individuals on ART

ABSTRACT: We report ChIP-sequencing data obtained of freshly isolated human CD14+ monocytes obtained from 3 HIV- controls and 6 HIV+ subjects. 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 HIV+ patients 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 HIV-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 HIV-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 HIV+ individuals with low or undetectable viral load.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185405 | GEO | 2021/11/26

REPOSITORIES: GEO

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Project description:Persistent and elevated systemic inflammation contributes to the increased risk of cardiovascular and metabolic diseases in persons with HIV (PWH). , but aspects of the innate and adaptive immune response to HIV and other chronic co-infections that promote the development of these comorbid conditions remain unclear. We used mass cytometry and the tracking responders expanding (T-REX) workflow to define differences in circulating cells of the innate and adaptive immune arms, which differentiate non-diabetic and prediabetic/diabetic persons with HIV (PWH) on long-term antiretroviral therapy (ART). We found a significantly higher proportion of circulating CD14+ monocytes complexed with T cells, B cells, and NK cells among PWH with diabetes. The CD3+ T cells in these complexes were predominantly CD8+ memory T cells. The CD3+ CD14+ T cell-monocyte complexes are pro-inflammatory and negatively associated with plasma interleukin-10 levels and circulating CD4+ T regulatory cells. Using transmission electron microscopy, we observed heterogeneous interactions between CD3+ T cells and monocytes within the complexes, including formation of immune synapses and phagocytosis. 10x Chromium single-cell sequencing RNA transcriptomic analysis of CD3+ CD14+ doublets showed differential expression of genes involved in T cell activation and the adaptive immune response compared to monocytes that were not complexed with other immune cells. Notably, there were significantly more copies of HIV RNA per cell in the CD3+ CD14+ T cell-monocyte complexes compared to CD14+ monocytes or CD3+ CD4+ T cells alone, and HIV virions were observed in both T cells and monocytes within the doublets?. Metabolically, CD3+ CD14+ T cell-monocyte complexes had high glucose-dependence with minimal mitochondrial dependence. Taken together, CD3+ CD14+ T cell-monocyte pairs are functional and physically interacting immune cell complexes which might be enriched with HIV. These complexesare increased among individuals with diabetes and may be a target for future HIV cure studies and diseases of aging.

Project description:A major population of placenta macrophages represented throughout the pregnancy consists of CD14+ macrophages, but their characteristics remain badly understood. Here we purified from placentas at term CD14+ macrophages using positive selection. The phenotyping of CD14+ macrophages performed using flow cytometry revealed that placenta CD14+ macrophages expressed a series of markers distinct of those of circulating monocytes monocyte-derived macrophages. Placenta CD14+ macrophages spontaneously matured in multinucleated giant cells (MGCs) as demonstrated by size, number of nuclei display and specific cytoskeleton organization. Placenta CD14+ macrophages and MGCs were phagocytic cells but the potential of MGCs to mount an inflammatory response was lower than that of their precursors. Placenta CD14+ macrophages and MGCs stimulated with interferon and interleukin-4 were not polarized into typical M1 or M2 profiles. Placenta macrophages exhibited specific activation transcriptional programs. Indeed, principal component analysis and hierarchical clustering show that placental macrophages formed a distinct group from circulating monocytes and monocyte-derived macrophages. Among placenta macrophages, it was also possible to distinguish CD14+ macrophages and MGCs. In addition, networks based on gene interactions were clearly different in CD14+ macrophages and MGCs. Finally, the microenvironment of placenta CD14+ macrophages governs their differentiation into MGCs because CD14+ macrophages incubated with trophoblasts exhibited exarcerbated characteristics of MGCs and because the co-incubation of circulating monocytes from working women with trophoblast supernatants resulted into the formation of MGCs whereas monocytes from non-pregnant women incubated with trophoblast supernatants did not differentiate into MGCs. Taken together, these results clearly demonstrated specific feaures of placenta CD14+ macrophages. Three replicates of each of the following: 1. Placental macrophages just after isolation (CD14+ macrophages) 2. Placental macrophages after 9 days in culture (MGCs) 3. CD14+ cells isolated from PBMC which are extracted from the whole human blood of healthy donors (Monocytes) 4. Macrophages derived from monocytes (MDMs)

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Comparative analysis of chromatin state in monocytes from HIV+ individuals on ART

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