Macrophage maturation from blood monocytes is altered in people with HIV, and is linked to serum lipid profiles and activation indices: A model for studying atherogenic mechanisms

Bowman, Emily; Cameron, Cheryl M.; Richardson, Brian; Kulkarni, Milind V.; Gabriel, Janelle; Cichon, Morgan J.; Riedl, Ken M.; Mustafa, Yousef; Cartwright, Michael; Snyder, Brandon; Raman, Subha V.; Zidar, David A.; Koletar, Susan L.; Playford, Martin P.; Mehta, Nehal N.; Sieg, Scott F.; Freeman, Michael L.; Lederman, Michael M.; Cameron, Mark J.; Funderburg, Nicholas T.

doi:10.1371/journal.ppat.1008869

Cited by 26 publications

(17 citation statements)

References 98 publications

(136 reference statements)

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“…The observed intrinsic proinflammatory phenotype of monocytes in PLHIV was stable over time and associated with upregulation of proinflammatory pathways, most notably the IL-1β pathway. This corroborates a recent study showing a pronounced proinflammatory phenotype, including upregulation of IL1B , of monocyte-derived macrophages in PLHIV ( 38 ). Long-term epigenetic reprogramming of monocytes in response to microbes has been termed trained immunity.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 93%

“…These data corroborate findings from earlier, smaller studies in PLHIV, which reported an increased production of pro-inflammatory cytokines to stimulation with ligands of TLR4 (30,31) or TLR7 (32,33) (38). Long-term epigenetic reprogramming of monocytes in response to microbes has been termed 'trained immunity'.…”

Section: Discussionsupporting

confidence: 89%

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

et al. 2021

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“…Methylation of selected SREBP1 CpG is also associated with adiposity (Justice et al, 2020). Also, SREBP1 has been implicated in establishing a proatherogenic lipid profile in monocytes (Bowman et al, 2020). In summary, several of the indicated genes have wellcharacterized functions in adipocytes, but evidence for regulation of blood cell homeostasis supports our differential methylation data.…”

Section: Discussionsupporting

confidence: 69%

Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men

et al. 2021

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We have previously shown that blood global DNA methylation (DNAm) differs between postprandial state (PS) and fasting state (FS) and is associated with BMI and polyunsaturated fatty acid (PUFA) (negatively and positively, respectively) in 12 metabolically healthy adult Mexican men (AMM cohort) equally distributed among conventional BMI classes. Here, we detailed those associations at CpG dinucleotide level by exploiting the Infinium methylation EPIC array (Illumina). We sought differentially methylated CpG (dmCpG) that were (1) associated with BMI (BMI-dmCpG) and/or fatty acids (FA) (FA-dmCpG) in FS or PS and (2) different across FS and PS within a BMI class. BMI-dmCpG and FA-dmCpG were more numerous in FS compared to PS and largely prandial state-specific. For saturated and monounsaturated FA, dmCpG overlap was higher across than within the respective saturation group. Several BMI- and FA-dmCpG mapped to genes involved in metabolic disease and in some cases matched published experimental data sets. Notably, SETDB1 and MTHFS promoter dmCpG could explain the previously observed associations between global DNAm, PUFA content, and BMI in FS. Surprisingly, overlap between BMI-dmCpG and FA-dmCpG was limited and the respective dmCpG were differentially distributed across functional genomic elements. BMI-dmCpG showed the highest overlap with dmCpG of the saturated FA palmitate, monounsaturated C20:1 and PUFA C20:2. Of these, selected promoter BMI-dmCpG showed opposite associations with palmitate compared to C20:1 and C20:2. As for the comparison between FS and PS within BMI classes, dmCpG were strikingly more abundant and variably methylated in overweight relative to normoweight or obese subjects (∼70–139-fold, respectively). Overweight-associated dmCpG-hosting genes were significantly enriched in targets for E47, SREBP1, and RREB1 transcription factors, which are known players in obesity and lipid homeostasis, but none overlapped with BMI-dmCpG. We show for the first time that the association of BMI and FA with methylation of disease-related genes is distinct in FS and PS and that limited overlap exists between BMI- and FA-dmCpG within and across prandial states. Our study also identifies a transcriptional regulation circuitry in overweight that might contribute to adaptation to that condition or to transition to obesity. Further work is necessary to define the pathophysiological implications of these findings.

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“…It is extremely difficult to determine selective killing of very low numbers of HIV-infected macrophages in the patients and even in in vitro HIV-infected macrophages. The high variability in SM-mediated killing of ex vivo generated MDMs from monocytes of ART-treated and naïve untreated groups may also be due to the myeloid population in the patients which is exposed to a variety of inflammatory/anti-inflammatory cytokines and exposure to a variety of opportunistic infections 56 . Exposure to ARV drugs may be somewhat toxic to these cells and affect their ability to respond to stress by altering their mitochondrial function 57 , 58 .…”

Section: Discussionmentioning

confidence: 99%

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

Caballero

Dong

Gajanayaka

et al. 2021

Sci Rep

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Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC) mimetics (SM) induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, chronically infected U1 cells, and ex-vivo derived MDMs from HIV-infected individuals. To understand the mechanism governing SM-induced cell death, we show that SM-induced cell death of primary HIV-infected macrophages was independent of the acquisition of M1 phenotype following HIV infection of macrophages. Instead, SM-induced cell death was found to be mediated by IAPs as downregulation of IAPs by siRNAs induced cell death of HIV-infected macrophages. Moreover, HIV infection caused receptor interacting protein kinase-1 (RIPK1) degradation which in concert with IAP1/2 downregulation following SM treatment may result in apoptosis of macrophages. Altogether, our results show that SM selectively induce apoptosis in primary human macrophages infected in vitro with HIV possibly through RIPK1. Moreover, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

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Macrophage maturation from blood monocytes is altered in people with HIV, and is linked to serum lipid profiles and activation indices: A model for studying atherogenic mechanisms

Cited by 26 publications

References 98 publications

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

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

Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

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