Type I interferon responses mediated by CD14⁺ monocytes drive CD4⁺ T-cell activation in PWH
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE317465 | GEO | 2026/01/30
REPOSITORIES: GEO
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Project description:The high prevalence of cognitive alterations in persons with HIV (PWH) despite effective antiretroviral therapy (ART) is associated with sustained neuroinflammation. Here, we uncover the signaling pathways that are essential for persistent immune activation and might underly development of HIV associated Neurocognitive Disorder (HAND). We analyze the brain proteome from PWH on ART during HAND progression. We observe that 73.3% of the significantly upregulated proteins in brains from PWH and HAND (compared to PWH with normal cognition) belong to immune pathways. Among them, 36.4% of upregulated innate immune-related proteins are within the type I interferon (IFN-I) signaling, suggesting that persistent IFN-I activation is central to HAND-associated brain immune activation. Single cell (sc)RNA-seq analysis confirmed that FN-I occurs mainly in astrocytes during acute HIV infection in the microglia-containing organoid (MCO) model of HIV infection and persistent in microglia in the brain of PLWH on ART. Of note, IFN-I persistence is independent of HIV status but associated with the induction of human endogenous retroviruses-W (HERV-W) Env during HAND progression after initial HIV infection and its associated immune activation. When induced, HERV-W Env directly activates IFN-I signaling in astrocytes, but not in microglia. Together, IFN-I signaling may be initiated directly in the astrocytes after acute HIV infection then sustained in the microglia during ART. IFN-I persists due to expression of HERV-W Env, thereby contributing to the persistent immune activation in the HAND brain on ART, independent of HIV and insensitive to ART. Our data link the neuroinflammation of persistent IFN-I signaling to the HAND brain on ART.
2024-05-25 | GSE233717 | GEO
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.
2023-09-01 | GSE229707 | GEO
Project description:Persistent systemic inflammation in persons with HIV (PWH) is accompanied by an increased risk of metabolic and cardiovascular diseases. Yet, changes in the innate and the adaptive immune in PWH who develop cardiometabolic disease remain insufficiently defined. Using mass cytometry we showed that PWH with prediabetes/diabetes had a significantly higher proportion of circulating CD14+ monocytes complexed with T cells. The CD3+ T cells and CD14+ monocytes consisted of dynamic heterogeneous complexes. Furthermore, we detected more HIV DNA in T cell-monocyte complexes compared to CD14+ monocytes or CD4+ T cells alone. Our results demonstrate that CD3+ CD14+ T cell-monocyte pairs are functional and physically interacting immune cell complexes that are higher among PWH with diabetes, suggesting that they may contribute to metabolic disease pathogenesis, and provide a strong incentive for future studies to investigate T cell-monocyte immune complexes as mechanistic in HIV cure reservoir and other diseases of aging.
2024-12-31 | GSE230276 | GEO
Project description:To examine the mechanisms that drive persistent neuroinflammation, we analyzed the proteome from 27 HIV-infected brains on antiretroviral therapy (ART) with different stages of HIV-associated neurocognitive disorders (HAND) by tandem mass tag quantitative proteomics. We observed that 73.3% of the upregulated proteins were from immune pathways, among which 36.4% were within the type I interferon (IFN-I) signaling. Single-cell RNA-seq analysis revealed that IFN-I signaling persisted in the brain microglia isolated from people with HIV (PWH) on suppressive ART. During the acute HIV infection, IFN-I signaling was activated in astrocytes in the brain organoids while it remained activated in the HAND brains even with undetectable HIV. HAND progression was associated with human endogenous retroviruses-W (HERV-W) Env expression in the HAND brains on suppressive ART. When overexpressed, HERV-W Env induced IFNβ in astrocytes. These findings point to a persistent IFN-I activation in the glial cells in HAND brains, suggesting a mechanistic link of sustained neuroinflammation with the prevalence of cognitive impairment in HAND receiving effective ART.
2025-08-25 | PXD042550 | Pride
Project description:Objective: People with HIV (PWH) experience excess comorbidities, including neurocognitive disorders, which are linked to inflammation, particularly monocyte-macrophage activation. Smoking contributes to morbidity and mortality in well-treated PWH. We investigated associations between smoking, neurocognitive function, and inflammation in PWH on ART. Design: We used baseline data on cognition and inflammation from a randomized treatment study among smoking and non-smoking PWH. Participants completed 4 neurocognitive tests (7 measures), with a composite score as the primary measure. Inflammatory markers were plasma sCD14, sCD163, and CCL2/MCP-1; %CD14+ monocytes expressing CD16, CD163, and CCR2; and %CD8+ T cells co-expressing CD38/HLA-DR. Exploratory analyses included a plasma cytokine/chemokine panel, hsCRP, neurofilament light chain (NFL) and monocyte transcriptomes by RNAseq. Results: We recruited 58 PWH (26 smokers, 32 non-smokers). Mean composite and individual neurocognitive scores did not differ significantly by smoking status except for the color shape task; smokers exhibited worse cognitive flexibility, with adjusted mean times 317.2 (95%CI 1.4, 632.9) msec longer than non-smokers. Smokers had higher plasma sCD14 than non-smokers (median(IQR) 1820(1678, 2105) versus 1551(1284, 1760) ng/ml, p=0.009). Other inflammatory markers were not significantly different between smokers and non-smokers. Monocyte transcriptomes showed several functions, regulators and gene sets that differed by smoking status. Conclusions: sCD14, a marker of monocyte activation, is elevated in PWH who smoke. While neurocognitive measures and other inflammatory markers did not generally differ, these data implicate smoking-related myeloid activation and monocyte gene dysregulation in the HIV/smoking synergy driving HIV-associated comorbidities.
2025-01-02 | GSE274848 | GEO
Project description:The intestinal environment facilitates HIV-1 infection via mechanisms involving the gut-homing vitamin A-derived retinoic acid (RA), which transcriptionally reprograms CD4+ T cells for increased HIV-1 replication/outgrowth. Consistently, colon-infiltrating CD4+ T cells carry replication-competent viral reservoirs in people with HIV-1 (PWH) receiving antiretroviral therapy (ART). Intriguingly, integrative infection in colon macrophages, a pool replenished by monocytes, represents a rare event in ART-treated PWH, thus questioning the effect of RA on macrophages. Here, we demonstrate that RA enhances R5 but not X4 HIV-1 replication in monocyte-derived macrophages (MDMs). RNA sequencing, gene set variation analysis, and HIV interactor NCBI database interrogation reveal RA-mediated transcriptional reprogramming associated with metabolic/inflammatory processes and HIV-1 resistance/dependency factors. Functional validations uncover post-entry mechanisms of RA action including SAMHD1-modulated reverse transcription and CDK9/RNA polymerase II (RNAPII)-dependent transcription under the control of mammalian target of rapamycin (mTOR). These results support a model in which macrophages residing in the intestine of ART-untreated PWH contribute to viral replication/dissemination in an mTOR-sensitive manner.
2023-12-31 | GSE226653 | GEO
Project description:Chronic immune activation is a hallmark of human immunodeficiency virus (HIV) infection and the best prognostic indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) restores normal immune response and effectively prolongs life. In HIV-infected individuals who are coinfected with hepatitis C virus (HCV) the immune system is activated despite effective HIV antiretroviral therapy controlling viral load. Here we examined CD14+ monocyte gene expression by high-density microarray analysis and T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV, monoinfected HIV and HIV/HCV coinfected subjects with undetected HIV viral load. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological (NP) performance, which was summarized as global deficit scores (GDS). Gene expression analysis of CD14+ monocytes from coinfected subjects revealed an elevated type 1 interferon (IFN) response profile unique to coinfection. For both CD4 and CD8 T cells, coinfection triggered significantly increased expression of activation markers CD38 and HLA-DR. In the coinfected group, mild cognitive impairment was associated with a type 1 IFN monocyte response but not plasma lipopolysaccharide. These observations raise the possibility that cognitive impairment evident in the HIV/HCV population is associated with the IFN response detected in coinfected individuals.
2012-06-07 | GSE38542 | GEO
Project description:Chronic immune activation is a hallmark of human immunodeficiency virus (HIV) infection and the best prognostic indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) restores normal immune response and effectively prolongs life. In HIV-infected individuals who are coinfected with hepatitis C virus (HCV) the immune system is activated despite effective HIV antiretroviral therapy controlling viral load. Here we examined CD14+ monocyte gene expression by high-density microarray analysis and T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV, monoinfected HIV and HIV/HCV coinfected subjects with undetected HIV viral load. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological (NP) performance, which was summarized as global deficit scores (GDS). Gene expression analysis of CD14+ monocytes from coinfected subjects revealed an elevated type 1 interferon (IFN) response profile unique to coinfection. For both CD4 and CD8 T cells, coinfection triggered significantly increased expression of activation markers CD38 and HLA-DR. In the coinfected group, mild cognitive impairment was associated with a type 1 IFN monocyte response but not plasma lipopolysaccharide. These observations raise the possibility that cognitive impairment evident in the HIV/HCV population is associated with the IFN response detected in coinfected individuals. Monocytes isolated from healthy controls (n=17), HCV monoinfected (n=19) and HIV/HCV coinfected (n=17) were analyzed for gene expression using high-density microarrays. Whole blood was collected in Vacutainer CPT tubes (BD Biosciences) and PBMCs were enriched by centrifugation. Typically, three million CD14+ monocytes were isolated from 30 ml of whole blood using an anti-CD14 monoclonal antibody immunomagnetic - ferrous bead conjugate according to the manufacturer’s instructions (Miltenyi Biotech). Monocyte purity exceeded 97% with <1% T or B cell contamination as determined by flow cytometry. Monocyte RNA was isolated using a Qiagen RNeasy Micro Kit with an RNA integrity value exceeding 9. Complementary DNA was synthesized and labeled with biotin (iExpress iAmplify kit, Applied Microarrays) and hybridized to Codelink Whole Human Genome Bioarrays (55K probes, Applied Microarrays). Slides were scanned (Axon GenePix 4000B, Molecular Devices), analyzed (CodeLink Expression Software Kit v4.1) and microarray data were normalized with loess normalization using R and Bioconductor package. Determination of differential gene expression and multiple testing correction / false discovery rate adjustments were performed using GeneSpring GX 7.3 software package (Agilent). Microarray data was analyzed using a variety of custom data analytic techniques for gene expression profile identification as described previously. Correlations were determined by Spearman rank correlation coefficient.
2012-06-06 | E-GEOD-38542 | biostudies-arrayexpress
Project description:The multifaceted and long-lived nature of HIV-1 reservoirs has proven to be a formidable obstacle in the development of a therapeutic cure of HIV-1. One of the major dimensions of the HIV-1 reservoir is its prevalence and persistence in tissue environments, including in lymph nodes (LN). Within LN, T follicular helper (Tfh) cells are widely considered as the dominant sub-reservoir in viremic people with HIV (PWH). However, whether Tfh cells survive to establish a reservoir in PWH undergoing suppressive antiretroviral therapy (ART) has remained controversial. To address these issues, we deeply phenotyped over 500,000 cells and identified over 2,000 HIV-1 infected cells by employing single-cell multiomics on LN from PWH during viremia and suppressed on ART. While we detected HIV-1 infected Tfh cells, the majority of infected cells during viremia and ART had non-follicular phenotypes and were instead heterogeneously distributed between various CD4+ T-cell subsets. Within-subset comparisons of HIV+ and HIV- cells revealed heightened activation signatures and altered cell cycle states during viremia, but largely similar features during ART. Furthermore, the comparison between viremia and ART in PWH highlighted a noncanonical Tfh subset - defined by high locus accessibility and transcription of PRDM1 - that is selectively depleted during viremia, recovers after ART, and is highly susceptible to infection in vitro. Our work suggests a revised direction for the HIV-1 cure field where a mandate of any comprehensive strategy will be to address the high proportional burden of non-follicular cells towards the HIV reservoir.
2025-12-16 | GSE313072 | GEO
Project description:The primary immune cells in the brain, microglia and CNS-associated macrophages (CAMs), are key targets for HIV in humans and SIV in nonhuman primates. Infection with these viruses can lead to neurological dysfunction collectively referred to as HAND. While antiretroviral therapy (ART) has proven effective in managing HAND, particularly the severe form known as HIV-associated dementia (HAD), its efficacy in preventing milder forms remains limited, leaving HAND a prevalent complication among PWH. Substance abuse, notably with opioids such as morphine and its synthetic product heroin, as well as pharmaceutical opioids, is relatively common in people with HIV (PWH) and the progression of HIV and its associated complications is exacerbated in opioid-using PWH. This study investigates the individual and combined effects of ART-treated SIV infection and morphine use on brain myeloid cells in rhesus macaques. Using single nucleus multiomic sequencing (integrating gene expression and chromatin accessibility), we examined the phenotypic, transcriptomic, and epigenomic changes in microglia and CAMs. Our findings confirm that ART significantly restores homeostasis in brain myeloid cells during SIV infection in macaques, paralleling its effects in HIV-infected humans. However, integration of data from ART-suppressed PWH with our macaque data suggested that there were more activation/inflammatory phenotypes of brain myeloid cells in PWH compared to ART-suppressed SIV-infected macaques. Additionally, we found that morphine exhibits immunosuppressive effects on brain myeloid cells, characterized by reduced antiviral phenotypes, downregulation of immune activation genes, including MHC class II and interferon-inducible proteins, and lack of the enrichment of the transcription factors in the AP-1 and ETS families activity. Gene co-expression network analysis further confirmed that the brain myeloid cell activation is associated with ART-treated infection, with no or negative correlation with morphine use. However, morphine exposures might indirectly affect the brain myeloid cells’ activation and functions, probably through endocrine receptors. These findings provide a deeper understanding of the effects of SIV infection on brain myeloid cells within the context of ART-treated SIV infection and opioid abuse, a critical consideration for PWH. Insights gained from this study could inform clinical approaches and therapeutic development for this vulnerable population.
2026-02-13 | GSE297853 | GEO