RNAseq analysis of blood specimens from ART-suppressed people with HIV prior to analytical treatment interruption
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE290636 | GEO | 2026/04/17
REPOSITORIES: GEO
Similar Datasets
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 earliest events of viral rebound following discontinuation of ART in persons living with HIV-1 (PLWH) remain largely unknown. Here we show that viral rebound in SIV-infected rhesus macaques following ART discontinuation involves serial clonal reactivation in gastrointestinal (GI) and lymph node (LN) tissues followed by rapid local and systemic spread. We investigated viral rebound dynamics in 18 SIV-infected rhesus macaques treated with antiretroviral therapy (ART) for 70 weeks and necropsied on day 12 after ART discontinuation. Using molecularly barcoded SIVmac239M, we tracked viral clonotypes following ATI in both peripheral blood and necropsy tissues. Viral rebound originated by reactivation of a single or a few clonotypes from a limited number of GI tissues and deep LNs, followed by replication of each clonotype and then serial reactivation of additional clonotypes from different anatomic sites, resulting in oligoclonal plasma viremia. Daily transcriptomic and proteomics profiling in peripheral blood identified early upregulation of pathways related to T cell signaling, cytokine responses, and cellular metabolism prior to detectable plasma viremia, presumably reflecting initial viral replication in tissues. Taken together, these data demonstrate the early clonal dynamics of viral rebound in SIV-infected macaques following ART discontinuation, which provides critical information for the development of next generation HIV-1 cure strategies.
2025-09-10 | GSE294867 | GEO
Project description:Evaluation of HIV cure strategies requires antiretroviral therapy (ART) interruption, but ethical and clinical considerations make this difficult in children. Uncovering predictors of time to viral rebound (TTR) and post-treatment control (PTC) of rebound viremia in a pediatric preclinical model may inform the design of studies testing novel cure interventions in these populations. We thus assessed 141 variables in SHIV-infected infant rhesus macaques (RMs) where ART initiation was staggered then followed by analytical treatment interruption (ATI). Viral rebound occurred in 25/30 RMs within 7-98 d of ATI, with TTR significantly delayed in the Early ART group compared to the Intermediate and Late ART groups (median TTR 84, 18, and 17 d, respectively; p<0.001). Peak plasma viral load pre-ART best described TTR, with increased predictive strength through the successive inclusion of six additional variables. Increased peak viral load pre-ART decreased the odds of no rebound and elevated Ki67+ effector memory CD8+ T cells in lymph nodes pre-ATI increased the odds of PTC. RNA sequencing of CD4+ T cells pre-ATI showed heme metabolism and IFNg response pathways were most upregulated in RMs with sustained suppression of viremia during ATI. Analysis of only the Early ART group also implicated TGFb pathway genes in lack of viral rebound off ART. This comprehensive investigation reveals major determinants of viral rebound dynamics following ART interruption that should be validated and explored as biomarkers to screen children with HIV being considered for ATI.
2025-09-11 | GSE261049 | GEO
Project description:The development of biomarkers that can predict viral rebound following discontinuation of antiretroviral therapy (ART) in HIV-1-infected humans would be an important advance in HIV-1 cure research. In a prior study, we initiated ART in 20 rhesus macaques on days 0, 1, 2, and 3 following SIVmac251 infection prior to plasma viremia1. Following 6 months of suppressive ART, we discontinued ART and observed viral rebound in 9 of 20 animals. Here we show that transcriptomic and proteomic signatures of inflammation and immune activation in peripheral blood during ART suppression predicted viral rebound following ART discontinuation. Higher levels of proinflammatory and cellular immune activation pathways, including TNF, IL-1, IL-6, monocyte, and T cell activation signaling pathways, correlated with viral rebound following ART discontinuation. Immune modulatory IL-10 and TGF-b signaling also correlated with viral rebound. We then validated these candidate biomarkers of viral rebound in a second cohort of SIV-infected, ART-suppressed macaques. Taken together, these data suggest that persistent upregulation of inflammatory and immune activation pathways despite suppressive ART may represent a peripheral blood biomarker signature of the rebound-competent viral reservoir. The development of interventions that target the viral reservoir and modulate this signature may open new avenues in HIV-1 cure research.
2023-08-30 | GSE203603 | GEO
Project description:People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1β, TLR expression, PPAR βδ) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNFa, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD.
2020-10-22 | GSE157884 | 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:A hallmark of HIV infection is disruption of intestinal barrier integrity that persists in people with HIV (PWH) despite treatment with antiretroviral therapy (ART). This disruption is central to HIV disease progression, yet the causes remain incompletely understood. We report a novel mechanism by which immunometabolic defects in colon resident CD8+ T cells in PWH lead to intestinal epithelial apoptosis and disruption of intestinal barrier integrity. We show that in PWH, these cells downregulate the lipid sensor peroxisome proliferator-activated receptor-g (PPARg), which results in reduced intracellular lipid droplets, impaired fatty acid oxidation, and acquisition of lipids by CD8+ T cells from intestinal epithelial cells, which then contributes to epithelial cell death. Our findings indicate that HIV-associated immunometabolic dysregulation of colon CD8+ T cell leads to loss of intestinal epithelial homeostasis. These results identify potential new strategies to reduce comorbidities in PWH and other disorders with disrupted intestinal barrier integrity.
2025-06-30 | GSE299833 | GEO
Project description:Genome-wide DNA methylation profiling of colon and ileal biopsies, blood samples from people living with HIV on ART and their matched HIV-negative counterparts. Despite having similar chronological ages, PWH on ART exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to HIV-negative controls. Investigating the relationship between microbial translocation and biological aging, PWH on ART had decreased levels of tight junction proteins in the colon and ileum, along with increased microbial translocation.
2024-02-28 | GSE245924 | GEO
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:RNAseq analysis of blood specimens from ART-suppressed people with HIV prior to analytical treatment interruption
| PRJNA1229454 | ENA