Dataset Information

Inflammatory microenvironment in immunometabolic-compromised treated HIV infection steered synaptic dysregulation

ABSTRACT: Multi-omics data-driven personalized health profiling can provide valuable insight into metabolic perturbations in people living with HIV (PWH) under successful antiretroviral therapy (ART). We integrated transcriptomics, proteomics, and metabolomics to identify and stratify the immunometabolically compromised treated PWH (n=158). Based on clinical and lifestyle data, 44% (70/158) of PWH were at risk of immunometabolic complications. We identified six plasma biomarkers to define the at-risk phenotype using advanced machine learning and a Bayesian classifier that drives a network of proteins reasoned for monocyte immunosenescence. We identified metabolic perturbations driven by central carbon metabolic flux led to chronic monocyte activation impairing its early functional properties. Further, we discovered that the host-induced spermidine-mediated microenvironment was responsible for chronic inflammation leading to synaptic dysregulation in vitro, potentiating the risk of neuropsychiatric clinical phenotypes in the at-risk PWH. Novel intervention targeting metabolically-perturbed chronic inflammatory conditions can lead to healthier aging in the at-risk PWH.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell

SUBMITTER: Akos Vegvari

LAB HEAD: Akos Vegvari

PROVIDER: PXD043296 | Pride | 2025-05-06

REPOSITORIES: Pride

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			Action	DRS
	20230523_HF2_01_BrainOrganoids_TMT_fractions_proteins.xlsx	Xlsx
	20230525_HF2_01_BrainOrganoids_TMT_Frac1.raw	Raw
	20230525_HF2_01_BrainOrganoids_TMT_Frac10.raw	Raw
	20230525_HF2_01_BrainOrganoids_TMT_Frac11.raw	Raw
	20230525_HF2_01_BrainOrganoids_TMT_Frac12.raw	Raw

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Publications

Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo.

Mikaeloff Flora F Gelpi Marco M Escós Alejandra A Wang Tianqi T Gupta Soham S Olofsson Anna A Akusjärvi Sara Svensson SS Schuster Sabrina S Naval Prajakta P Sood Vikas V Nikouyan Negin N Knudsen Andreas D AD Vestad Beate B Høgh Julie J Hov Johannes R JR Benfield Thomas T Trøseid Marius M Pawar Vinay V Rucevic Marijana M Benfeitas Rui R Végvári Ákos Á O'Mahony Liam L Savai Rajkumar R Björkström Niklas K NK Lourda Magda M de Magalhães João Pedro JP Weiss Siegfried S Mardinoglu Adil A Varshney Mukesh Kumar MK Karlsson Annika C AC Syed Yasir Ahmed YA Nielsen Susanne D SD Neogi Ujjwal U

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20250227 16

Risk stratification using multi-omics data deepens understanding of immunometabolism in successfully treated people with HIV (PWH) is inadequately explained. A personalized medicine approach integrating blood cell transcriptomics, plasma proteomics, and metabolomics is employed to identify the mechanisms of immunometabolic complications in prolonged treated PWH from the COCOMO cohort. Among the PWHs, 44% of PWH are at risk of experiencing immunometabolic complications identified using the networ ...[more]

PMID: 40013867

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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.