Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo
Abstract 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...
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2025-04-01
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| Online Access: | https://doi.org/10.1002/advs.202416453 |
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| author | Flora Mikaeloff Marco Gelpi Alejandra Escós Tianqi Wang Soham Gupta Anna Olofsson Sara Svensson Akusjärvi Sabrina Schuster Prajakta Naval Vikas Sood Negin Nikouyan Andreas D. Knudsen Beate Vestad Julie Høgh Johannes R. Hov Thomas Benfield Marius Trøseid Vinay Pawar Marijana Rucevic Rui Benfeitas Ákos Végvári Liam O'Mahony Rajkumar Savai Niklas K. Björkström Magda Lourda João Pedro deMagalhães Siegfried Weiss Adil Mardinoglu Mukesh Kumar Varshney Annika C. Karlsson Yasir Ahmed Syed Susanne D. Nielsen Ujjwal Neogi |
| author_facet | Flora Mikaeloff Marco Gelpi Alejandra Escós Tianqi Wang Soham Gupta Anna Olofsson Sara Svensson Akusjärvi Sabrina Schuster Prajakta Naval Vikas Sood Negin Nikouyan Andreas D. Knudsen Beate Vestad Julie Høgh Johannes R. Hov Thomas Benfield Marius Trøseid Vinay Pawar Marijana Rucevic Rui Benfeitas Ákos Végvári Liam O'Mahony Rajkumar Savai Niklas K. Björkström Magda Lourda João Pedro deMagalhães Siegfried Weiss Adil Mardinoglu Mukesh Kumar Varshney Annika C. Karlsson Yasir Ahmed Syed Susanne D. Nielsen Ujjwal Neogi |
| author_sort | Flora Mikaeloff |
| collection | DOAJ |
| description | Abstract 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 network‐based patient stratification method. Utilizing advanced machine learning techniques and a Bayesian classifier, five plasma protein biomarkers; Tubulin Folding Cofactor B (TBCB), Gamma‐Glutamylcyclotransferase (GGCT), Taxilin Alpha (TXLNA), Pyridoxal Phosphate Binding Protein (PLPBP) and Large Tumor Suppressor Kinase 1 (LATS1) are identified as highly differentially abundant between healthy control (HC)‐like and immunometabolically at‐risk PWHs (all FDR<10−10). The personalized metabolic models predict metabolic perturbations, revealing disruptions in central carbon metabolic fluxes and host tryptophan metabolism in at‐risk phenotype. Functional assays in primary cells and cortical forebrain organoids (FBOs) further validate this. Metabolic perturbations lead to persistent monocyte activation, thereby impairing their functions ex vivo. Furthermore, the chronic inflammatory plasma microenvironment contributes to synaptic dysregulation in FBOs. The endogenous plasma inflammatory microenvironment is responsible for chronic inflammation in treated immunometabolically complicated at‐risk PWH who have a higher risk of cardiovascular and neuropsychiatric disorders. |
| format | Article |
| id | doaj-art-3290c33e0e5e4cd7a7fc41cd85421e78 |
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| language | English |
| publishDate | 2025-04-01 |
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| spelling | doaj-art-3290c33e0e5e4cd7a7fc41cd85421e782025-08-20T02:18:32ZengWileyAdvanced Science2198-38442025-04-011216n/an/a10.1002/advs.202416453Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex VivoFlora Mikaeloff0Marco Gelpi1Alejandra Escós2Tianqi Wang3Soham Gupta4Anna Olofsson5Sara Svensson Akusjärvi6Sabrina Schuster7Prajakta Naval8Vikas Sood9Negin Nikouyan10Andreas D. Knudsen11Beate Vestad12Julie Høgh13Johannes R. Hov14Thomas Benfield15Marius Trøseid16Vinay Pawar17Marijana Rucevic18Rui Benfeitas19Ákos Végvári20Liam O'Mahony21Rajkumar Savai22Niklas K. Björkström23Magda Lourda24João Pedro deMagalhães25Siegfried Weiss26Adil Mardinoglu27Mukesh Kumar Varshney28Annika C. Karlsson29Yasir Ahmed Syed30Susanne D. Nielsen31Ujjwal Neogi32The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenCopenhagen University Hospital Rigshospitalet Copenhagen 2100 DenmarkThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenNeuroscience and Mental Health Innovation Institute and School of Biosciences, Hadyn Ellis Building Cardiff University Cardiff CF24 4HQ UKThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenDivision of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenDivision of Chemistry I, Department of Medical Biochemistry and Biophysics Karolinska Institutet Solna 171 65 SwedenThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenCopenhagen University Hospital Rigshospitalet Copenhagen 2100 DenmarkResearch Institute of Internal Medicine Oslo University Hospital Rikshospitalet Oslo 0372 NorwayCopenhagen University Hospital Rigshospitalet Copenhagen 2100 DenmarkNorwegian PSC Research Center Oslo University Hospital Rikshospitalet Oslo 0372 NorwayDepartment of Infectious Diseases Copenhagen University Hospital – Amager and Hvidovre Hvidovre 2650 DenmarkResearch Institute of Internal Medicine Oslo University Hospital Rikshospitalet Oslo 0372 NorwayThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenOlink AB Uppsala 753 30 SwedenThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenDivision of Chemistry I, Department of Medical Biochemistry and Biophysics Karolinska Institutet Solna 171 65 SwedenDepartments of Medicine and Microbiology, APC Microbiome Ireland University College Cork Cork T12 K8AF IrelandLung Microenvironmental Niche in Cancerogenesis, Institute for Lung Health (ILH) Justus Liebig University 35392 Giessen GermanyCenter for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet Karolinska University Hospital Huddinge 141 52 SwedenCenter for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet Karolinska University Hospital Huddinge 141 52 SwedenGenomics of Ageing and Rejuvenation Lab Institute of Inflammation and Ageing University of Birmingham Birmingham B15 2WB UKDepartment of Molecular Immunology Helmholtz Centre for Infection Research 38124 Braunschweig GermanyScience for Life Laboratory KTH – Royal Institute of Technology Solna 171 65 SwedenThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenDivision of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenNeuroscience and Mental Health Innovation Institute and School of Biosciences, Hadyn Ellis Building Cardiff University Cardiff CF24 4HQ UKCopenhagen University Hospital Rigshospitalet Copenhagen 2100 DenmarkThe Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet Huddinge 141 52 SwedenAbstract 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 network‐based patient stratification method. Utilizing advanced machine learning techniques and a Bayesian classifier, five plasma protein biomarkers; Tubulin Folding Cofactor B (TBCB), Gamma‐Glutamylcyclotransferase (GGCT), Taxilin Alpha (TXLNA), Pyridoxal Phosphate Binding Protein (PLPBP) and Large Tumor Suppressor Kinase 1 (LATS1) are identified as highly differentially abundant between healthy control (HC)‐like and immunometabolically at‐risk PWHs (all FDR<10−10). The personalized metabolic models predict metabolic perturbations, revealing disruptions in central carbon metabolic fluxes and host tryptophan metabolism in at‐risk phenotype. Functional assays in primary cells and cortical forebrain organoids (FBOs) further validate this. Metabolic perturbations lead to persistent monocyte activation, thereby impairing their functions ex vivo. Furthermore, the chronic inflammatory plasma microenvironment contributes to synaptic dysregulation in FBOs. The endogenous plasma inflammatory microenvironment is responsible for chronic inflammation in treated immunometabolically complicated at‐risk PWH who have a higher risk of cardiovascular and neuropsychiatric disorders.https://doi.org/10.1002/advs.202416453HIV/AIDSIntegrative omicspatient stratificationpersonalized metabolic models |
| spellingShingle | Flora Mikaeloff Marco Gelpi Alejandra Escós Tianqi Wang Soham Gupta Anna Olofsson Sara Svensson Akusjärvi Sabrina Schuster Prajakta Naval Vikas Sood Negin Nikouyan Andreas D. Knudsen Beate Vestad Julie Høgh Johannes R. Hov Thomas Benfield Marius Trøseid Vinay Pawar Marijana Rucevic Rui Benfeitas Ákos Végvári Liam O'Mahony Rajkumar Savai Niklas K. Björkström Magda Lourda João Pedro deMagalhães Siegfried Weiss Adil Mardinoglu Mukesh Kumar Varshney Annika C. Karlsson Yasir Ahmed Syed Susanne D. Nielsen Ujjwal Neogi Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo Advanced Science HIV/AIDS Integrative omics patient stratification personalized metabolic models |
| title | Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo |
| title_full | Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo |
| title_fullStr | Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo |
| title_full_unstemmed | Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo |
| title_short | Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo |
| title_sort | host plasma microenvironment in immunometabolically impaired hiv infection leads to dysregulated monocyte function and synaptic transmission ex vivo |
| topic | HIV/AIDS Integrative omics patient stratification personalized metabolic models |
| url | https://doi.org/10.1002/advs.202416453 |
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