Host plasma microenvironment in immunometabolically impaired HIV infection leads to dysregulated monocyte function and synaptic transmission ex vivo

Mikaeloff, Flora, Gelpi, Marco, Escós, Alejandra, Wang, Tianqi, Gupta, Soham, Olofsson, Anna, Svensson Akusjärvi, Sara, Schuster, Sabrina, Naval, Prajakta, Sood, Vikas, Nikouyan, Negin, Knudsen, Andreas D., Vestad, Beate, Høgh, Julie, Hov, Johannes R., Benfield, Thomas, Trøseid, Marius, Pawar, Vinay, Rucevic, Marijana, Benfeitas, Rui, Végvári, Ákos, O'Mahony, Liam, Savai, Rajkumar, Björkström, Niklas K., Lourda, Magda, de Magalhães, João Pedro, Weiss, Siegfried, Mardinoglu, Adil, Varshney, Mukesh Kumar, Karlsson, Annika C., Syed, Yasir Ahmed ORCID: https://orcid.org/0000-0001-9495-307X, Nielsen, Susanne D. and Neogi, Ujjwal 2025. Host plasma microenvironment in immunometabolically impaired HIV infection leads to dysregulated monocyte function and synaptic transmission ex vivo. Advanced Science , 2416453. 10.1002/advs.202416453

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Biosciences
Publisher:	Wiley
ISSN:	2198-3844
Funders:	Swedish Research Council, Karolinska Instititute Consolidator
Date of First Compliant Deposit:	19 February 2025
Date of Acceptance:	17 February 2025
Last Modified:	04 Mar 2025 10:30
URI:	https://orca.cardiff.ac.uk/id/eprint/176320

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