# Immune cell subset profiling and metabolic dysregulation define the divergent immune microenvironments in HIV immunological non‐responders

## TL;DR

This study finds that some HIV patients don't recover well from immune damage due to metabolic issues and immune cell imbalances, suggesting new treatment strategies.

## Contribution

The study identifies five hub genes and metabolic dysregulation as key factors in poor immune recovery among HIV patients.

## Key findings

- INRs show reduced Th1, Th17, and Tfh cells with increased immune activation and exhaustion markers.
- Five hub genes (ATP5O, PIGY, UQCRQ, COX7C, BLVRB) are linked to immune recovery outcomes.
- INRs exhibit diminished CD4⁺ T cells and reduced resting memory B cells, indicating persistent immune dysfunction.

## Abstract

A subset of people living with HIV (PLWH) exhibit poor immune recovery despite effective antiretroviral therapy (ART), remaining at risk of disease progression. The immunometabolic mechanisms underlying this immunological non‐response remain unclear.

We integrated transcriptomic and immunophenotypic approaches to characterise immune differences between immunological responders (IRs) and non‐responders (INRs). Public datasets were analysed to identify differentially expressed genes (DEGs), followed by enrichment analysis, predictive modelling, immune infiltration assessment, and regulatory network construction. In parallel, flow cytometry was performed to assess T and B cell subsets in an independent cohort including IRs, INRs, treatment‐naïve patients (TNPs), and healthy controls (HCs).

DEGs between IRs and INRs were enriched in mitochondrial and ribosomal pathways. INRs showed reduced Th1, Th17, and Tfh cells, alongside increased markers of immune activation and exhaustion. Predictive modelling identified five hub genes (ATP5O, PIGY, UQCRQ, COX7C, and BLVRB) associated with immune recovery, and clustering based on their expression defined two transcriptionally distinct subtypes. Flow cytometry further confirmed that INRs exhibited diminished CD4⁺ T cell counts, increased PD‐1⁺ and HLA‐DR⁺ expression, and reduced resting memory B cells, reflecting persistent immune dysfunction.

This study underscores the pivotal role of immunometabolic dysregulation in shaping heterogeneous immune responses to ART. By integrating computational and experimental data, we identified key biomarkers and regulatory pathways associated with immune recovery. Our findings highlight the central influence of metabolic processes on immune restoration outcomes and propose personalised metabolic interventions as a promising strategy to enhance therapeutic efficacy in HIV‐infected individuals.

Integrative transcriptomic and immunophenotypic profiling reveals that immunological non‐responders to ART display mitochondrial and ribosomal dysregulation, reduced Th1/Th17/Tfh responses, and impaired B cell memory. Five hub genes (ATP5O, PIGY, UQCRQ, COX7C, BLVRB) emerge as biomarkers, highlighting immunometabolic pathways as targets to enhance immune recovery in HIV.