Single-cell profiling reveals immunometabolic remodeling with T-cell dysfunction in HIV-1 infected people

Immunometabolism plays a vital role in the immunopathogenesis of people living with human immunodeficiency virus type 1 (HIV-1) (PLWH). However, the precise relationship between metabolic profiles and T-cell dysfunction in this population remains unclear. This study aimed to investigate the metabolic reprogramming and underlying mechanisms contributing to T-cell dysfunction in PLWH, highlighting potential pathogenic mechanisms during chronic HIV-1 infection.

This study re-analyzed single-cell RNA sequencing data from the Genome Sequence Archive of the Beijing Institute of Genomics Data Center, Chinese Academy of Sciences. The dataset comprised samples from healthy donors (HD), HIV-1-infected treatment-naive patients (TN), and patients undergoing antiviral therapy. Various analytical approaches-including functional analysis, transcription factor analysis, network analysis, and enrichment analysis-were performed to assess T-cell functional and metabolic characteristics, as well as to identify potential targets within metabolic-epigenetic or non-epigenetic regulatory axes involved in T-cell dysfunction.

By analyzing the transcriptional profiles, a total of 58,752 CD4⁺ T cells and 68,907 CD8⁺ T cells were identified and annotated. Among these, the naive subset CD8-CCR7 was significantly reduced in TN patients compared to HD (P < 0.05), whereas CD4-CCR7 showed a decreasing trend. Conversely, the effector subset CD8⁺ activated effector/memory T cells (CD8-EMRA) were significantly increased in TN patients (P < 0.05), while cytolytic CD4⁺ T cells (CD4-CTL) displayed an increasing trend. ART did not effectively reverse these alterations. Additionally, naive subsets and CD8-EMRA cells were associated with disease progression. Further analysis revealed that naive subsets exhibited hyper-activation and increased differentiation, whereas effector subsets showed excessive activation and a strong interferon (IFN) response in PLWH compared to HD (P < 0.05). Intriguingly, we observed substantial metabolic alterations linked to immune dysfunction within the four T-cell subsets. Specifically, elevated levels of the methyltransferases absent, small, or homeotic-like 1 (ASH1L) and SET domain containing 1B (SETD1B) may have promoted the differentiation and exhaustion of the CD4-CCR7 subset via the ASH1L/SETD1B-H3K4me3-FOXP1 axis. These enzymes were also associated with the exhaustion of CD8-CCR7 cells in TN patients through ASH1L/SETD1B-H3K4me3 axis. Additionally, isocitrate dehydrogenase 2 (IDH2)-mediated production of α-ketoglutarate (α-KG) may have contributed to the dysfunction of CD8-CCR7 cells by activating Janus kinase (JAK)-signal transducer and activator of transcription (STAT)3-dependent interferon signaling during HIV-1 infection. Conversely, increased activity of SET domain containing 2 methyltransferase was closely linked to hyperactivation, a strong type I interferon response, and cellular senescence in CD4-CTL cells from TN patients. Furthermore, heightened expression of solute carrier family 7 member 5 correlated with exhaustion of effector subsets in TN individuals. The IDH2-STAT1 axis may have also played a crucial role in driving the over-activation and exhaustion of CD8-EMRA cells through interferon signaling pathways.

These findings indicate that amino acid- and IDH2-related metabolism may contribute to the dysfunction of both naive and effector subsets by metabolic-epigenetic or non-epigenetic regulatory axes in PLWH.