Immune checkpoint landscape in CD4⁺ T cells stratifies HIV-infected individuals by clinical progression.

Immune checkpoint (IC) pathways play a central role in modulating HIV-specific T cell responses and may influence the degree of viral control. Here, we performed a comparative transcriptomic analysis of CD4⁺ T cells from HIV-infected individuals classified as elite controllers (EC), viremic controllers (VC), and chronic progressors (CP), aiming to identify IC signatures associated with viral control. ECs exhibited distinct expression profiles, characterized by significant upregulation of CEACAM1 and CD274 (PD-L1), and downregulation of CD200, TIGIT, CTLA4, BTLA, and ADGRG1 relative to CPs. VC samples displayed intermediate expression levels. Principal component analysis (PCA) of IC genes revealed clear separation between ECs and CPs, driven largely by the differential expression of PDCD1, CTLA4, TIGIT, and CD28. ECs were also enriched in effector memory and Th2 CD4⁺ T cell subsets, which correlated positively with CEACAM1 and PD-L1, and inversely with TIGIT and CTLA4. Co-expression network analysis identified two distinct gene modules: one (M2) containing CEACAM1 and PD-L1, enriched for interferon signaling and NF-κB pathways, and another (M4) comprising TIGIT, CD200, and BTLA, enriched for TCR signaling and metabolic processes. Finally, comparison of ECs, ART-naïve, and ART-treated individuals showed that pre-ART subjects displayed significantly elevated ADGRG1 expression, which decreased following ART initiation, resembling the EC profile. These findings reveal checkpoint-related molecular signatures and cell subset compositions that stratify HIV-infected individuals by disease control phenotype, and highlight potential targets for immunomodulatory therapies aimed at achieving functional cure.