Single-cell characterization of the CD8+ T cell landscape and repertoire in HIV-1 Infection following antiretroviral therapy

Although antiretroviral therapy (ART) effectively suppresses HIV-1 viremia, immune dysfunction often persists. Here, we integrated single-cell RNA and T cell receptor (TCR) sequencing data to delineate the alterations of CD8⁺ T cells. Based on cross-sectional samples from different individuals (healthy donors, treatment-naïve individuals, and ART-treated individuals), we found ART promoted the transition of CD8⁺ T cells from exhausted toward naïve and memory-like subsets. Weighted gene co-expression network analysis identified distinct modules, including three (SM2-SM4) highly expressed in treatment-naïve individuals and one (SM6) significantly elevated post-ART. The reduced TCR diversity and increased clonality observed post-infection were not fully restored by ART, although ART partly altered clonal structure and CDR3 length. We established a predictive model based on the TCR features of CD8⁺ T cells, which accurately distinguished healthy donors, treatment-naïve individuals, and ART-treated individuals. These findings clarify the complex landscape of CD8⁺ T cell reconstitution, and identify key transcriptional networks and clonal dynamics during ART.