Youth Who Control HIV on Antiretroviral Therapy Display Unique Plasma Biomarkers and Cellular Transcriptome Profiles Including DNA Repair and RNA Processing

Combination antiretroviral therapy (ART) suppresses detectible HIV-1 replication, but latent reservoirs and persistent immune activation contribute to residual viral-associated morbidities and potential viral reactivation. youth with HIV (YWH) virally suppressed on ART early in infection before CD4 T cell decline with fewer comorbidities compared to adults represent a critical population for identifying markers associated with viral control and predictors of viral breakthrough. This study employed a multi-omics approach to evaluate plasma biomarkers and cellular gene expression profiles in 52 participants, including 27 YWH on ART for 144 weeks and 25 youth with no infection (NI) (ages 18-24). Among the 27 YWH, 19 were virally suppressed (VS; <50 RNA copies/mL), while eight were non-suppressed (VNS; >50 RNA copies/mL). VS YWH displayed unique bioprofiles distinct from either VNS or NI. Early viral suppression mitigates inflammatory pathways and normalizes key biomarkers associated with HIV-related comorbidities. Genes upregulated in pathways linked to cellular homeostasis such as DNA repair, RNA processing, and transcription regulation may diminish viral breakthrough and maintain sustained HIV control on ART. Candidate markers and putative molecular mechanisms were identified, offering potential therapeutic targets to limit viral persistence, enhance HIV treatment strategies, and pave the way for improved clinical outcomes.