Chinese HIV Controllers Exhibit Different Immunophenotypic Profiles and Viral Reservoir Dynamics Compared to Normal Progressors: A Real‐World Cohort Study

ABSTRACT HIV controllers (HICs) maintain low‐level viremia and normal CD4 + T‐cell counts without antiviral therapy (ART). This study aimed to characterized immunophenotypic and reservoir dynamics in Chinese HICs, revealing key distinctions from normal progressors (NPs). This prospective single‐center study enrolled HICs (ART‐free HIV RNA < 2000 copies/mL ≥ 12 months) and age/sex‐matched NPs served as controls at PUMCH (2000–2024). Longitudinal immunophenotyping of PBMCs was performed and used PCR to detected total HIV‐1 DNA. Among 1792 PLWH, 46 (2.5%) HICs (median age 31 years, 69% male) were enrolled in this study underwent 6 (5–12.5) years follow‐up, including 8 elite controllers and 38 viral controllers. Baseline CD4 + T‐cell counts were 567 (507–757) cells/μL, VL 2.64 (2.35–2.98) log10 copies/mL. Compared with NPs, HICs exhibited higher NK‐cell percentage, B‐cell percentage, naive CD4 + T‐cell counts and CD4/CD8 ratio, lower activated CD8 + T‐cells (CD38 + orHLA‐DR + ) percentage and total HIV‐DNA at baseline ( p < 0.05). ART reduced HIV‐DNA in NPs but remained higher than HICs ( p < 0.05). Five HICs discontinued follow‐up, 43.9% (18/41) HICs lost virological control at 6 (5–9) years. HICs experiencing lost virological control exhibited elevated baseline HIV‐DNA, activated CD8 + T‐cells percentage and lower CD4/CD8 ratio. Preceding control loss, declining CD4 + T‐cell counts (predominantly naive subsets), CD4/CD8 ratios and rising activated CD8 + T‐cells percentage were observed. Conversely, HICs maintaining virological control retained stable CD38 + CD8 + T‐cell percentages, CD4/CD8 ratio and naive CD4 + T‐cell counts exhibited increased elevated HLA‐DR + CD8 + T‐cell percentage. Chinese HICs exhibit different immunophenotypes with reduced HIV‐DNA versus NPs. Longitudinal tracking of HIV‐1 DNA, activated CD8 + T‐cell, naïve CD4 + T‐cell dynamics, and CD4/CD8 stability predict virologic failure in HICs.